her2-negative breast tumours: Topics by Science.gov

Sample records for her2-negative breast tumours

Breast cancer stem cells in HER2-negative breast cancer cells contribute to HER2-mediated radioresistance and molecular subtype conversion: clinical implications for serum HER2 in recurrent HER2-negative breast cancer.

PubMed

Kim, Yun Gyoung; Yoon, Yi Na; Choi, Hyang Suk; Kim, Ji-Hyun; Seol, Hyesil; Lee, Jin Kyung; Seong, Min-Ki; Park, In Chul; Kim, Kwang Il; Kim, Hyun-Ah; Kim, Jae-Sung; Noh, Woo Chul

2018-01-19

Although it has been proposed that the beneficial effect of HER2-targeted therapy in HER2-negative breast cancer is associated with the molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Our study showed that breast cancer stem cells (BCSCs) mediated HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44 + /CD24 -/low BCSCs from HER2-negative breast cancer MCF7 cells overexpressed HER2 and EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44 + /CD24 -/low cells with decreased levels of HER2 and EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer could be useful for targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serial serum HER2 measurement synchronously reflected the disease relapse and the change in tumor burden in some patients who were initially diagnosed as HER2-negative breast cancer, which indicated that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in patients with recurrent HER2-negative breast cancer. Therefore, our data have provided in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer.
SLP-2 overexpression could serve as a prognostic factor in node positive and HER2 negative breast cancer.

PubMed

Cao, Wenfeng; Zhang, Bin; Li, Jin; Liu, Yanxue; Liu, Zhihua; Sun, Baocun

2011-12-01

This study aimed to evaluate the utility as a prognostic factor of SLP-2 on the outcome of breast cancer patients. We performed immunohistochemical analysis to examine the SLP-2 expression in a large panel of invasive breast cancer samples. Of the 496 samples, 261 showed overexpression of SLP-2. Importantly, there were significant associations between SLP-2 overexpression and tumour size (p = 0.002), lymph node/distant metastases, clinical stage (p < 0.001), HER2/neu expression (p = 0.003). In addition, there were obvious differences in levels of SLP-2 expression within four molecular subtypes of breast cancer (p = 0.011). High level SLP-2 expression was shown in tumour samples of HER2 and luminal B subtypes, and low level SLP-2 expression was shown in luminal A and triple negative subtypes, suggesting that overexpression of SLP-2 was closely correlated with HER2/neu expression, and that both SLP-2 and HER2/neu can play a role in lymph node/distant metastases of breast cancers. Thus lymph node status, HER2/neu and SLP-2 high-level expression can act as independent prognostic factors. There is an obvious link between SLP-2 and HER2/neu expression. Overexpression of SLP-2 is associated with poorer total survival, especially in lymph node positive coupled with HER2/neu negative patients.
HER2 expression identifies dynamic functional states within circulating breast cancer cells.

PubMed

Jordan, Nicole Vincent; Bardia, Aditya; Wittner, Ben S; Benes, Cyril; Ligorio, Matteo; Zheng, Yu; Yu, Min; Sundaresan, Tilak K; Licausi, Joseph A; Desai, Rushil; O'Keefe, Ryan M; Ebright, Richard Y; Boukhali, Myriam; Sil, Srinjoy; Onozato, Maristela L; Iafrate, Anthony J; Kapur, Ravi; Sgroi, Dennis; Ting, David T; Toner, Mehmet; Ramaswamy, Sridhar; Haas, Wilhelm; Maheswaran, Shyamala; Haber, Daniel A

2016-09-01

Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER + /HER2 - primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2 + and HER2 - subpopulations: HER2 + circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2 - circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2 + and HER2 - circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2 + and HER2 - circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2 + state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2 - phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.
Activating HER2 mutations in HER2 gene amplification negative breast cancer.

PubMed

Bose, Ron; Kavuri, Shyam M; Searleman, Adam C; Shen, Wei; Shen, Dong; Koboldt, Daniel C; Monsey, John; Goel, Nicholas; Aronson, Adam B; Li, Shunqiang; Ma, Cynthia X; Ding, Li; Mardis, Elaine R; Ellis, Matthew J

2013-02-01

Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs.
Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

ClinicalTrials.gov

2018-04-20

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma
Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells.

PubMed

Shimoyama, Kyoko; Kagawa, Shunsuke; Ishida, Michihiro; Watanabe, Shinichiro; Noma, Kazuhiro; Takehara, Kiyoto; Tazawa, Hiroshi; Hashimoto, Yuuri; Tanabe, Shunsuke; Matsuoka, Junji; Kobayashi, Hisataka; Fujiwara, Toshiyoshi

2015-02-01

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25% of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.
Activating HER2 mutations in HER2 gene amplification negative breast cancer

PubMed Central

Bose, Ron; Kavuri, Shyam M.; Searleman, Adam C.; Shen, Wei; Shen, Dong; Koboldt, Daniel C.; Monsey, John; Goel, Nicholas; Aronson, Adam B.; Li, Shunqiang; Ma, Cynthia X.; Ding, Li; Mardis, Elaine R.; Ellis, Matthew J.

2012-01-01

Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. PMID:23220880
Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease

PubMed Central

Zidan, J; Dashkovsky, I; Stayerman, C; Basher, W; Cozacov, C; Hadary, A

2005-01-01

HER-2 overexpression, a predictive marker of tumour aggressiveness and responsiveness to therapy, occurs in 20–30% of breast cancer. Although breast cancer is a heterogeneous disease, HER-2 measurement is carried out in primary tumour. This study aims to evaluate HER-2 overexpression in primary and metastases and its effect on treatment decisions. Biopsies from primary breast cancer and corresponding metastases from 58 patients were studied. HER-2 overexpression was evaluated immunohistochemically in all primary and metastatic sites. Positive overexpression in primary and/or metastases was confirmed by fluorescence in situ hybridisation (FISH). Discordance in HER-2 overexpression between primary and metastatic sites was 14% (eight of 58 patients). Concordance was found in 50 (86%) of patients (95% CI: 77–95). In one patient (2%), HER-2 was negative in metastasis but positive in primary. In seven (12%) patients, HER-2 was positive in metastases and negative in primary (95% CI: 3.7–20), and three of them responded to trastuzumab. Gene amplification by FISH was found in all cases with HER-2 positive (+2 and +3) by immunohistochemistry. Our data suggest that a possible discordance of HER-2 overexpression between primary and metastases should be considered when making treatment decisions in patients with primary HER-2-negative tumours. PMID:16106267
A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer

PubMed Central

Bussolati, G; Montemurro, F; Righi, L; Donadio, M; Aglietta, M; Sapino, A

2005-01-01

The immunohistochemical determination of HER-2 to identify patients with advanced breast cancer candidates for Trastuzumab treatment proved neither accurate nor fully reliable, possibly because none of the current reagents detects the specific antigenic site target of Trastuzumab. To circumvent this problem, we conjugated the NH2 groups of Trastuzumab with biotin, and the compound obtained, designated BiotHER, was added directly to tissue sections. Biotin-labelling was revealed with horseradish peroxidase-conjugated streptavidin. Specificity and sensitivity of BiotHER immunostaining with respect to HER-2 amplification were tested on 164 breast carcinoma samples. BiotHER staining was detected on the tumour cell membrane of 12% of all specimens and in 49% specimens with gene amplification, while absent in nonamplified tumours. Predictivity of BiotHER status with respect to the clinical outcome was analysed in 54 patients with HER-2 amplified advanced breast cancer treated with Trastuzumab plus chemotherapy. BiotHER staining, detected in 50% of tumours with HER-2 amplification, was an independent predictor of clinical outcome. In fact, BiotHER positivity was independently associated with increased likelihood of tumour response and reduced risk of tumour progression and death. Biotinylated Trastuzumab can thus be used for immunohistochemical detection of HER-2 overexpression in breast cancer, and has the potential to identify patients likely to benefit from Trastuzumab treatment. PMID:15812476
ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer.

PubMed

Pinhel, Isabel; Hills, Margaret; Drury, Suzanne; Salter, Janine; Sumo, Georges; A'Hern, Roger; Bliss, Judith M; Sestak, Ivana; Cuzick, Jack; Barrett-Lee, Peter; Harris, Adrian; Dowsett, Mitch

2012-03-14

Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas. ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors. ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts. ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease. Clinical trial identifier: ISRCTN31514446.
The HER2 Signaling Network in Breast Cancer--Like a Spider in its Web.

PubMed

Dittrich, A; Gautrey, H; Browell, D; Tyson-Capper, A

2014-12-01

The human epidermal growth factor receptor 2 (HER2) is a major player in the survival and proliferation of tumour cells and is overexpressed in up to 30 % of breast cancer cases. A considerable amount of work has been undertaken to unravel the activity and function of HER2 to try and develop effective therapies that impede its action in HER2 positive breast tumours. Research has focused on exploring the HER2 activated phosphoinositide-3-kinase (PI3K)/AKT and rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathways for therapies. Despite the advances, cases of drug resistance and recurrence of disease still remain a challenge to overcome. An important aspect for drug resistance is the complexity of the HER2 signaling network. This includes the crosstalk between HER2 and hormone receptors; its function as a transcription factor; the regulation of HER2 by protein-tyrosine phosphatases and a complex network of positive and negative feedback-loops. This review summarises the current knowledge of many different HER2 interactions to illustrate the complexity of the HER2 network from the transcription of HER2 to the effect of its downstream targets. Exploring the novel avenues of the HER2 signaling could yield a better understanding of treatment resistance and give rise to developing new and more effective therapies.
Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status

PubMed Central

Fehm, Tanja; Becker, Sven; Duerr-Stoerzer, Silke; Sotlar, Karl; Mueller, Volkmar; Wallwiener, Diethelm; Lane, Nancy; Solomayer, Erich; Uhr, Jonathan

2007-01-01

Introduction At the time when metastatic disease is identified, assessment of human epidermal growth factor receptor (HER)2 status might help to optimize treatment decisions if HER2 status was not determined at first diagnosis and if HER2 positivity has been acquired during disease progression. Within this context, determination of serum HER2 or evaluation of HER2 status in circulating tumor cells (CTCs) may be of clinical relevance because metastatic tissue may be difficult to obtain for analysis as a result of its localization. The aim of this study was therefore to determine the HER2 status in serum and corresponding CTCs in patients with metastatic breast cancer whose primary tumors were HER2 negative or of unknown HER2 status. Methods Blood samples were obtained from 77 metastatic breast cancer patients with negative (n = 44) or unknown (n = 33) HER2 status. Serum HER2 was determined using a commercial HER2/neu ELISA kit. CTCs were detected by slide-based assay using immunomagnetic enrichment and characterized by phenotyping and genotyping. Alternatively, a commercial kit, based on RT-PCR, was used to detect and characterize CTCs. Results Twenty out of 77 patients with metastatic disease had elevated serum levels of HER2. Blood samples could be analyzed for the presence of CTCs in 67 patients. Eight out of 21 patients with detectable CTCs exhibited HER2 amplification. Twenty-three out of 77 patients were HER2 positive using at least one method. Concordance between HER2 status of CTCs and serum HER2 was observed in 15 of 21 patients (71%). In six patients conflicting results were obtained. Three patients with elevated serum HER2 status had HER2-negative CTCs, whereas three patients with HER2-positive CTCs had normal serum HER2 levels. Conclusion A subgroup of patients with initially negative or unknown HER2 status can have elevated serum HER2 levels and/or HER2-positive CTCs at the time of development of metastatic disease. Although only a small number of
Medical image segmentation to estimate HER2 gene status in breast cancer

NASA Astrophysics Data System (ADS)

Palacios-Navarro, Guillermo; Acirón-Pomar, José Manuel; Vilchez-Sorribas, Enrique; Zambrano, Eddie Galarza

2016-02-01

This work deals with the estimation of HER2 Gene status in breast tumour images treated with in situ hybridization techniques (ISH). We propose a simple algorithm to obtain the amplification factor of HER2 gene. The obtained results are very close to those obtained by specialists in a manual way. The developed algorithm is based on colour image segmentation and has been included in a software application tool for breast tumour analysis. The developed tool focus on the estimation of the seriousness of tumours, facilitating the work of pathologists and contributing to a better diagnosis.
Targeting CXCR1/2 Significantly Reduces Breast Cancer Stem Cell Activity and Increases the Efficacy of Inhibiting HER2 via HER2-dependent and -independent Mechanisms

PubMed Central

Singh, Jagdeep K.; Farnie, Gillian; Bundred, Nigel J.; Simões, Bruno M; Shergill, Amrita; Landberg, Göran; Howell, Sacha; Clarke, Robert B.

2012-01-01

Purpose Breast cancer stem-like cells (CSCs) are an important therapeutic target as they are predicted to be responsible for tumour initiation, maintenance and metastases. Interleukin-8 (IL-8) is upregulated in breast cancer and associated with poor prognosis. Breast cancer cell line studies indicate that IL-8 via its cognate receptors, CXCR1 and CXCR2, is important in regulating breast CSC activity. We investigated the role of IL-8 in the regulation of CSC activity using patient-derived breast cancers and determined the potential benefit of combining CXCR1/2 inhibition with HER2-targeted therapy. Experimental design CSC activity of metastatic and invasive human breast cancers (n=19) was assessed ex vivo using the mammosphere colony forming assay. Results Metastatic fluid IL-8 level correlated directly with mammosphere formation (r=0.652; P<0.05; n=10). Recombinant IL-8 directly increased mammosphere formation/self-renewal in metastatic and invasive breast cancers (n=17). IL-8 induced activation of EGFR/HER2 and downstream signalling pathways and effects were abrogated by inhibition of SRC, EGFR/HER2, PI3K or MEK. Furthermore, lapatinib inhibited the mammosphere-promoting effect of IL-8 in both HER2-positive and negative patient-derived cancers. CXCR1/2 inhibition also blocked the effect of IL-8 on mammosphere formation and added to the efficacy of lapatinib in HER2-positive cancers. Conclusions These studies establish a role for IL-8 in the regulation of patient-derived breast CSC activity and demonstrate that IL-8/CXCR1/2 signalling is partly mediated via a novel SRC and EGFR/HER2-dependent pathway. Combining CXCR1/2 inhibitors with current HER2-targeted therapies has potential as an effective therapeutic strategy to reduce CSC activity in breast cancer and improve the survival of HER2-positive patients. PMID:23149820
Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.

PubMed

Shetty, Praveenkumar; Patil, Vidya S; Mohan, Rajashekar; D'souza, Leonard Clinton; Bargale, Anil; Patil, Basavaraj R; Dinesh, U S; Haridas, Vikram; Kulkarni, Shrirang P

2017-07-01

Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.
HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

PubMed Central

Nami, Babak; Wang, Zhixiang

2017-01-01

HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab. PMID:28445439
Triple-negative (ER, PgR, HER-2/neu) breast cancer in Indian women

PubMed Central

Patil, Vinayak W; Singhai, Rajeev; Patil, Amit V; Gurav, Prakash D

2011-01-01

The aim of our study was to analyze triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER-2/neu) and which represents a subset of breast cancer with different biologic behavior. We investigated the clinicopathological characteristics and prognostic indicators of lymph node-negative TN breast cancer. Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Grant Medical College and Sir JJ Group of Hospitals, Mumbai, India, from May 2007 to October 2010. Clinicopathological variables and clinical outcomes were evaluated. Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (<35 years, P = 0.003) and a higher histopathologic and nuclear grade (P < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for Bcl-2 expression (P < 0.001), positive for the epidermal growth factor receptor (P = 0.003), and a high level of p53 (P < 0.001) and Ki-67 expression (P < 0.00). The relapse rates during the follow-up period (median 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (P = 0.004). Relapse-free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer: 3.5-year RFS rate 85.5% versus 94.2%, respectively; P = 0.001. On multivariate analysis, young age, close resection margin, and triple negativity were independent predictors of shorter RFS. TN breast cancer had a higher relapse rate and more aggressive clinicopathological characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into risk factor analysis for node-negative breast cancer. PMID:24367172
Evaluation of HER-2/neu status in breast cancer specimens using immunohistochemistry (IHC) & fluorescence in-situ hybridization (FISH) assay.

PubMed

Goud, Kalal Iravathy; Dayakar, Seetha; Vijayalaxmi, Kolanupaka; Babu, Saidam Jangu; Reddy, P Vijay Anand

2012-03-01

Fluorescence in situ hybridization (FISH) is increasingly being recognized as the most accurate and predictive test for HER 2/neu gene amplification and response to therapy in breast cancer. In the present study we investigated HER-2/neu gene amplification by FISH in breast carcinoma tissue specimens and compared the results with that of immunohistochemical (IHC) analysis. A total of 90 breast carcinoma tissue samples were used for immunohistochemical (IHC) and FISH analysis. IHC was performed by using mouse monoclonal antibody to the intracellular domain of HER-2/neu protein. Each slide was scored in a blinded fashion by two pathologists according to the manufacturer's recommended criteria. FISH analysis was performed on paraffin embedded breast tumour tissue sections. The polysomy for centromere 17 (Spec green signal) was read as green signals less than 4 as moderate polysomy, and more than 4 as highly polysomy. Thirty of the 90 patients had negative results by IHC and FISH. Of the 28 patients with the score of 2+ by IHC, 20 were FISH positive for HER-2/neu gene amplification, three were FISH negative and five patients showed equivocal (1.8-2.2) results by FISH. These five cases were retested for IHC and FISH on different paraffin embedded tissue blocks, and all five were found positive for HER-2/neu gene amplification. Twenty five patients with the score of 3+ by IHC were FISH positive for HER-2/neu gene amplification (>2.2). Seven cases with the score of 3+ by IHC were FISH negative for HER-2/neu gene amplification (>2.2), and showed polysomy of chromosome number 17 high polysomy > 4. Our results indicated that HER-2/neu status by FISH should be performed in all cases of breast tumour with a 2+ score by IHC. Cases demonstrating a 3+ score by IHC may be subjected to FISH to rule out polysomy of chromosome 17 which could be falsely interpreted as HER-2/neu overexpression by IHC analysis. There is also a need for establishing a clinically validated cut-off value
Evaluation of HER-2/neu status in breast cancer specimens using immunohistochemistry (IHC) & fluorescence in-situ hybridization (FISH) assay

PubMed Central

Goud, Kalal Iravathy; Dayakar, Seetha; Vijayalaxmi, Kolanupaka; Babu, Saidam Jangu; Vijay, Anand Reddy P.

2012-01-01

Background & objectives: Fluorescence in situ hybridization (FISH) is increasingly being recognized as the most accurate and predictive test for HER2/neu gene amplification and response to therapy in breast cancer. In the present study we investigated HER-2/neu gene amplification by FISH in breast carcinoma tissue specimens and compared the results with that of immunohistochemical (IHC) analysis. Methods: A total of 90 breast carcinoma tissue samples were used for immunohistochemical (IHC) and FISH analysis. IHC was performed by using mouse monoclonal antibody to the intracellular domain of HER-2/neu protein. Each slide was scored in a blinded fashion by two pathologists according to the manufacturer's recommended criteria. FISH analysis was performed on paraffin embedded breast tumour tissue sections. The polysomy for centromere 17 (Spec green signal) was read as green signals less than 4 as moderate polysomy, and more than 4 as highly polysomy. Results: Thirty of the 90 patients had negative results by IHC and FISH. Of the 28 patients with the score of 2+ by IHC, 20 were FISH positive for HER-2/neu gene amplification, three were FISH negative and five patients showed equivocal (1.8-2.2) results by FISH. These five cases were retested for IHC and FISH on different paraffin embedded tissue blocks, and all five were found positive for HER-2/neu gene amplification. Twenty five patients with the score of 3+ by IHC were FISH positive for HER-2/neu gene amplification (>2.2). Seven cases with the score of 3+ by IHC were FISH negative for HER-2/neu gene amplification (>2.2), and showed polysomy of chromosome number 17 high polysomy > 4. Interpretation & conclusions: Our results indicated that HER-2/neu status by FISH should be performed in all cases of breast tumour with a 2+ score by IHC. Cases demonstrating a 3+ score by IHC may be subjected to FISH to rule out polysomy of chromosome 17 which could be falsely interpreted as HER-2/neu overexpression by IHC analysis
Evaluation of non-genomic, clinical risk and survival results in endocrine-sensitive, HER-2 negative, node negative breast cancer.

PubMed

Baena Cañada, José M; Gámez Casado, Salvador; Rodríguez Pérez, Lourdes; Quílez Cutillas, Alicia; Cortés Carmona, Cristina; Rosado Varela, Petra; Estalella Mendoza, Sara; Ramírez Daffós, Patricia; Benítez Rodríguez, Encarnación

2018-02-28

In endocrine-sensitive, HER-2 negative, node negative breast cancer, the presence of a low genomic risk allows treatment with adjuvant endocrine therapy alone, obtaining excellent survival rates. The justification for this study is to show that excellent survival rates are also obtained by treating with adjuvant hormone therapy alone, based on clinical risk assessment. A descriptive, observational and retrospective study was performed between 2006 and 2016 with endocrine-sensitive, HER-2 negative, node negative breast cancer, greater than 1cm or between 0.6 and 1cm with unfavourable features. Retrospective review of health records. Mortality data of the National Registry of Deaths. A total of 203 patients were evaluable for survival. One hundred and twenty-three (60.50%) were treated with adjuvant endocrine therapy alone, 77 (37.90%) with chemotherapy and endocrine therapy, one (0.50%) with chemotherapy alone and 2 (1%) were not treated. The overall survival rate at 5 years was 97% (95% confidence interval [CI] 94-100). Distant recurrence-free interval was 94% (95% CI 90-98). In the subgroup of patients treated with endocrine therapy alone, overall survival and distant recurrence-free interval rates at 5 years were 98% (95% CI 95-100) and 97% (95% CI 93-100), respectively. Patients with endocrine-sensitive, HER-2-negative, node negative breast cancer treated with endocrine therapy alone according to their clinical risk have similar survival outcomes as those treated with endocrine therapy according to their genomic risk. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer

PubMed Central

Hergueta-Redondo, Marta; Sarrio, David; Molina-Crespo, Ángela; Vicario, Rocío; Bernadó-Morales, Cristina; Martínez, Lidia; Rojo-Sebastián, Alejandro; Serra-Musach, Jordi; Mota, Alba; Martínez-Ramírez, Ángel; Castilla, Maria Ángeles; González-Martin, Antonio; Pernas, Sonia; Cano, Amparo; Cortes, Javier; Nuciforo, Paolo G.; Peg, Vicente; Palacios, José; Pujana, Miguel Ángel; Arribas, Joaquín; Moreno-Bueno, Gema

2016-01-01

Around, 30–40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer. PMID:27462779
Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.

PubMed

Hergueta-Redondo, Marta; Sarrio, David; Molina-Crespo, Ángela; Vicario, Rocío; Bernadó-Morales, Cristina; Martínez, Lidia; Rojo-Sebastián, Alejandro; Serra-Musach, Jordi; Mota, Alba; Martínez-Ramírez, Ángel; Castilla, Mª Ángeles; González-Martin, Antonio; Pernas, Sonia; Cano, Amparo; Cortes, Javier; Nuciforo, Paolo G; Peg, Vicente; Palacios, José; Pujana, Miguel Ángel; Arribas, Joaquín; Moreno-Bueno, Gema

2016-08-30

Around, 30-40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.
Genotyping tumour DNA in cerebrospinal fluid and plasma of a HER2-positive breast cancer patient with brain metastases

PubMed Central

Siravegna, Giulia; Geuna, Elena; Mussolin, Benedetta; Crisafulli, Giovanni; Bartolini, Alice; Galizia, Danilo; Casorzo, Laura; Sarotto, Ivana; Scaltriti, Maurizio; Sapino, Anna; Bardelli, Alberto; Montemurro, Filippo

2017-01-01

Background Central nervous system (CNS) involvement contributes to significant morbidity and mortality in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) and represents a major challenge for clinicians. Liquid biopsy of cerebrospinal fluid (CSF)-derived circulating tumour DNA (ctDNA) harbours clinically relevant genomic alterations in patients with CNS metastases and could be effective in tracking tumour evolution. Methods In a HER2-positive mBC patient with brain metastases, we applied droplet digital PCR (ddPCR) and next-generation whole exome sequencing (WES) analysis to measure ctDNA dynamic changes in CSF and plasma collected during treatment. Results Baseline CSF-derived ctDNA analysis revealed TP53 and PIK3CA mutations as well as ERBB2 and cMYC amplification. Post-treatment ctDNA analysis showed decreased markers level in plasma, consistent with extra-CNS disease control, while increased in the CSF, confirming poor treatment benefit in the CNS. Discussion Analysis of ctDNA in the CSF of HER2-positive mBC is feasible and could represent a useful companion for clinical management of brain metastases. PMID:29067216
Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719
GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

PubMed Central

Cox, David G.; Curtit, Elsa; Romieu, Gilles; Fumoleau, Pierre; Rios, Maria; Bonnefoi, Hervé; Bachelot, Thomas; Soulié, Patrick; Jouannaud, Christelle; Bourgeois, Hugues; Petit, Thierry; Tennevet, Isabelle; Assouline, David; Mathieu, Marie-Christine; Jacquin, Jean-Philippe; Lavau-Denes, Sandrine; Darut-Jouve, Ariane; Ferrero, Jean-Marc; Tarpin, Carole; Lévy, Christelle; Delecroix, Valérie; Trillet-Lenoir, Véronique; Cojocarasu, Oana; Meunier, Jérôme; Pierga, Jean-Yves; Faure-Mercier, Céline; Blanché, Hélène; Sahbatou, Mourad; Boland, Anne; Bacq, Delphine; Besse, Céline; Deleuze, Jean-François; Pauporté, Iris; Thomas, Gilles; Pivot, Xavier

2016-01-01

Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10−12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10−11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors. PMID:27764800
Triple-Negative or HER2-Positive Status Predicts Higher Rates of Locoregional Recurrence in Node-Positive Breast Cancer Patients After Mastectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Shulian; Li Yexiong, E-mail: yexiong@yahoo.com; Song Yongwen

2011-07-15

Purpose: To evaluate the prognostic value of determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression in node-positive breast cancer patients treated with mastectomy. Methods and Materials: The records of 835 node-positive breast cancer patients who had undergone mastectomy between January 2000 and December 2004 were analyzed retrospectively. Of these, 764 patients (91.5%) received chemotherapy; 68 of 398 patients (20.9%) with T1-2N1 disease and 352 of 437 patients (80.5%) with T3-4 or N2-3 disease received postoperative radiotherapy. Patients were classified into four subgroups according to hormone receptor (Rec+ or Rec-) and HER2 expression profiles:more » Rec-/HER2- (triple negative; n = 141), Rec-/HER2+ (n = 99), Rec+/HER2+ (n = 157), and Rec+/HER2- (n = 438). The endpoints were the duration of locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, and overall survival. Results: Patients with triple-negative, Rec-/HER2+, and Rec+/HER2+ expression profiles had a significantly lower 5-year locoregional recurrence-free survival than those with Rec+/HER2- profiles (86.5% vs. 93.6%, p = 0.002). Compared with those with Rec+/HER2+ and Rec+/HER2- profiles, patients with Rec-/HER2- and Rec-/HER2+ profiles had significantly lower 5-year distant metastasis-free survival (69.1% vs. 78.5%, p = 0.000), lower disease-free survival (66.6% vs. 75.6%, p = 0.000), and lower overall survival (71.4% vs. 84.2%, p = 0.000). Triple-negative or Rec-/HER2+ breast cancers had an increased likelihood of relapse and death within the first 3 years after treatment. Conclusions: Triple-negative and HER2-positive profiles are useful markers of prognosis for locoregional recurrence and survival in node-positive breast cancer patients treated with mastectomy.« less
Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

PubMed

McArthur, Heather L; Mahoney, Kathleen M; Morris, Patrick G; Patil, Sujata; Jacks, Lindsay M; Howard, Jane; Norton, Larry; Hudis, Clifford A

2011-12-15

Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Copyright © 2011 American Cancer Society.
Body mass index and risk of luminal, HER2-overexpressing, and triple negative breast cancer.

PubMed

Chen, Lu; Cook, Linda S; Tang, Mei-Tzu C; Porter, Peggy L; Hill, Deirdre A; Wiggins, Charles L; Li, Christopher I

2016-06-01

Triple negative (TN, tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2)) and HER2-overexpressing (H2E, ER-/HER2+) tumors are two particularly aggressive subtypes of breast cancer. There is a lack of knowledge regarding the etiologies of these cancers and in particular how anthropometric factors are related to risk. We conducted a population-based case-case study consisting of 2659 women aged 20-69 years diagnosed with invasive breast cancer from 2004 to 2012. Four case groups defined based on joint ER/PR/HER2 status were included: TN, H2E, luminal A (ER+/HER2-), and luminal B (ER+/HER2+). Polytomous logistic regression was used to estimate odds ratios (ORs) and associated 95 % confidence intervals (CIs) where luminal A patients served as the reference group. Obese premenopausal women [body mass index (BMI) ≥30 kg/m(2)] had an 82 % (95 % CI 1.32-2.51) increased risk of TN breast cancer compared to women whose BMI <25 kg/m(2), and those in the highest weight quartile (quartiles were categorized based on the distribution among luminal A patients) had a 79 % (95 % CI 1.23-2.64) increased risk of TN disease compared to those in the lowest quartile. Among postmenopausal women obesity was associated with reduced risks of both TN (OR = 0.74, 95 % CI 0.54-1.00) and H2E (OR = 0.47, 95 % CI 0.32-0.69) cancers. Our results suggest obesity has divergent impacts on risk of aggressive subtypes of breast cancer in premenopausal versus postmenopausal women, which may contribute to the higher incidence rates of TN cancers observed among younger African American and Hispanic women.
Distinct Tertiary Lymphoid Structure Associations and Their Prognostic Relevance in HER2 Positive and Negative Breast Cancers.

PubMed

Liu, Xia; Tsang, Julia Y S; Hlaing, Thazin; Hu, Jintao; Ni, Yun-Bi; Chan, Siu Ki; Cheung, Sai Yin; Tse, Gary M

2017-11-01

The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as tertiary lymphoid structures (TLS), play a key role in determining patient survival. In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined. Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c-kit expression. Tertiary lymphoid structures were significantly related to better disease-free survival (DFS) in HER2 positive (HER2+) breast cancers (log-rank = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2-) TLS positive (particularly estrogen receptor positive [ER+] HER2-) cases. In the ER+ HER2- cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement. Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies. Despite recent interest on the clinical value of tumor infiltrating lymphocyte (TIL), little was known on the clinical significance on their spatial organization as tertiary lymphoid structures (TLS
Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival.

PubMed

Yap, Y S; Cornelio, G H; Devi, B C R; Khorprasert, C; Kim, S B; Kim, T Y; Lee, S C; Park, Y H; Sohn, J H; Sutandyo, N; Wong, D W Y; Kobayashi, M; Landis, S H; Yeoh, E M; Moon, H; Ro, J

2012-09-25

In Asia, large-scale studies on anti-HER2 treatment in HER2-positive breast cancer patients with brain metastases are limited. We studied the treatment patterns of these patients in Asia to evaluate the impact of anti-HER2 treatment on the time to occurrence of brain metastases (TTBM) and survival after brain metastasis (BM). A retrospective study of HER2-positive breast cancer patients diagnosed with BM between January 2006 and December 2008 in six Asian countries was conducted. Demographics, tumour characteristics, treatment details, and events dates were collected from medical records. Data from 280 patients were analysed. Before BM, 63% received anti-HER2 treatment. These patients had significantly longer TTBM than those without anti-HER2 treatment (median 33 vs 19 months; P<0.002). After BM, 93% received radiotherapy, 57% received chemotherapy, and 41% received anti-HER2 treatment (trastuzumab and/or lapatinib). Use of both anti-HER2 agents, primarily sequentially, after BM demonstrated the longest survival after BM and was associated with a significant survival benefit over no anti-HER2 treatment (median 26 vs 6 months; hazard ratio 0.37; 95% CI 0.19-0.72). Anti-HER2 treatment before BM was associated with longer TTBM. Anti-HER2 treatment after BM was associated with a survival benefit, especially when both trastuzumab and lapatinib were utilised.
FLT PET in Measuring Treatment Response in Patients With Newly Diagnosed Estrogen Receptor-Positive, HER2-Negative Stage I-III Breast Cancer

ClinicalTrials.gov

2018-04-13

Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer
Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment.

PubMed

Di Luca, Alessio; Henry, Michael; Meleady, Paula; O'Connor, Robert

2015-08-04

Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib). Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. This proteomic
Challenges in the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer with brain metastases.

PubMed

Liu, Minetta C; Cortés, Javier; O'Shaughnessy, Joyce

2016-06-01

Brain metastases are a major cause of morbidity and mortality for women with hormone receptor (HR)-positive breast cancer, yet little is known about the optimal treatment of brain disease in this group of patients. Although these patients are at lower risk for brain metastases relative to those with HER2-positive and triple-negative disease, they comprise the majority of women diagnosed with breast cancer. Surgery and radiation continue to have a role in the treatment of brain metastases, but there is a dearth of effective systemic therapies due to the poor penetrability of many systemic drugs across the blood-brain barrier (BBB). Additionally, patients with brain metastases have long been excluded from clinical trials, and few studies have been conducted to evaluate the safety and effectiveness of systemic therapies specifically for the treatment of HER2-negative breast cancer brain metastases. New approaches are on the horizon, such as nanoparticle-based cytotoxic drugs that have the potential to cross the BBB and provide clinically meaningful benefits to patients with this life-threatening consequence of HR-positive breast cancer.
Estrogen/Progesterone Receptor Negativity and HER2 Positivity Predict Locoregional Recurrence in Patients With T1a,bN0 Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albert, Jeffrey M.; Gonzalez-Angulo, Ana M.; Guray, Merih

2010-08-01

Purpose: Data have suggested that the molecular features of breast cancer are important determinants of outcome; however, few studies have correlated these features with locoregional recurrence (LRR). In the present study, we evaluated estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as predictors of LRR in patients with lymph node-negative disease and tumors {<=}1 cm, because these patients often do not receive adjuvant chemotherapy or trastuzumab. Methods and Materials: The data from 911 patients with stage T1a,bN0 breast cancer who had received definitive treatment at our institution between 1997 and 2002 were retrospectively reviewed.more » We prospectively analyzed ER/PR/HER2 expression from the archival tissue blocks of 756 patients. These 756 patients represented the cohort for the present study. Results: With a median follow-up of 6.0 years, the 5- and 8-year Kaplan-Meier LRR rate was 1.6% and 5.9%, respectively, with no difference noted in those who underwent breast conservation therapy vs. mastectomy (p = .347). The 8-year LRR rates were greater in the patients with ER-negative (10.6% vs. 4.2%, p = .016), PR-negative (9.0% vs. 4.2%, p = .009), or HER2-positive (17.5% vs. 3.9%, p = 0.009) tumors. On multivariate analysis, ER-negative and PR-negative disease (hazard ratio, 2.37; p = .046) and HER2-positive disease (hazard ratio, 3.13, p = .016) independently predicted for LRR. Conclusion: Patients with ER/PR-negative or HER2-positive T1a,bN0 breast cancer had a greater risk of LRR. Therapeutic strategies, such as the use of chemotherapy and/or anti-HER2 therapies, should be considered for future clinical trials for these patients.« less
GATA3 expression in triple-negative breast cancers.

PubMed

Byrne, David J; Deb, Siddhartha; Takano, Elena A; Fox, Stephen B

2017-07-01

GATA-binding protein 3 (GATA3) is a well-studied transcription factor found to be essential in the development of luminal breast epithelium and has been identified in a variety of tumour types, including breast and urothelial carcinomas, making it a useful immunohistochemistry marker in the diagnosis of both primary and metastatic disease. We investigated GATA3 protein expression in a 106 primary triple-negative breast carcinomas (100 basal-like, six non-basal-like) using Cell Marque mouse monoclonal anti-GATA3 (L50-823). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to quantify mRNA expression in 22 triple-negative breast cancers (TNBCs) (20 primary and two cell lines), four luminal (three primary and one cell line) and five human epidermal growth factor receptor 2 (HER2) (four primary and one cell line) amplified tumours. In 98 TNBCs where IHC was assessable, 47 (48%) had a 1+ or greater staining with 20 (21%) having high GATA3 expression when using a weighted scoring. Our study has demonstrated that GATA3 expression is common in primary triple-negative breast carcinomas. It also suggests that although GATA3 is an oestrogen receptor (ER) regulated gene, it still proves useful in differentiating between primary and metastatic tumours in patients with a history of breast cancer regardless of its molecular subtype. © 2017 John Wiley & Sons Ltd.
Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer.

PubMed

Kim, Esther S; Scott, Lesley J

2017-06-01

Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.
Vaccine Therapy in Preventing Cancer Recurrence in Patients With Non-Metastatic, Node Positive, HER2 Negative Breast Cancer That is in Remission

ClinicalTrials.gov

2017-12-07

HER2/Neu Negative; No Evidence of Disease; One or More Positive Axillary Nodes; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer
Prolonged Response to Trastuzumab in a Patient With HER2-Nonamplified Breast Cancer With Elevated HER2 Dimerization Harboring an ERBB2 S310F Mutation.

PubMed

Chumsri, Saranya; Weidler, Jodi; Ali, Siraj; Balasubramanian, Sohail; Wallweber, Gerald; DeFazio-Eli, Lisa; Chenna, Ahmed; Huang, Weidong; DeRidder, Angela; Goicocheal, Lindsay; Perez, Edith A

2015-09-01

In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation. Copyright © 2015 by the National Comprehensive Cancer Network.
Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

ClinicalTrials.gov

2018-06-11

Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7
Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib

PubMed Central

Acharya, Sunil; Xu, Jia; Wang, Xiao; Jain, Shalini; Wang, Hai; Zhang, Qingling; Chang, Chia-Chi; Bower, Joseph; Arun, Banu; Seewaldt, Victoria; Yu, Dihua

2016-01-01

Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression. PMID:27293993

HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer.

PubMed

Press, Michael F; Finn, Richard S; Cameron, David; Di Leo, Angelo; Geyer, Charles E; Villalobos, Ivonne E; Santiago, Angela; Guzman, Roberta; Gasparyan, Armen; Ma, Yanling; Danenberg, Kathy; Martin, Anne Marie; Williams, Lisa; Oliva, Cristina; Stein, Steven; Gagnon, Robert; Arbushites, Michael; Koehler, Maria T

2008-12-01

Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. In available breast cancer tissue from EGF30001 (paclitaxel +/- lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine +/- lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among "HER-2-negative" breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.
A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer.

PubMed

Schuler, Martin; Awada, Ahmad; Harter, Philipp; Canon, Jean Luc; Possinger, Kurt; Schmidt, Marcus; De Grève, Jacques; Neven, Patrick; Dirix, Luc; Jonat, Walter; Beckmann, Matthias W; Schütte, Jochen; Fasching, Peter A; Gottschalk, Nina; Besse-Hammer, Tatiana; Fleischer, Frank; Wind, Sven; Uttenreuther-Fischer, Martina; Piccart, Martine; Harbeck, Nadia

2012-08-01

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.
Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca

ClinicalTrials.gov

2018-04-17

Breast Adenocarcinoma; Estrogen Receptor- Negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive Tumor; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Triple-negative Breast Carcinoma
Basal/HER2 breast carcinomas

PubMed Central

Martin-Castillo, Begoña; Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufí, Silvia; Moreno, José Manuel; Corominas-Faja, Bruna; Urruticoechea, Ander; Martín, Ángel G.; López-Bonet, Eugeni; Menendez, Javier A.

2013-01-01

High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain “hidden” from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better
Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting

ClinicalTrials.gov

2018-01-11

Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer
Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells

PubMed Central

2010-01-01

Trastuzumab (Herceptin®), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab. PMID:18941743
Relevance of deep learning to facilitate the diagnosis of HER2 status in breast cancer

NASA Astrophysics Data System (ADS)

Vandenberghe, Michel E.; Scott, Marietta L. J.; Scorer, Paul W.; Söderberg, Magnus; Balcerzak, Denis; Barker, Craig

2017-04-01

Tissue biomarker scoring by pathologists is central to defining the appropriate therapy for patients with cancer. Yet, inter-pathologist variability in the interpretation of ambiguous cases can affect diagnostic accuracy. Modern artificial intelligence methods such as deep learning have the potential to supplement pathologist expertise to ensure constant diagnostic accuracy. We developed a computational approach based on deep learning that automatically scores HER2, a biomarker that defines patient eligibility for anti-HER2 targeted therapies in breast cancer. In a cohort of 71 breast tumour resection samples, automated scoring showed a concordance of 83% with a pathologist. The twelve discordant cases were then independently reviewed, leading to a modification of diagnosis from initial pathologist assessment for eight cases. Diagnostic discordance was found to be largely caused by perceptual differences in assessing HER2 expression due to high HER2 staining heterogeneity. This study provides evidence that deep learning aided diagnosis can facilitate clinical decision making in breast cancer by identifying cases at high risk of misdiagnosis.
Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

PubMed

Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

2016-08-01

Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.
Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

ClinicalTrials.gov

2018-04-18

Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer
Surveillance of women with a personal history of breast cancer by tumour subtype.

PubMed

Benveniste, A P; Dryden, M J; Bedrosian, I; Morrow, P K; Bassett, R L; Yang, W

2017-03-01

To determine if the rate and timing of a second breast cancer event (SBCE) in women with a personal history of breast cancer varies by disease subtype or breast imaging method. A retrospective review was performed of women with a SBCE from January 2006 to December 2010 at a single institution. Data analysed included oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status of the primary and second breast cancers; mammographic and ultrasound (US) features from SBCE; and the time interval between both events. Of 207 patients diagnosed with a SBCE, the median age at first diagnosis was 50.6 years, range 24.8 to 80.2; at second diagnosis was 56.2 years, range 25.8 to 87.9. Eleven percent of SBCE were diagnosed >10 years after the primary cancer diagnosis. The median time between the first and second diagnosis for ER-positive patients was 2.7 years (range 0.7-17.4 years); and 1.9 years for ER-negative patients, (range 0.4-23.4 years; p<0.002). Patients with triple-negative breast cancer (TNBC) had a shorter time between diagnoses than others (p=0.0003). At 3, 5, and 10 years, 85%, 92%, and 97% of ER-negative and 54%, 81%, and 95% of ER-positive tumours, respectively, had recurred. ER-negative tumours and TNBC were more likely to be visible at US. There may be a role for customised imaging surveillance of women with a personal history of breast cancer (PHBC) after 10 years. Further studies are necessary to determine if US may be valuable in the surveillance of patients with ER-negative and TNBC tumours. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Capecitabine/cisplatin doublet in anthracycline and taxane pretreated and HER-2 negative metastatic breast carcinoma patients.

PubMed

Ozdemir, N; Aksoy, S; Sendur, M A; Akinci, M B; Yazici, O; Budakoglu, B; Abali, H; Oksuzoglu, B; Zengin, N

2013-01-01

To evaluate the activity and toxicity of the combination of capecitabine and cisplatin (CapCisp) in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma (MBC) female patients. Patients with HER-2 negative MBC pretreated with anthracycline and taxane and who were then treated with CapCisp combination were retrospectively evaluated. All patients received Cap 1000 mg/m(2) on days 1-14, and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. In case of disease control without severe toxicity, single agent Cap was continued until progression or unacceptable toxicities after Cisp cessation. Sixty-four MBC patients with median age 43 years (range 20-66) were included the study. Infiltrative ductal carcinoma prevailed (85.9%). Ten percent of the patients had grade I, 42% grade II, and 48.0% grade III tumors. Estrogen receptor (ER) and progesterone receptor (PR) were positive in 48.4 and 51.6% of the patients, respectively. Twenty-eight percent of the patients had triple negative tumors. Almost the entire patient group had this regimen as a third-line treatment. The median combination chemotherapy cycles were 6 (range 2-8). Twenty-seven non-progressive patients continued treatment with single-agent Cap. Median single-agent Cap cycles after the combination chemotherapy were 4 (range 1-38). Disease control rate was 81.3% (complete response 6.3%; partial response 48.4%, stable disease 26.6%, progressive disease 18.8%). Median follow-up time was 10.6 months. Median time to disease progression was 7 months, median overall survival (OS) was 17 months (95% CI, 6.9-16.1) measured from the start of CapCisp chemotherapy. There were no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (8.1%), nausea - vomiting (7.8%) and thrombocytopenia (6.3%). CapCisp doublet has an encouraging antitumor activity with acceptable and manageable toxicity in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma patients.
US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.

PubMed

Howlader, Nadia; Altekruse, Sean F; Li, Christopher I; Chen, Vivien W; Clarke, Christina A; Ries, Lynn A G; Cronin, Kathleen A

2014-04-28

In 2010, Surveillance, Epidemiology, and End Results (SEER) registries began collecting human epidermal growth factor 2 (HER2) receptor status for breast cancer cases. Breast cancer subtypes defined by joint hormone receptor (HR; estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status were assessed across the 28% of the US population that is covered by SEER registries. Age-specific incidence rates by subtype were calculated for non-Hispanic (NH) white, NH black, NH Asian Pacific Islander (API), and Hispanic women. Joint HR/HER2 status distributions by age, race/ethnicity, county-level poverty, registry, stage, Bloom-Richardson grade, tumor size, and nodal status were evaluated using multivariable adjusted polytomous logistic regression. All statistical tests were two-sided. Among case patients with known HR/HER2 status, 36810 (72.7%) were found to be HR(+)/HER2(-), 6193 (12.2%) were triple-negative (HR(-)/HER2(-)), 5240 (10.3%) were HR(+)/HER2(+), and 2328 (4.6%) were HR(-)/HER2(+); 6912 (12%) had unknown HR/HER2 status. NH white women had the highest incidence rate of the HR(+)/HER2(-) subtype, and NH black women had the highest rate of the triple-negative subtype. Compared with women with the HR(+)/HER2(-) subtype, triple-negative patients were more likely to be NH black and Hispanic; HR(+)/HER2(+) patients were more likely to be NH API; and HR(-)/HER2(+) patients were more likely to be NH black, NH API, and Hispanic. Patients with triple-negative, HR(+)/HER2(+), and HR(-)/HER2(+) breast cancer were 10% to 30% less likely to be diagnosed at older ages compared with HR(+)/HER2(-) patients and 6.4-fold to 20.0-fold more likely to present with high-grade disease. In the future, SEER data can be used to monitor clinical outcomes in women diagnosed with different molecular subtypes of breast cancer for a large portion (approximately 28%) of the US population. Published by Oxford University Press 2014.
HER2 Genetic Link to Breast Cancer

Cancer.gov

When researchers discovered the HER2 gene's importance to breast cancer growth, this led to the development of trastuzumab and other treatments that have improved survival for women with HER2-positive breast cancer.
Divisional role of quantitative HER2 testing in breast cancer.

PubMed

Yamamoto-Ibusuki, Mutsuko; Yamamoto, Yutaka; Fu, Peifen; Yamamoto, Satoko; Fujiwara, Saori; Honda, Yumi; Iyama, Ken-ichi; Iwase, Hirotaka

2015-03-01

Human epidermal growth factor receptor 2 (HER2) is amplified in human breast cancers in which therapy targeted to HER2 significantly improves patient outcome. We re-visited the use of real-time quantitative polymerase chain reaction (qPCR)-based assays using formalin-fixed paraffin-embedded (FFPE) tissues as alternative methods and investigated their particular clinical relevance. DNA and RNA were isolated from FFPE specimens and HER2 status was assessed by qPCR in 249 consecutive patients with primary breast cancer. Concordance with results forg immunohistochemistry (IHC) and in situ hybridization (ISH), clinical characteristics and survival was assessed. HER2 gene copy number had a stronger correlation with clinicopathological characteristics and excellent concordance with IHC/ISH results (Sensitivity: 96.7 %; concordance: 99.2 %). HER2 gene expression showed inadequate sensitivity, rendering it unsuitable to determine HER2 status (Sensitivity: 46.7 %; concordance: 92.1 %), but lower HER2 gene expression, leading to the classification of many cases as "false negative", contributed to a prediction of better prognosis within the HER2-amplified subpopulation. Quantitative HER2 assessments are suggested to have evolved their accuracy in this decade, which can be a potential alternative for HER2 diagnosis in line with the in situ method, while HER2 gene expression levels could provide additional information regarding prognosis or therapeutic strategy within a HER2-amplified subpopulation.
Relevance of deep learning to facilitate the diagnosis of HER2 status in breast cancer

PubMed Central

Vandenberghe, Michel E.; Scott, Marietta L. J.; Scorer, Paul W.; Söderberg, Magnus; Balcerzak, Denis; Barker, Craig

2017-01-01

Tissue biomarker scoring by pathologists is central to defining the appropriate therapy for patients with cancer. Yet, inter-pathologist variability in the interpretation of ambiguous cases can affect diagnostic accuracy. Modern artificial intelligence methods such as deep learning have the potential to supplement pathologist expertise to ensure constant diagnostic accuracy. We developed a computational approach based on deep learning that automatically scores HER2, a biomarker that defines patient eligibility for anti-HER2 targeted therapies in breast cancer. In a cohort of 71 breast tumour resection samples, automated scoring showed a concordance of 83% with a pathologist. The twelve discordant cases were then independently reviewed, leading to a modification of diagnosis from initial pathologist assessment for eight cases. Diagnostic discordance was found to be largely caused by perceptual differences in assessing HER2 expression due to high HER2 staining heterogeneity. This study provides evidence that deep learning aided diagnosis can facilitate clinical decision making in breast cancer by identifying cases at high risk of misdiagnosis. PMID:28378829
Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease.

PubMed

Press, M F; Pike, M C; Chazin, V R; Hung, G; Udove, J A; Markowicz, M; Danyluk, J; Godolphin, W; Sliwkowski, M; Akita, R

1993-10-15

The HER-2/neu proto-oncogene (also known as c-erb B-2) is homologous with, but distinct from, the epidermal growth factor receptor. Amplification of this gene in node-positive breast cancers has been shown to correlate with both earlier relapse and shorter overall survival. In node-negative breast cancer patients, the subgroup for which accurate prognostic data could make a significant contribution to treatment decisions, the prognostic utility of HER-2/neu amplification and/or overexpression has been controversial. The purpose of this report is to address the issues surrounding this controversy and to evaluate the prognostic utility of overexpression in a carefully followed group of patients using appropriately characterized reagents and methods. In this report we present data from a study of HER-2/neu expression designed specifically to test whether or not overexpression is associated with an increased risk of recurrence in node-negative breast cancers. From a cohort of 704 women with node-negative breast cancer who experienced recurrent disease (relapsed cases) 105 were matched with 105 women with no recurrence (disease-free controls) after the equivalent follow-up period. Immunohistochemistry was used to assess HER-2/neu expression in archival tissue blocks from both relapsed cases and their matched disease-free controls. Importantly, a series of molecularly characterized breast cancer specimens were used to confirm that the antibody used was of sufficient sensitivity and specificity to identify those cancers overexpressing the HER-2/neu protein in this formalin-fixed, paraffin-embedded tissue cohort. In addition, a quantitative approach was developed to more accurately assess the amount of HER-2/neu protein identified by immunostaining tumor tissue. This was done using a purified HER-2/neu protein synthesized in a bacterial expression vector and protein lysates derived from a series of cell lines, engineered to express a defined range of HER-2/neu oncoprotein
Comparisons of tumor-infiltrating lymphocyte levels and the 21-gene recurrence score in ER-positive/HER2-negative breast cancer.

PubMed

Ahn, Sung Gwe; Cha, Yoon Jin; Bae, Soon June; Yoon, Chanik; Lee, Hak Woo; Jeong, Joon

2018-03-24

Recent studies have shown that tumors with extensive tumor-infiltrating lymphocytes (TILs) have a higher probability of pathologic complete response, even in luminal/human epidermal growth factor 2 (HER2)-negative breast cancer. We compared TIL levels and the 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer. We evaluated the percentage of stromal TILs in 198 ER-positive/HER2-negative patients in whom RS was obtained by examining slides of surgical specimens by standardized methodology proposed by the international TIL Working Group. TIL levels were categorized as high (≥ 60%), intermediate (11-59%), or low (≤ 10%). All tumors were treatment-naïve. Ninety-seven (49.0%), 88 (44.4%), and 13 patients (6.6%) had low, intermediate, and high TIL levels, respectively. There was a significant but weak correlation between continuous RS and continuous TIL levels (Pearson's R = 0.201, p = 0.004). The mean RS was significantly highest in high TIL tumors (17.8 ± 10.7 in low TIL tumors, 19.4 ± 8.7 in intermediate TIL tumors, and 26.2 ± 8.2 in high TIL tumors; p = 0.014). However, when we compared categorized RS and TIL levels, we found that tumors with high TIL levels tended to have higher RS (≥ 26) but it was not significant (p = 0.155). Furthermore, multivariate analysis revealed that high RS was not an independent factor associated with high TIL levels. Chemo-endocrine therapy was more frequently performed among patients with high TILs and less frequently among those with low or intermediate TILs (p < 0.001). Despite of a weak correlation between continuous TIL levels and RS, we found that tumors with high TIL levels tended to have a higher RS in ER-positive/HER2-negative breast cancer. Further study is warranted considering the clinical outcomes.
Quantitative measurement of HER2 expression in breast cancers: comparison with 'real-world' routine HER2 testing in a multicenter Collaborative Biomarker Study and correlation with overall survival.

PubMed

Yardley, Denise A; Kaufman, Peter A; Huang, Weidong; Krekow, Lea; Savin, Michael; Lawler, William E; Zrada, Stephen; Starr, Alexander; Einhorn, Harvey; Schwartzberg, Lee S; Adams, John W; Lie, Yolanda; Paquet, Agnes C; Sperinde, Jeff; Haddad, Mojgan; Anderson, Steve; Brigino, Marlon; Pesano, Rick; Bates, Michael P; Weidler, Jodi; Bosserman, Linda

2015-03-18

Accurate assessment of HER2 status is critical in determining appropriate therapy for breast cancer patients but the best HER2 testing methodology has yet to be defined. In this study, we compared quantitative HER2 expression by the HERmark™ Breast Cancer Assay (HERmark) with routine HER2 testing by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and correlated HER2 results with overall survival (OS) of breast cancer patients in a multicenter Collaborative Biomarker Study (CBS). Two hundred and thirty-two formalin-fixed, paraffin-embedded breast cancer tissues and local laboratory HER2 testing results were provided by 11 CBS sites. HERmark assay and central laboratory HER2 IHC retesting were retrospectively performed in a blinded fashion. HER2 results by all testing methods were obtained in 192 cases. HERmark yielded a continuum of total HER2 expression (H2T) ranging from 0.3 to 403 RF/mm2 (approximately 3 logs). The distribution of H2T levels correlated significantly (P<0.0001) with all routine HER2 testing results. The concordance of positive and negative values (equivocal cases excluded) between HERmark and routine HER2 testing was 84% for local IHC, 96% for central IHC, 85% for local FISH, and 84% for local HER2 status. OS analysis revealed a significant correlation of shorter OS with HER2 positivity by local IHC (HR=2.6, P=0.016), central IHC (HR=3.2, P=0.015), and HERmark (HR=5.1, P<0.0001) in this cohort of patients most of whom received no HER2-targeted therapy. The OS curve of discordant low (HER2 positive but H2T low, 10% of all cases) was aligned with concordant negative (HER2 negative and H2T low, HR=1.9, P=0.444), but showed a significantly longer OS than concordant positive (HER2 positive and H2T high, HR=0.31, P=0.024). Conversely, the OS curve of discordant high (HER2 negative but H2T high, 9% of all cases) was aligned with concordant positive (HR=0.41, P=0.105), but showed a significantly shorter OS than concordant
HER2-Positive Breast Cancer: What Is It?

MedlinePlus

... it? A friend of mine has HER2-positive breast cancer. Can you tell me what this means? Answers from Timothy J. Moynihan, M.D. HER2-positive breast cancer is a breast cancer that tests positive for ...
Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

PubMed Central

Darb-Esfahani, Silvia; Denkert, Carsten; Stenzinger, Albrecht; Salat, Christoph; Sinn, Bruno; Schem, Christian; Endris, Volker; Klare, Peter; Schmitt, Wolfgang; Blohmer, Jens-Uwe; Weichert, Wilko; Möbs, Markus; Tesch, Hans; Kümmel, Sherko; Sinn, Peter; Jackisch, Christian; Dietel, Manfred; Reimer, Toralf; Loi, Sherene; Untch, Michael; von Minckwitz, Gunter; Nekljudova, Valentina; Loibl, Sibylle

2016-01-01

Background TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. Methods 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Results Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). Conclusions Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes. PMID:27611952

Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy.

PubMed

Darb-Esfahani, Silvia; Denkert, Carsten; Stenzinger, Albrecht; Salat, Christoph; Sinn, Bruno; Schem, Christian; Endris, Volker; Klare, Peter; Schmitt, Wolfgang; Blohmer, Jens-Uwe; Weichert, Wilko; Möbs, Markus; Tesch, Hans; Kümmel, Sherko; Sinn, Peter; Jackisch, Christian; Dietel, Manfred; Reimer, Toralf; Loi, Sherene; Untch, Michael; von Minckwitz, Gunter; Nekljudova, Valentina; Loibl, Sibylle

2016-10-18

TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.
Adjuvant chemotherapy decisions in clinical practice for early-stage node-negative, estrogen receptor-positive, HER2-negative breast cancer: challenges and considerations.

PubMed

Nagaraj, Gayathri; Ma, Cynthia X

2013-03-01

Decisions regarding adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative, lymph node-negative breast cancer have traditionally relied on clinical and pathologic parameters. However, the molecular heterogeneity and the complex tumor genome demand more sophisticated approaches to the problem. Several multigene-based assays have been developed to better prognosticate the risk of recurrence and death and predict benefit of therapy in this patient population. Oncologists are often faced with the challenge of incorporating these various complex genome-based biomarkers along with the traditional biomarkers in clinical decision-making. The NCCN Clinical Practice Guidelines in Oncology for Breast Cancer are helpful in providing a general recommendation. However, uncertainty remains in the absence of definitive data for various clinical scenarios. This case report describes a postmenopausal woman with stage I breast cancer that is low-grade and ER-rich, and has an intermediate Oncotype DX recurrence score of 28.
Comparison of the prevalence of KRAS-LCS6 polymorphism (rs61764370) within different tumour types (colorectal, breast, non-small cell lung cancer and brain tumours). A study of the Czech population.

PubMed

Uvirova, Magdalena; Simova, Jarmila; Kubova, Barbora; Dvorackova, Nina; Tomaskova, Hana; Sedivcova, Monika; Dite, Petr

2015-09-01

A germline SNP (rs61764370) is located in a let-7 complementary site (LCS6) in the 3'UTR of KRAS oncogene, and it was found to alter the binding capability of the mature let-7 microRNA to the KRAS mRNA. The aim of the study was to evaluate the frequency of the KRAS-LCS6 variant allele in different cancer types that included patients with colorectal cancer (CRC), breast cancer (BC), non-small cell lung cancer (NSCLC) and brain tumour patient subgroups from the Czech Republic. The occurrence of this genetic variant was correlated with the presence of selected somatic mutations representing predictive biomarkers in the respective tumours. DNA of tumour tissues was isolated from 428 colorectal cancer samples, 311 non-small cell lung cancer samples, 195 breast cancer samples and 151 samples with brain tumour. Analysis of SNP (rs61764370) was performed by the PCR+RFLP method and direct sequencing. KRAS, BRAF and EGFR mutation status was assessed using real-time PCR. The status of the HER2 gene was assessed using the FISH method. The KRAS-LCS6 TG genotype has been detected in 16.4% (32/195) of breast cancer cases (in HER2 positive breast cancer 3.3%, in HER2 negative breast cancer 20.1%), in 12.4% (53/428) of CRC cases (KRAS/BRAF wild type CRC in 10.6%, KRAS mutant CRC in 10.1%, BRAF V600E mutant CRC in 18.5%), in 13.2% (41/311) of NSCLC samples, (EGFR mutant NSCLC patients in 8%, EGFR wild type NSCLC in 12.9%), and 17.9% (27/151) of brain tumour cases. The KRAS-LCS6 TG genotype was not significantly different across the studied tumours. In our study, the GG genotype has not been found among the cancer samples. Based on the findings, it is concluded that the occurrence of the KRAS-LCS6 TG genotype was statistically significantly different in association with status of the HER2 gene in breast cancer. Furthermore, significant association between the mutation status of analysed somatic variants in genes of the EGFR signalling pathway (KRAS, BRAF, EGFR) and the KRAS-LCS6
Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study

PubMed Central

Kovatich, Albert J.; Hooke, Jeffrey A.; Liu, Jianfang; Kvecher, Leonid; Fantacone-Campbell, J. Leigh; Mitchell, Edith P.; Rui, Hallgeir; Shriver, Craig D.; Hu, Hai

2015-01-01

Background Risk assessment of a benign breast disease/lesion (BBD) for invasive breast cancer (IBC) is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co-occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC), an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC. Methods A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA) was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC) were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models. Results Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell-shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR) depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI<25 kg/m2; OR = 2.13, 95%CI = 1.20-3.80 at BMI>25 kg/m2). This association is only significant with HER2-negative IBC subtypes. Conclusions We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co-occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs. PMID:26098961
HR+/Her2- breast cancer in pre-menopausal women: The impact of younger age on clinical characteristics at diagnosis, disease management and survival.

PubMed

De Camargo Cancela, Marianna; Comber, Harry; Sharp, Linda

2016-12-01

Young women (20-39 years-old) with breast cancer are diagnosed with more aggressive tumours and consequently have poorer survival. However, there is an evidence gap as to whether age has an independent effect on survival of pre-menopausal women diagnosed with HR+/Her2- tumours. The aim of this population-based study was to compare characteristics at diagnosis, determinants of treatment and survival in women aged 20-39 and 40-49 years diagnosed with HR+/Her2- tumours. From the National Cancer Registry Ireland, we identified women aged 20-49 diagnosed with a first invasive HR+/Her2- breast cancer during 2002-2008. Women aged 20-39 were compared to those aged 40-49 years. Poisson regression with robust error variance was used to explore the impact of age on treatment receipt. Associations between age and survival from all causes was investigated using Cox models. In multivariate models, women aged 20-39 significantly more often having no cancer-directed surgery (IRR=1.49, 95%CI 1.07, 2.08). In those having surgery, younger age was associated with significantly higher likelihood of receiving chemotherapy; age was not associated with receipt of adjuvant radiotherapy or endocrine therapy. Women aged 20-39 undergoing surgery were significantly more likely to die than women aged 40-49 (HR=1.84, 95%CI: 1.31, 2.59). Age is an independent prognostic factor in younger women diagnosed with HR+/Her2- breast cancer, supporting the hypothesis that breast cancer in women under 40 has more aggressive behaviour, even within HR+/Her2- tumours. Future research should explore the reasons for poorer survival in order to inform strategies to improve outcomes in this age group. Copyright Â© 2016 Elsevier Ltd. All rights reserved.
Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2-Primary Breast Cancer

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-1-0444 TITLE: Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2- Primary Breast Cancer...Prescribed by ANSI Std. Z39.18 Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2- Primary Breast Cancer? 30 Sep 2015 - 29 Sep...Financial Report Ulaner, Gary PROGRESS REPORT: October 2016 DoD W81XWH-14-1-0444 Could HER2 heterogeneity open new therapeutic options in patients with
Medico-economic impact of MSKCC non-sentinel node prediction nomogram for ER-positive HER2-negative breast cancers.

PubMed

Bonsang-Kitzis, Hélène; Mouttet-Boizat, Delphine; Guillot, Eugénie; Feron, Jean-Guillaume; Fourchotte, Virginie; Alran, Séverine; Pierga, Jean-Yves; Cottu, Paul; Lerebours, Florence; Stevens, Denise; Vincent-Salomon, Anne; Sigal-Zafrani, Brigitte; Campana, François; Rouzier, Roman; Reyal, Fabien

2017-01-01

Avoiding axillary lymph node dissection (ALND) for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB) could decrease morbidity with minimal clinical significance. The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN) prediction nomogram for ER+ HER2- breast cancer patients. We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients' characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results. A 0.3 threshold discriminate the type of sentinel node (SN) metastases: 98.8% of patients with pN0(i+) and 91.6% of patients with pN1(mic) had a MSKCC score under 0.3 (false negative rate = 6.4%). If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients. We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+) or pN1(mic) ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3.
Medico-economic impact of MSKCC non-sentinel node prediction nomogram for ER-positive HER2-negative breast cancers

PubMed Central

Guillot, Eugénie; Feron, Jean-Guillaume; Fourchotte, Virginie; Alran, Séverine; Pierga, Jean-Yves; Cottu, Paul; Lerebours, Florence; Stevens, Denise; Vincent-Salomon, Anne; Sigal-Zafrani, Brigitte; Campana, François; Rouzier, Roman; Reyal, Fabien

2017-01-01

Background Avoiding axillary lymph node dissection (ALND) for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB) could decrease morbidity with minimal clinical significance. Purpose The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN) prediction nomogram for ER+ HER2- breast cancer patients. Methods We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients’ characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results. Results A 0.3 threshold discriminate the type of sentinel node (SN) metastases: 98.8% of patients with pN0(i+) and 91.6% of patients with pN1(mic) had a MSKCC score under 0.3 (false negative rate = 6.4%). If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients. Conclusion We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+) or pN1(mic) ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3. PMID:28241044
Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

PubMed Central

Advani, Pooja; Cornell, Lauren; Chumsri, Saranya; Moreno-Aspitia, Alvaro

2015-01-01

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. PMID:26451122
Breast cancer risk factors and HER2 over-expression in tumors.

PubMed

Swede, H; Moysich, K B; Freudenheim, J L; Quirk, J T; Muti, P C; Hurd, T C; Edge, S B; Winston, J S; Michalek, A M

2001-01-01

Few epidemiologic studies have investigated the potential role of HER2 in the etiology of breast cancer. We conducted a case-case study of 156 women with incident, invasive ductal carcinoma. Multivariate unconditional logistic regression was used to estimate the odds ratios for a HER2 positive tumor in relation to known and putative risk factors of breast cancer. HER2 status was detected by immunohistochemistry on archival tissue. HER2 positive breast cancers tended to be larger and were less likely to express estrogen receptors, and the incidence rate was higher in patients less than 40 years old. We observed an association between a self-reported history of benign breast disease and the occurrence of HER2 positive breast cancer (OR, 2.1;95% CI, 1.1-4.1). We did not detect associations between HER2 over-expression and family history of breast cancer, parity, late age at first birth, ever having breast fed an infant, or oral contraceptive use. Our findings merit consideration in light of recent evidence of HER2 amplification or over-expression in benign breast disease. Should the link to breast cancer be established, HER2 positive benign breast disease could potentially serve as an early marker for preventive intervention.
3D culture of Her2+ breast cancer cells promotes AKT to MAPK switching and a loss of therapeutic response.

PubMed

Gangadhara, Sharath; Smith, Chris; Barrett-Lee, Peter; Hiscox, Stephen

2016-06-01

The Her2 receptor is overexpressed in up to 25 % of breast cancers and is associated with a poor prognosis. Around half of Her2+ breast cancers also express the estrogen receptor and treatment for such tumours can involve both endocrine and Her2-targeted therapies. However, despite preclinical data supporting the effectiveness of these agents, responses can vary widely in the clinical setting. In light of the increasing evidence pointing to the interplay between the tumour and its extracellular microenvironment as a significant determinant of therapeutic sensitivity and response here we investigated the impact of 3D matrix culture of breast cancer cells on their therapeutic sensitivity. A 3D Matrigel-based culture system was established and optimized for the growth of ER+/Her2+ breast cancer cell models. Growth of cells in response to trastuzumab and endocrine agents in 3D culture versus routine monolayer culture were assessed using cell counting and Ki67 staining. Endogenous and trastuzumab-modulated signalling pathway activity in 2D and 3D cultures were assessed using Western blotting. Breast cancer cells in 3D culture displayed an attenuated response to both endocrine agents and trastuzumab compared with cells cultured in traditional 2D monolayers. Underlying this phenomenon was an apparent matrix-induced shift from AKT to MAPK signalling; consequently, suppression of MAPK in 3D cultures restores therapeutic response. These data suggest that breast cancer cells in 3D culture display a reduced sensitivity to therapeutic agents which may be mediated by internal MAPK-mediated signalling. Targeting of adaptive pathways that maintain growth in 3D culture may represent an effective strategy to improve therapeutic response clinically.
The role of neratinib in HER2-driven breast cancer.

PubMed

Cherian, Mathew A; Ma, Cynthia X

2017-06-30

Up to 25% of patients with early-stage HER2+ breast cancer relapse despite adjuvant trastuzumab-based regimens and virtually all patients with metastatic disease eventually die from resistance to existing treatment options. In addition, recent studies indicate that activating HER2 mutations without gene amplification could drive tumor growth in a subset of HER2-ve breast cancer that is not currently eligible for HER2-targeted agents. Neratinib is an irreversible HER kinase inhibitor with activity as extended adjuvant therapy following standard trastuzumab-based adjuvant treatment in a Phase III trial. Phase II trials of neratinib demonstrate promising activity in combination with cytotoxic agents in trastuzumab resistant metastatic HER2+ breast cancer, and either as monotherapy or in combination with fulvestrant for HER2-mutated breast cancers. We anticipate a potential role for neratinib in the therapy of these patient populations.
Clinical significance of Mena and Her-2 expression in breast cancer.

PubMed

Du, J W; Xu, K Y; Fang, L Y; Qi, X L

2012-01-01

The aim of this study was to determine the expression patterns of Mena and Her-2 in breast cancer tissues and to explore their clinical significance and correlation with clinicopathological parameters. The expression of Mena and Her-2 was detected in 40 breast cancer tissues and 14 normal breast tissues by immunohistochemistry, and the relationship of Mena and Her-2 expression with clinicopathological parameters was analyzed. Both Mena (70%) and Her-2 (40%) were more commonly expressed in breast cancer than in normal breast tissue (7.1%, 0%, respectively; p < 0.05); further, Mena and Her-2 expression in breast cancer were positively correlated (r = 0.530, p < 0.05). In comparing expression with clinicopathological parameters of tumor samples, Mena and Her-2 were both associated with axillary lymph node metastasis and TNM stage (p < 0.05), but not with patient age or pathological type. Mena and Her-2 are related to the malignancy degree and metastasis of breast cancer, and thus may play a coordinating role in the occurrence and progression of breast cancer.
Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status

PubMed Central

Ma, Huiyan; Xu, Xinxin; Ursin, Giske; Simon, Michael S; Marchbanks, Polly A; Malone, Kathleen E; Lu, Yani; McDonald, Jill A; Folger, Suzanne G; Weiss, Linda K; Sullivan-Halley, Jane; Deapen, Dennis M; Press, Michael F; Bernstein, Leslie

2015-01-01

Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women’s Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2−) subtypes (both Ptrend ≤ 0.04), but not with other subtypes (all Ptrend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2–breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend ≤ 0.06). The test for homogeneity of trends (HER2– vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (Phomogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts. PMID:25924995
Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

PubMed

Cadoo, Karen A; Morris, Patrick G; Cowell, Elizabeth P; Patil, Sujata; Hudis, Clifford A; McArthur, Heather L

2016-12-01

The benefit of adjuvant trastuzumab with chemotherapy is well established for women with higher risk human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer. However, its role in older patients with smaller, node-negative tumors is less clear. We conducted a retrospective, sequential cohort study of this population to describe the impact of trastuzumab on breast cancer outcomes and cardiac safety. Women ≥ 55 years with ≤ 2 cm, node-negative, HER2 + breast cancer were identified and electronic medical records reviewed. A no-trastuzumab cohort of 116 women diagnosed between January 1, 1999 and May 14, 2004 and a trastuzumab cohort of 128 women diagnosed between May 16, 2006 and December 31, 2010 were identified. Overall survival and distant relapse-free survival were estimated by Kaplan-Meier methods. The median ages of the trastuzumab and no-trastuzumab cohorts were 62 and 64 years, respectively. More patients in the trastuzumab cohort had grade III (P = .001), lymphovascular invasion (P = .001), or estrogen receptor-negative (P < .001) cancers. The majority of the trastuzumab cohort received chemotherapy versus one-half of the no-trastuzumab cohort (98% vs. 53%; P < .0001). The median follow-up was 4 versus 9 years in the trastuzumab versus no-trastuzumab cohorts; therefore, outcomes at 4 years are reported. Despite the higher-risk tumor features in the trastuzumab group, the 4-year overall survival was 99% in both cohorts; the distant relapse-free survival was 99% versus 97% in the trastuzumab versus no-trastuzumab cohorts. Four (3.1%; 95% confidence interval, 1.0%-7.8%) women in the trastuzumab cohort and 1 in the no-trastuzumab cohort developed symptomatic heart failure. There were no cardiac-related deaths in either arm. Following adjuvant trastuzumab with chemotherapy, selected older women with small, node-negative, HER2 + breast cancers have excellent disease control. The rate of cardiac events is low. Copyright © 2016 Elsevier
Alternative HER/PTEN/Akt Pathway Activation in HPV Positive and Negative Penile Carcinomas

PubMed Central

Stankiewicz, Elzbieta; Prowse, David M.; Ng, Mansum; Cuzick, Jack; Mesher, David; Hiscock, Frances; Lu, Yong-Jie; Watkin, Nicholas; Corbishley, Catherine; Lam, Wayne; Berney, Daniel M.

2011-01-01

Background The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH). Methodology/Principal Findings 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs. Conclusions/Significance EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression
Alternative HER/PTEN/Akt pathway activation in HPV positive and negative penile carcinomas.

PubMed

Stankiewicz, Elzbieta; Prowse, David M; Ng, Mansum; Cuzick, Jack; Mesher, David; Hiscock, Frances; Lu, Yong-Jie; Watkin, Nicholas; Corbishley, Catherine; Lam, Wayne; Berney, Daniel M

2011-03-02

The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH). 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs. EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection
HER2-positive male breast cancer: an update

PubMed Central

Ottini, Laura; Capalbo, Carlo; Rizzolo, Piera; Silvestri, Valentina; Bronte, Giuseppe; Rizzo, Sergio; Russo, Antonio

2010-01-01

Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents a very interesting molecular target and a number of compounds (trastuzumab [Herceptin®; F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb®, GlaxoSmithKline, London, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist. In all cases, MBC patients received trastuzumab concomitantly with other drugs and no severe toxicity above grade 3 was observed. However, MBC patients that would be candidate for trastuzumab therapy (ie, HER2+/ER+ or HER2+/ER− MBCs) represent only a very small percentage of MBC cases. This is noteworthy, when taking into account that trastuzumab is an important and expensive component of systemic BC therapy. Since there is no data supporting the fact that response to therapy is different for men or women, we concluded that systemic therapy in MBC should be considered on the same basis as for FBC. Particularly in male patients, trastuzumab should be
Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

PubMed

Pernas, Sonia; Martin, Miguel; Kaufman, Peter A; Gil-Martin, Marta; Gomez Pardo, Patricia; Lopez-Tarruella, Sara; Manso, Luis; Ciruelos, Eva; Perez-Fidalgo, Jose Alejandro; Hernando, Cristina; Ademuyiwa, Foluso O; Weilbaecher, Katherine; Mayer, Ingrid; Pluard, Timothy J; Martinez Garcia, Maria; Vahdat, Linda; Perez-Garcia, Jose; Wach, Achim; Barker, Debra; Fung, Samson; Romagnoli, Barbara; Cortes, Javier

2018-04-26

The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m 2 on days 2 and 9 of a 21-day cycle
Adjuvant Anti-HER2 Therapy, Treatment-Related Amenorrhea, and Survival in Premenopausal HER2-Positive Early Breast Cancer Patients.

PubMed

Lambertini, Matteo; Campbell, Christine; Bines, José; Korde, Larissa A; Izquierdo, Miguel; Fumagalli, Debora; Del Mastro, Lucia; Ignatiadis, Michail; Pritchard, Kathleen; Wolff, Antonio C; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Barrios, Carlos H; Baselga, José; Moreno-Aspitia, Alvaro; Piccart, Martine; Gelber, Richard D; de Azambuja, Evandro

2018-06-05

In premenopausal patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown. In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor-positive and -negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided. A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor-positive disease. Median age was 43 (interquartile range = 38-47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab→lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor-positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor-negative patients. In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor-positive/HER2-positive early breast cancer patients.

Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.

PubMed

Yu, Ke-Da; Jiang, Yi-Zhou; Hao, Shuang; Shao, Zhi-Ming

2015-10-05

The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated. Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). The majority of ER-/PgR+/HER
Oxidative stress specifically downregulates survivin to promote breast tumour formation.

PubMed

Pervin, S; Tran, L; Urman, R; Braga, M; Parveen, M; Li, S A; Chaudhuri, G; Singh, R

2013-03-05

Breast cancer, a heterogeneous disease has been broadly classified into oestrogen receptor positive (ER+) or oestrogen receptor negative (ER-) tumour types. Each of these tumours is dependent on specific signalling pathways for their progression. While high levels of survivin, an anti-apoptotic protein, increases aggressive behaviour in ER- breast tumours, oxidative stress (OS) promotes the progression of ER+ breast tumours. Mechanisms and molecular targets by which OS promotes tumourigenesis remain poorly understood. DETA-NONOate, a nitric oxide (NO)-donor induces OS in breast cancer cell lines by early re-localisation and downregulation of cellular survivin. Using in vivo models of HMLE(HRAS) xenografts and E2-induced breast tumours in ACI rats, we demonstrate that high OS downregulates survivin during initiation of tumourigenesis. Overexpression of survivin in HMLE(HRAS) cells led to a significant delay in tumour initiation and tumour volume in nude mice. This inverse relationship between survivin and OS was also observed in ER+ human breast tumours. We also demonstrate an upregulation of NADPH oxidase-1 (NOX1) and its activating protein p67, which are novel markers of OS in E2-induced tumours in ACI rats and as well as in ER+ human breast tumours. Our data, therefore, suggest that downregulation of survivin could be an important early event by which OS initiates breast tumour formation.
EGFR and HER2 signaling in breast cancer brain metastasis

PubMed Central

Sirkisoon, Sherona R.; Carpenter, Richard L.; Rimkus, Tadas; Miller, Lance; Metheny-Barlow, Linda; Lo, Hui-Wen

2016-01-01

Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis. PMID:26709660
Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

PubMed

Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

2018-03-28

Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

PubMed Central

Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Slamon, Dennis; McGowan, Patricia; Duffy, Michael J.

2013-01-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab. PMID:24009064
Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

PubMed

Canonici, Alexandra; Gijsen, Merel; Mullooly, Maeve; Bennett, Ruth; Bouguern, Noujoude; Pedersen, Kasper; O'Brien, Neil A; Roxanis, Ioannis; Li, Ji-Liang; Bridge, Esther; Finn, Richard; Siamon, Dennis; McGowan, Patricia; Duffy, Michael J; O'Donovan, Norma; Crown, John; Kong, Anthony

2013-10-01

Trastuzumab has been shown to improve the survival outcomes of HER2 positive breast cancer patients. However, a significant proportion of HER2-positive patients are either inherently resistant or develop resistance to trastuzumab. We assessed the effects of neratinib, an irreversible panHER inhibitor, in a panel of 36 breast cancer cell lines. We further assessed its effects with or without trastuzumab in several sensitive and resistant breast cancer cells as well as a BT474 xenograft model. We confirmed that neratinib was significantly more active in HER2-amplified than HER2 non-amplified cell lines. Neratinib decreased the activation of the 4 HER receptors and inhibited downstream pathways. However, HER3 and Akt were reactivated at 24 hours, which was prevented by the combination of trastuzumab and neratinib. Neratinib also decreased pHER2 and pHER3 in acquired trastuzumab resistant cells. Neratinib in combination with trastuzumab had a greater growth inhibitory effect than either drug alone in 4 HER2 positive cell lines. Furthermore, trastuzumab in combination with neratinib was growth inhibitory in SKBR3 and BT474 cells which had acquired resistance to trastuzumab as well as in a BT474 xenograft model. Innately trastuzumab resistant cell lines showed sensitivity to neratinib, but the combination did not enhance response compared to neratinib alone. Levels of HER2 and phospho-HER2 showed a direct correlation with sensitivity to neratinib. Our data indicate that neratinib is an effective anti-HER2 therapy and counteracted both innate and acquired trastuzumab resistance in HER2 positive breast cancer. Our results suggest that combined treatment with trastuzumab and neratinib is likely to be more effective than either treatment alone for both trastuzumab-sensitive breast cancer as well as HER2-positive tumors with acquired resistance to trastuzumab.
Synthesis and characterization of Her2-NLP peptide conjugates targeting circulating breast cancer cells: cellular uptake and localization by fluorescent microscopic imaging.

PubMed

Cai, Huawei; Singh, Ajay N; Sun, Xiankai; Peng, Fangyu

2015-01-01

To synthesize a fluorescent Her2-NLP peptide conjugate consisting of Her2/neu targeting peptide and nuclear localization sequence peptide (NLP) and assess its cellular uptake and intracellular localization for radionuclide cancer therapy targeting Her2/neu-positive circulating breast cancer cells (CBCC). Fluorescent Cy5.5 Her2-NLP peptide conjugate was synthesized by coupling a bivalent peptide sequence, which consisted of a Her2-binding peptide (NH2-GSGKCCYSL) and an NLP peptide (CGYGPKKKRKVGG) linked by a polyethylene glycol (PEG) chain with 6 repeating units, with an activated Cy5.5 ester. The conjugate was separated and purified by HPLC and then characterized by Maldi-MS. The intracellular localization of fluorescent Cy5.5 Her2-NLP peptide conjugate was assessed by fluorescent microscopic imaging using a confocal microscope after incubation of Cy5.5-Her2-NLP with Her2/neu positive breast cancer cells and Her2/neu negative control breast cancer cells, respectively. Fluorescent signals were detected in cytoplasm of Her2/neu positive breast cancer cells (SKBR-3 and BT474 cell lines), but not or little in cytoplasm of Her2/neu negative breast cancer cells (MDA-MB-231), after incubation of the breast cancer cells with Cy5.5-Her2-NLP conjugates in vitro. No fluorescent signals were detected within the nuclei of Her2/neu positive SKBR-3 and BT474 breast cancer cells, neither Her2/neu negative MDA-MB-231 cells, incubated with the Cy5.5-Her2-NLP peptide conjugates, suggesting poor nuclear localization of the Cy5.5-Her2-NLP conjugates localized within the cytoplasm after their cellular uptake and internalization by the Her2/neu positive breast cancer cells. Her2-binding peptide (KCCYSL) is a promising agent for radionuclide therapy of Her2/neu positive breast cancer using a β(-) or α emitting radionuclide, but poor nuclear localization of the Her2-NLP peptide conjugates may limit its use for eradication of Her2/neu-positive CBCC using I-125 or other Auger electron
HER-2 amplification in tubular carcinoma of the breast.

PubMed

Oakley, Gerard J; Tubbs, Raymond R; Crowe, Joseph; Sebek, Bruce; Budd, G Thomas; Patrick, Rebecca J; Procop, Gary W

2006-07-01

The prognostic and therapeutic implications of HER-2 gene amplification and estrogen and progesterone receptor status in breast cancer are well described. To address the relative paucity of information concerning HER-2 amplification for tubular carcinomas, we assessed the frequency of gene amplification in 55 tubular carcinomas of the breast from 54 patients, 5 of which had axillary node metastases. The HER-2 gene copy number was assessed by fluorescence in situ hybridization for the majority of tumors analyzed, whereas estrogen and progesterone receptor status was achieved by immunohistochemical analysis. HER-2 gene amplification was not observed in any of the tumors examined, and most were estrogen receptor-positive. This HER-2 gene amplification frequency was significantly lower than the frequency of gene amplification previously reported for all invasive ductal carcinoma of no special type (P < .01). HER-2 gene amplification likely occurs infrequently, or not at all, in tubular carcinomas of the breast, whereas most express estrogen receptors.
Correlation of HER-2 over-expression with clinico-pathological parameters in Tunisian breast carcinoma.

PubMed

Ayadi, Lobna; Khabir, Abdelmajid; Amouri, Habib; Karray, Sondes; Dammak, Abdallah; Guermazi, Mohamed; Boudawara, Tahya

2008-10-22

Breast carcinoma is a disease with a tremendous heterogeneity in its clinical behavior. Newer prognostic factors and predictors of response to therapy are needed. The aim of this study was to evaluate the expression of HER-2, estrogen receptor (ER) and progesterone receptors (PR) in breast carcinoma and to compare it with other prognostic parameters such as histological type and grade, tumor size, patients' age, and lymph node metastases. This is a retrospective study conducted in the department of pathology at Sfax University Hospital. Confirmed 155 Cases of breast carcinoma were reviewed in the period between January 2000 and December 2004. We used immunohistochemistry to evaluate the expression of HER-2, ER, and PR receptor and Chi-square and Fisher exact test to correlate immunohistochemical findings with prognostic parameters for breast carcinoma such as patients' age, tumor size, histological type, histological grade and lymph node status. The mean age of patients was 51.5 years, ranging from 22 to 89 years. 80 (51.6%) of the patients were below 50 years. The percentage of expression of HER-2, ER and PR was 26, 59.4, and 52.3%, respectively. HER-2 was over-expressed (3+) in 18.1% of the cases, was inversely related to ER expression (p = 0.00) and to PR expression (p = 0.048). This over-expression was also associated with a high tumor grade with marginal significance (p = 0.072). A negative correlation was noted between ER and PR expression and SBR grade (p = 0.000) and ER and age (p = 0.002). HER-2 over-expression was observed in 18.1% of Tunisian breast carcinoma affecting female patients. This group presents apparently an aggressive form of breast carcinoma with high histological grade and negative ER.
Correlation of HER-2 over-expression with clinico-pathological parameters in Tunisian breast carcinoma

PubMed Central

Ayadi, Lobna; Khabir, Abdelmajid; Amouri, Habib; Karray, Sondes; Dammak, Abdallah; Guermazi, Mohamed; Boudawara, Tahya

2008-01-01

Background Breast carcinoma is a disease with a tremendous heterogeneity in its clinical behavior. Newer prognostic factors and predictors of response to therapy are needed. The aim of this study was to evaluate the expression of HER-2, estrogen receptor (ER) and progesterone receptors (PR) in breast carcinoma and to compare it with other prognostic parameters such as histological type and grade, tumor size, patients' age, and lymph node metastases. Patients and methods This is a retrospective study conducted in the department of pathology at Sfax University Hospital. Confirmed 155 Cases of breast carcinoma were reviewed in the period between January 2000 and December 2004. We used immunohistochemistry to evaluate the expression of HER-2, ER, and PR receptor and Chi-square and Fisher exact test to correlate immunohistochemical findings with prognostic parameters for breast carcinoma such as patients' age, tumor size, histological type, histological grade and lymph node status. Results The mean age of patients was 51.5 years, ranging from 22 to 89 years. 80 (51.6%) of the patients were below 50 years. The percentage of expression of HER-2, ER and PR was 26, 59.4, and 52.3%, respectively. HER-2 was over-expressed (3+) in 18.1% of the cases, was inversely related to ER expression (p = 0.00) and to PR expression (p = 0.048). This over-expression was also associated with a high tumor grade with marginal significance (p = 0.072). A negative correlation was noted between ER and PR expression and SBR grade (p = 0.000) and ER and age (p = 0.002). Conclusion HER-2 over-expression was observed in 18.1% of Tunisian breast carcinoma affecting female patients. This group presents apparently an aggressive form of breast carcinoma with high histological grade and negative ER. PMID:18945339
Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer

ClinicalTrials.gov

2018-03-22

Breast Adenocarcinoma; HER2/Neu Negative; Invasive Breast Carcinoma; Metastatic Malignant Solid Neoplasm; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Unresectable Solid Neoplasm
Selective Inhibition of HER2-Positive Breast Cancer Cells by the HIV Protease Inhibitor Nelfinavir

PubMed Central

2012-01-01

Background Human epidermal growth factor receptor 2 (HER2)–positive breast cancer is highly aggressive and has higher risk of recurrence than HER2-negative cancer. With few treatment options available, new drug targets specific for HER2-positive breast cancer are needed. Methods We conducted a pharmacological profiling of seven genotypically distinct breast cancer cell lines using a subset of inhibitors of breast cancer cells from a screen of the Johns Hopkins Drug Library. To identify molecular targets of nelfinavir, identified in the screen as a selective inhibitor of HER2-positive cells, we conducted a genome-wide screen of a haploinsufficiency yeast mutant collection. We evaluated antitumor activity of nelfinavir with xenografts in athymic nude mouse models (n = 4–6 per group) of human breast cancer and repeated mixed-effects regression analysis. All statistical tests were two-sided. Results Pharmacological profiling showed that nelfinavir, an anti-HIV drug, selectively inhibited the growth of HER2-positive breast cancer cells in vitro. A genome-wide screening of haploinsufficiency yeast mutants revealed that nelfinavir inhibited heat shock protein 90 (HSP90) function. Further characterization using proteolytic footprinting experiments indicated that nelfinavir inhibited HSP90 in breast cancer cells through a novel mechanism. In vivo, nelfinavir selectively inhibited the growth of HER2-positive breast cancer cells (tumor volume index of HCC1954 cells on day 29, vehicle vs nelfinavir, mean = 14.42 vs 5.16, difference = 9.25, 95% confidence interval [CI] = 5.93 to 12.56, P < .001; tumor volume index of BT474 cells on day 26, vehicle vs nelfinavir, mean = 2.21 vs 0.90, difference = 1.31, 95% CI = 0.83 to 1.78, P < .001). Moreover, nelfinavir inhibited the growth of trastuzumab- and/or lapatinib-resistant, HER2-positive breast cancer cells in vitro at clinically achievable concentrations. Conclusion Nelfinavir was found to be a new class of HSP90 inhibitor and
Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery

ClinicalTrials.gov

2018-02-12

Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer
HER Story: The Next Chapter in HER-2-Directed Therapy for Advanced Breast Cancer

PubMed Central

Joy, Anil A.; Rayson, Daniel; McLeod, Deanna; Brezden-Masley, Christine; Boileau, Jean-François; Gelmon, Karen A.

2013-01-01

Untreated human epidermal growth factor receptor-2 (HER-2)-positive advanced breast cancer (ABC) is an aggressive disease, associated with a poor prognosis and short overall survival. HER-2-directed therapy prolongs both time to disease progression and overall survival when combined with chemotherapy and has become the standard of care for those with HER-2-positive breast cancer in the early and advanced settings. Despite the remarkable therapeutic impact HER-2-directed therapy has had on disease outcomes, some patients with HER-2-positive disease will have primary resistant disease and others will respond initially but will eventually have progression, underscoring the need for other novel therapeutic options. This article reviews recent phase III trial data and discusses a practical approach to sequencing of HER-2-directed therapy in patients with HER-2-positive ABC. The significant cumulative survival gains seen in these trials are slowly reshaping the landscape of HER-2-positive ABC outcomes. PMID:24212500
The Lifetime Economic Burden of Inaccurate HER2 Testing: Estimating the Costs of False-Positive and False-Negative HER2 Test Results in US Patients with Early-Stage Breast Cancer.

PubMed

Garrison, Louis P; Babigumira, Joseph B; Masaquel, Anthony; Wang, Bruce C M; Lalla, Deepa; Brammer, Melissa

2015-06-01

Patients with breast cancer whose tumors test positive for human epidermal growth factor receptor 2 (HER2) are treated with HER2-targeted therapies such as trastuzumab, but limitations with HER2 testing may lead to false-positive (FP) or false-negative (FN) results. To develop a US-level model to estimate the effect of tumor misclassification on health care costs and patient quality-adjusted life-years (QALYs). Decision analysis was used to estimate the number of patients with early-stage breast cancer (EBC) whose HER2 status was misclassified in 2012. FP results were assumed to generate unnecessary trastuzumab costs and unnecessary cases of trastuzumab-related cardiotoxicity. FN results were assumed to save money on trastuzumab, but with a loss of QALYs and greater risk of disease recurrence and its associated costs. QALYs were valued at $100,000 under a net monetary benefit approach. Among 226,870 women diagnosed with EBC in 2012, 3.12% (n = 7,070) and 2.18% (n = 4,955) were estimated to have had FP and FN test results, respectively. Approximately 8400 QALYs (discounted, lifetime) were lost among women not receiving trastuzumab because of FN results. The estimated incremental per-patient lifetime burden of FP or FN results was $58,900 and $116,000, respectively. The implied incremental losses to society were $417 million and $575 million, respectively. HER2 tests result in misclassification and nonoptimal treatment of approximately 12,025 US patients with EBC annually. The total economic societal loss of nearly $1 billion suggests that improvements in HER2 testing accuracy are needed and that further clinical and economic studies are warranted. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis.

PubMed

Leone, José Pablo; Leone, Julieta; Zwenger, Ariel Osvaldo; Iturbe, Julián; Leone, Bernardo Amadeo; Vallejo, Carlos Teodoro

2017-03-01

The presence of brain metastases at the time of initial breast cancer diagnosis (BMIBCD) is uncommon. Hence, the prognostic assessment and management of these patients is very challenging. The aim of this study was to analyse the influence of tumour subtype compared with other prognostic factors in the survival of patients with BMIBCD. We evaluated women with BMIBCD, reported to Surveillance, Epidemiology and End Results program from 2010 to 2013. Patients with other primary malignancy were excluded. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS). We included 740 patients. Median OS for the whole population was 10 months, and 20.7% of patients were alive at 36 months. Tumour subtype distribution was: 46.6% hormone receptor (HR)+/HER2-, 17% HR+/HER2+, 14.1% HR-/HER2+ and 22.3% triple-negative. Univariate analysis showed that the presence of liver metastases, lung metastases and triple-negative patients (median OS 6 months) had worse prognosis. The HR+/HER2+ subtype had the longest OS with a median of 22 months. In multivariate analysis, older age (hazard ratio 1.8), lobular histology (hazard ratio 2.08), triple-negative subtype (hazard ratio 2.25), liver metastases (hazard ratio 1.6) and unmarried patients (hazard ratio 1.39) had significantly shorter OS. Although the prognosis of patients with BMIBCD is generally poor, 20.7% were still alive 3 years after the diagnosis. There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS are age at diagnosis, marital status, histology and liver metastases. Copyright © 2017 Elsevier Ltd. All rights reserved.
Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial.

PubMed

Earl, Helena M; Hiller, Louise; Dunn, Janet A; Blenkinsop, Clare; Grybowicz, Louise; Vallier, Anne-Laure; Abraham, Jean; Thomas, Jeremy; Provenzano, Elena; Hughes-Davies, Luke; Gounaris, Ioannis; McAdam, Karen; Chan, Stephen; Ahmad, Rizvana; Hickish, Tamas; Houston, Stephen; Rea, Daniel; Bartlett, John; Caldas, Carlos; Cameron, David A; Hayward, Larry

2015-06-01

The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer. In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m(2) once every 21 days) followed by three cycles of fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235). Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18-27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13-21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]). Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and
HER2 induces expression of leptin in human breast epithelial cells.

PubMed

Cha, Yujin; Kang, Youjin; Moon, Aree

2012-12-01

A close association between the obesity hormone leptin and breast cancer progression has been suggested. The present study investigated the molecular mechanism for enhanced leptin expression in breast cancer cells and its functional significance in breast cancer aggressiveness. We examined whether leptin expression level is affected by the oncoprotein human epidermal growth factor receptor2 (HER2), which is overexpressed in ∼30% of breast tumors. Here, we report, for the first time, that HER2 induces transcriptional activation of leptin in MCF10A human breast epithelial cells. We also showed that p38 mitogen-activated protein kinase signaling was involved in leptin expression induced by HER2. We showed a crucial role of leptin in the invasiveness of HER2-MCF10A cells using an siRNA molecule targeting leptin. Taken together, the results indicate a molecular link between HER2 and leptin, providing supporting evidence that leptin represents a target for breast cancer therapy. [BMB Reports 2012; 45(12): 719-723].
HER2 induces expression of leptin in human breast epithelial cells

PubMed Central

Cha, Yujin; Kang, Youjin; Moon, Aree

2012-01-01

A close association between the obesity hormone leptin and breast cancer progression has been suggested. The present study investigated the molecular mechanism for enhanced leptin expression in breast cancer cells and its functional significance in breast cancer aggressiveness. We examined whether leptin expression level is affected by the oncoprotein human epidermal growth factor receptor2 (HER2), which is overexpressed in ∼30% of breast tumors. Here, we report, for the first time, that HER2 induces transcriptional activation of leptin in MCF10A human breast epithelial cells. We also showed that p38 mitogen-activated protein kinase signaling was involved in leptin expression induced by HER2. We showed a crucial role of leptin in the invasiveness of HER2-MCF10A cells using an siRNA molecule targeting leptin. Taken together, the results indicate a molecular link between HER2 and leptin, providing supporting evidence that leptin represents a target for breast cancer therapy. [BMB Reports 2012; 45(12): 719-723] PMID:23261058
Could HER2 Heterogeneity Open New Therapeutic Options in Patients with HER2-Primary Breast Cancer

DTIC Science & Technology

2015-10-01

purpose of this study is to determine if targeted imaging with a HER2 targeting PET tracer can detect HER2-positive metastases in patients with HER2... PET /CT. Two of five patients with suspicious foci had biopsy proven HER2-positive metastases. In this early stage clinical trial, 89 Zr-trastuzumab... PET /CT may detect HER2-positive metastases in patients with HER2-negtive primary breast cancer. This is an initial proof-of-concept that targeted

Primary squamous cell carcinoma of the breast with unusual basal-HER2 phenotype.

PubMed

Shui, Ruohong; Li, Anqi; Yang, Fei; Zhou, Xiaoyan; Yu, Baohua; Xu, Xiaoli; Yang, Wentao

2014-01-01

To report three cases of primary squamous cell carcinoma of the breast with an unusual "basal-HER2" phenotype. Clinical data were analyzed. Morphological features were observed. Immunohistochemical study for ER, PR, HER2, Ki-67, CK 5/6, CK10/13, CK14, EGFR, P63 and FISH detection of HER2 gene amplification were performed. Three patients were all female with 26, 57 and 66 years old. The tumors were 3 cm, 4 cm and 5 cm in size respectively. Morphologically, all three tumors were pure squamous cell carcinoma and entirely composed metaplastic squamous cells. Two tumors were moderately differentiated and one was poorly differentiated. All three patients were positive for P63 or CK10/13. All three tumors exhibited basal-HER2 phenotype: negative for ER and PR, positive for HER2 protein and HER2 gene amplification, and positive for at least two basal markers. SCC with basal-HER2 phenotype is an extremely rare subset of breast carcinoma. Since it may have worse prognosis than typical basal-like SCC, recognization of this unusual SCC in routine work may have obvious clinical significance.
A Study of Neoadjuvant Paclitaxel in Combination With Bavituximab in Early- Stage Triple- Negative Breast Cancer

ClinicalTrials.gov

2017-03-08

Breast Cancer; Triple Negative Breast Neoplasms; Triple-Negative Breast Neoplasm; Triple-Negative Breast Cancer; Triple Negative Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Neoplasms; ER-Negative PR-Negative HER2-Negative Breast Cancer
HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

PubMed Central

Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

2015-01-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790
HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

PubMed

Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

2015-09-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.
NatHER: protocol for systematic evaluation of trends in survival among patients with HER2-positive advanced breast cancer.

PubMed

Korner, Eli J; Morris, Anne; Allen, Isabel Elaine; Hurvitz, Sara; Beattie, Mary S; Kalesan, Bindu

2015-10-01

Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. This study will evaluate current and evolving trends in survival associated with
A FISH-based method for assessment of HER-2 amplification status in breast cancer circulating tumor cells following CellSearch isolation.

PubMed

Frithiof, Henrik; Aaltonen, Kristina; Rydén, Lisa

2016-01-01

Amplification of the HER-2/neu ( HER-2 ) proto-oncogene occurs in 10%-15% of primary breast cancer, leading to an activated HER-2 receptor, augmenting growth of cancer cells. Tumor classification is determined in primary tumor tissue and metastatic biopsies. However, malignant cells tend to alter their phenotype during disease progression. Circulating tumor cell (CTC) analysis may serve as an alternative to repeated biopsies. The Food and Drug Administration-approved CellSearch system allows determination of the HER-2 protein, but not of the HER-2 gene. The aim of this study was to optimize a fluorescence in situ hybridization (FISH)-based method to quantitatively determine HER-2 amplification in breast cancer CTCs following CellSearch-based isolation and verify the method in patient samples. Using healthy donor blood spiked with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer cell lines, SKBr-3 and BT-474, and a corresponding negative control (the HER-2-negative MCF-7 cell line), an in vitro CTC model system was designed. Following isolation in the CellSearch system, CTC samples were further enriched and fixed on microscope slides. Immunocytochemical staining with cytokeratin and 4',6-diamidino-2'-phenylindole dihydrochloride identified CTCs under a fluorescence microscope. A FISH-based procedure was optimized by applying the HER2 IQFISH pharmDx assay for assessment of HER-2 amplification status in breast cancer CTCs. A method for defining the presence of HER-2 amplification in single breast cancer CTCs after CellSearch isolation was established using cell lines as positive and negative controls. The method was validated in blood from breast cancer patients showing that one out of six patients acquired CTC HER-2 amplification during treatment against metastatic disease. HER-2 amplification status of CTCs can be determined following CellSearch isolation and further enrichment. FISH is superior to protein assessment of HER-2 status in
Keratin 17 is overexpressed and predicts poor survival in estrogen receptor-negative/human epidermal growth factor receptor-2-negative breast cancer.

PubMed

Merkin, Ross D; Vanner, Elizabeth A; Romeiser, Jamie L; Shroyer, A Laurie W; Escobar-Hoyos, Luisa F; Li, Jinyu; Powers, Robert S; Burke, Stephanie; Shroyer, Kenneth R

2017-04-01

Clinicopathological features of breast cancer have limited accuracy to predict survival. By immunohistochemistry (IHC), keratin 17 (K17) expression has been correlated with triple-negative status (estrogen receptor [ER]/progesterone receptor/human epidermal growth factor receptor-2 [HER2] negative) and decreased survival, but K17 messenger RNA (mRNA) expression has not been evaluated in breast cancer. K17 is a potential prognostic cancer biomarker, targeting p27, and driving cell cycle progression. This study compared K17 protein and mRNA expression to ER/progesterone receptor/HER2 receptor status and event-free survival. K17 IHC was performed on 164 invasive breast cancers and K17 mRNA was evaluated in 1097 breast cancers. The mRNA status of other keratins (16/14/9) was evaluated in 113 ER - /HER2 - ductal carcinomas. IHC demonstrated intense cytoplasmic and membranous K17 localization in myoepithelial cells of benign ducts and lobules and tumor cells of ductal carcinoma in situ. In ductal carcinomas, K17 protein was detected in most triple-negative tumors (28/34, 82%), some non-triple-negative tumors (52/112, 46%), but never in lobular carcinomas (0/15). In ductal carcinomas, high K17 mRNA was associated with reduced 5-year event-free survival in advanced tumor stage (n = 149, hazard ratio [HR] = 3.68, P = .018), and large (n = 73, HR = 3.95, P = .047), triple-negative (n = 103, HR = 2.73, P = .073), and ER - /HER2 - (n = 113, HR = 2.99, P = .049) tumors. There were significant correlations among keratins 17, 16, 14, and 9 mRNA levels suggesting these keratins (all encoded on chromosome 17) could be coordinately expressed in breast cancer. Thus, K17 is expressed in a subset of triple-negative breast cancers, and is a marker of poor prognosis in patients with advanced stage and ER - /HER2 - breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.
Human epidermal growth factor receptor 2 testing in invasive breast cancer: should histological grade, type and oestrogen receptor status influence the decision to repeat testing?

PubMed

Rakha, Emad A; Pigera, Marian; Shin, Sandra J; D'Alfonso, Timothy; Ellis, Ian O; Lee, Andrew H S

2016-07-01

The recent American Society of Clinical Oncology/College of American Pathologists guidelines for human epidermal growth factor receptor 2 (HER2) testing in breast cancer recommend repeat testing based on tumour grade, tumour type, and hormone receptor status. The aim of this study was to test the value of these criteria. HER2 status was concordant in the core biopsies and excision specimens in 392 of 400 invasive carcinomas. The major reasons for discordance were amplification around the cut-off for positivity and tumour heterogeneity. Of 116 grade 3 carcinomas that were HER2-negative in the core biopsy, four were HER2-positive in the excision specimen. Three of these four either showed borderline negative amplification in the core biopsy or were heterogeneous. None of the 55 grade 1 carcinomas were HER2-positive. Review of repeat testing of HER2 in routine practice suggested that it may also be of value for multifocal tumours and if recommended by the person assessing the in-situ hybridization. Mandatory repeat HER2 testing of grade 3 HER2-negative carcinomas is not appropriate. This is particularly true if repeat testing is performed after borderline negative amplification in the core biopsy or in HER2-negative heterogeneous carcinomas. © 2015 John Wiley & Sons Ltd.
Neratinib Efficacy and Circulating Tumor DNA Detection of HER2 Mutations in HER2 Nonamplified Metastatic Breast Cancer.

PubMed

Ma, Cynthia X; Bose, Ron; Gao, Feng; Freedman, Rachel A; Telli, Melinda L; Kimmick, Gretchen; Winer, Eric; Naughton, Michael; Goetz, Matthew P; Russell, Christy; Tripathy, Debu; Cobleigh, Melody; Forero, Andres; Pluard, Timothy J; Anders, Carey; Niravath, Polly Ann; Thomas, Shana; Anderson, Jill; Bumb, Caroline; Banks, Kimberly C; Lanman, Richard B; Bryce, Richard; Lalani, Alshad S; Pfeifer, John; Hayes, Daniel F; Pegram, Mark; Blackwell, Kimberly; Bedard, Philippe L; Al-Kateb, Hussam; Ellis, Matthew J C

2017-10-01

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2 mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2 mut detection. Experimental Design: Tumor tissue positive for HER2 mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2 mut ). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2 mut (lobular 7.8% vs. ductal 1.6%; P = 0.026). Thirteen additional HER2 mut cases were identified locally. Twenty-one of these 22 HER2 mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31-74) years and three (2-10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%-55%], including one CR, one PR, and three SD ≥24 weeks. Median PFS was 16 (90% CI, 8-31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2 mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%-94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%-100%). In addition, ctDNA HER2 mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2 mut , nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2 mut cancers for clinical trial participation. Clin Cancer Res; 23(19); 5687-95. ©2017 AACR . ©2017 American Association for Cancer Research.
HER2 and β-catenin protein location: importance in the prognosis of breast cancer patients and their correlation when breast cancer cells suffer stressful situations.

PubMed

Cuello-Carrión, F Darío; Shortrede, Jorge E; Alvarez-Olmedo, Daiana; Cayado-Gutiérrez, Niubys; Castro, Gisela N; Zoppino, Felipe C M; Guerrero, Martín; Martinis, Estefania; Wuilloud, Rodolfo; Gómez, Nidia N; Biaggio, Verónica; Orozco, Javier; Gago, Francisco E; Ciocca, Leonardo A; Fanelli, Mariel A; Ciocca, Daniel R

2015-02-01

In human breast cancer, β-catenin localization has been related with disease prognosis. Since HER2-positive patients are an important subgroup, and that in breast cancer cells a direct interaction of β-catenin/HER2 has been reported, in the present study we have explored whether β-catenin location is related with the disease survival. The study was performed in a tumor bank from patients (n = 140) that did not receive specific anti-HER2 therapy. The proteins were detected by immunohistochemistry in serial sections, 47 (33.5%) patients were HER2-positive with a long follow-up. HER2-positive patients that displayed β-catenin at the plasma membrane (completely surrounding the tumour cells) showed a significant better disease-free survival and overall survival than the patients showing the protein on other locations. Then we explored the dynamics of the co-expression of β-catenin and HER2 in human MCF-7 and SKBR3 cells exposed to different stressful situations. In untreated conditions MCF-7 and SKBR3 cells showed very different β-catenin localization. In MCF-7 cells, cadmium administration caused a striking change in β-catenin localization driving it from plasma membrane to cytoplasmic and perinuclear areas and HER2 showed a similar localization patterns. The changes induced by cadmium were compared with heat shock, H2O2 and tamoxifen treatments. In conclusion, this study shows the dynamical associations of HER2 and β-catenin and their changes in subcellular localizations driven by stressful situations. In addition, we report for the first time the correlation between plasma membrane associated β-catenin in HER2-positive breast cancer and survival outcome, and the importance of the protein localization in breast cancer samples.
Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells.

PubMed

Ma, Jui-Wen; Hung, Chao-Ming; Lin, Ying-Chao; Ho, Chi-Tang; Kao, Jung-Yie; Way, Tzong-Der

2016-09-13

Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER-2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These findings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.
Comparison of central HER2 testing with quantitative total HER2 expression and HER2 homodimer measurements using a novel proximity-based assay.

PubMed

Huang, Weidong; Reinholz, Monica; Weidler, Jodi; Yolanda, Lie; Paquet, Agnes; Whitcomb, Jeannette; Lingle, Wilma; Jenkins, Robert B; Chen, Beiyun; Larson, Jeffrey S; Tan, Yuping; Sherwood, Thomas; Bates, Michael; Perez, Edith A

2010-08-01

The accuracy and reliability of immunohistochemical analysis and in situ hybridization for the assessment of HER2 status remains a subject of debate. We developed a novel assay (HERmark Breast Cancer Assay, Monogram Biosciences, South San Francisco, CA) that provides precise quantification of total HER2 protein expression (H2T) and HER2 homodimers (H2D) in formalin-fixed, paraffin-embedded tissue specimens. H2T and H2D results of 237 breast cancers were compared with those of immunohistochemical studies and fluorescence in situ hybridization (FISH) centrally performed at the Mayo Clinic, Rochester, MN. H2T described a continuum across a wide dynamic range ( approximately 2.5 log). Excluding the equivocal cases, HERmark showed 98% concordance with immunohistochemical studies for positive and negative assay values. For the 94 immunohistochemically equivocal cases, 67% and 39% concordance values were observed between HERmark and FISH for positive and negative assay values, respectively. Polysomy 17 in the absence of HER2 gene amplification did not result in HER2 overexpression as evaluated quantitatively using the HERmark assay.
Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis.

PubMed

Hayashi, Naoki; Niikura, Naoki; Masuda, Norikazu; Takashima, Seiki; Nakamura, Rikiya; Watanabe, Ken-ichi; Kanbayashi, Chizuko; Ishida, Mayumi; Hozumi, Yasuo; Tsuneizumi, Michiko; Kondo, Naoto; Naito, Yoichi; Honda, Yayoi; Matsui, Akira; Fujisawa, Tomomi; Oshitanai, Risa; Yasojima, Hiroyuki; Yamauchi, Hideko; Saji, Shigehira; Iwata, Hiroji

2015-01-01

The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20-86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER-HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER-HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p < 0.001) and ER-HER2+ (p = 0.018) groups. Treatment with trastuzumab before developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p < 0.001). For HER2-positive patients with brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.
HER2-positive breast cancer, how far away from the cure?-on the current situation of anti-HER2 therapy in breast cancer treatment and survival of patients.

PubMed

Liao, Ning

2016-06-01

With the diagnosis and treatment of tumor enter into the area of precision medical, based on selected targeted molecular typing of patients with individualized diagnosis and treatment play an important role. HER gene encoded epidermal growth factor receptor 2 (HER2) leading to increased early distant metastasis of breast cancer in patients and poor prognosis. However, a number of clinical studies provided evidence-based anti-HER2 targeted therapy and confirmed the benefit of anti-HER2 targeted therapy in patient survival. In recent years, through the tireless efforts of scholars in the field of breast cancer in our country, the whole diagnosis and treatment of breast cancer has accomplished an international standard. But based on a variety of factors, the anti-HER2 targeted therapy between China and the developed countries, and between different areas in China still exists certain gaps, is now a problem need to be solved. This article will analyzing the diagnostic and treatment on HER2-positive breast cancer in the United States and China, exploring reasons and looking for answers to narrow down the gap in the treatment of HER2-positive breast cancer between China and the United States. Improve the anti-HER2 targeted therapy in our country, let the patients get maximum benefit from anti-HER2 targeted therapy.
PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance.

PubMed

Stern, Howard M; Gardner, Humphrey; Burzykowski, Tomasz; Elatre, Wafaa; O'Brien, Carol; Lackner, Mark R; Pestano, Gary A; Santiago, Angela; Villalobos, Ivonne; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Nuciforo, Paolo; Bee, Valerie; Mackey, John; Slamon, Dennis J; Press, Michael F

2015-05-01

To investigate the clinical relevance of PTEN in HER2-amplified and HER2-nonamplified disease. We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN immunohistochemical (IHC) assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple-negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared with patients with tumors exhibiting any PTEN staining patterns (low, moderate, or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population, there were no statistically significant differences in clinical outcome based on PTEN status. This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. ©2015 American Association for Cancer Research.
PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance

PubMed Central

Stern, Howard M.; Gardner, Humphrey; Burzykowski, Tomasz; Elatre, Wafaa; O’Brien, Carol; Lackner, Mark R.; Pestano, Gary A.; Santiago, Angela; Villalobos, Ivonne; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Nuciforo, Paolo; Bee, Valerie; Mackey, John; Slamon, Dennis J.; Press, Michael F.

2015-01-01

Purpose To investigate the clinical relevance of PTEN in HER2-amplified and HER2-non-amplified disease. Experimental Design We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN IHC assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. Results In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared to patients with tumors exhibiting any PTEN staining patterns (low, moderate or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population there were no statistically significant differences in clinical outcome based on PTEN status. Conclusions This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. PMID:25649019
Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

PubMed

Chen, Albert C; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K; Gutierrez, M Carolina; Osborne, C Kent; Schiff, Rachel

2012-07-01

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.
Upregulation of Mucin4 in ER-positive/HER2-Overexpressing Breast Cancer Xenografts with Acquired Resistance to Endocrine and HER2-Targeted Therapies

PubMed Central

Chen, Albert C.; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J.; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K.; Gutierrez, M. Carolina; Osborne, C. Kent; Schiff, Rachel

2012-01-01

Background We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. Methods MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin & eosin and mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER and HER2 signaling pathways was measured by immunohistochemistry and Western blotting. Results The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam+LT) or estrogen deprivation (ED+LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype—a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene, progesterone receptor. Conclusions Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive. PMID:22644656
Validation of a fully automated HER2 staining kit in breast cancer.

PubMed

Moelans, Cathy B; Kibbelaar, Robby E; van den Heuvel, Marius C; Castigliego, Domenico; de Weger, Roel A; van Diest, Paul J

2010-01-01

Testing for HER2 amplification and/or overexpression is currently routine practice to guide Herceptin therapy in invasive breast cancer. At present, HER2 status is most commonly assessed by immunohistochemistry (IHC). Standardization of HER2 IHC assays is of utmost clinical and economical importance. At present, HER2 IHC is most commonly performed with the HercepTest which contains a polyclonal antibody and applies a manual staining procedure. Analytical variability in HER2 IHC testing could be diminished by a fully automatic staining system with a monoclonal antibody. 219 invasive breast cancers were fully automatically stained with the monoclonal antibody-based Oracle HER2 Bond IHC kit and manually with the HercepTest. All cases were tested for amplification with chromogenic in situ hybridization (CISH). HercepTest yielded an overall sharper membrane staining, with less cytoplasmic and stromal background than Oracle in 17% of cases. Overall concordance between both IHC techniques was 89% (195/219) with a kappa value of 0.776 (95% CI 0.698-0.854), indicating a substantial agreement. Most (22/24) discrepancies between HercepTest and Oracle showed a weaker staining for Oracle. Thirteen of the 24 discrepant cases were high-level HER2 amplified by CISH, and in 12 of these HercepTest IHC better reflected gene amplification status. All the 13 HER2 amplified discrepant cases were at least 2+ by HercepTest, while 10/13 of these were at least 2+ for Oracle. Considering CISH as gold standard, sensitivity of HercepTest and Oracle was 91% and 83%, and specificity was 94% and 98%, respectively. Positive and negative predictive values for HercepTest and Oracle were 90% and 95% for HercepTest and 96% and 91% for Oracle, respectively. Fully-automated HER2 staining with the monoclonal antibody in the Oracle kit shows a high level of agreement with manual staining by the polyclonal antibody in the HercepTest. Although Oracle shows in general some more cytoplasmic staining and may
cSrc and Her2 Signaling Pathways Cooperate with Estrogen to Promote ER Phosphorylation, Ubiquitination and Proteolysis in ER Negative Breast Cancers

DTIC Science & Technology

2007-03-01

68 HR positive tumors were compared with 23 ’triple receptor-negative’ tumors (negative for ER and PR by IHC and for HER2 by FISH ), Src levels were...47. Rosen,N., Bolen,J.B., Schwartz,A.M., Cohen,P., DeSeau,V., and Israel ,M.A. 1986. Analysis of pp60c-src protein kinase activity in human tumor...www.aacrjournals.org cancers has been associated with poor prognosis (41, 42). Cyclin D1 deficient mice are resistant to breast cancers induced by transgenic ErbB2/neu

Membrane Estrogen and HER-2 Receptors in Human Breast Cancer

DTIC Science & Technology

2002-07-01

activation of G-proteins, adenylate cyclase, inositol phosphate, calcium homeostasis and/or MAP kinase. These interactions may promote phosphorylation of ER...of breast cancer cells and interact with transmembrane HER-2 growth factor receptors. Expression of HER-2 receptors occurs in many breast cancers...reports of significant cross-talk and interaction between erb B (HER) pathways and estrogen receptor signaling (3,24,27,34-36). It is generally held
Melatonin Represses Metastasis in Her2-postive Human Breast Cancer Cells by Suppressing RSK2 Expression

PubMed Central

Mao, Lulu; Summers, Whitney; Xiang, Shulin; Yuan, Lin; Dauchy, Robert T.; Reynolds, Amberly; Wren-Dail, Melissa A.; Pointer, David; Frasch, Tripp; Blask, David E.; Hill, Steven M.

2016-01-01

The importance of the circadian/melatonin signal in suppressing the metastatic progression of breast and other cancers has been reported by numerous laboratories including our own. Currently, the mechanisms underlying the anti-metastatic actions of melatonin have not been well established. In the present study, the anti-metastatic actions of melatonin were evaluated and compared on the ERα-negative, Her2-positive SKBR-3 breast tumor cell line and ERα-positive MCF-7 cells overexpressing a constitutively active HER2.1 construct (MCF-7Her2.1 cells). Activation of Her2 is reported to induce the expression and/or phosphorylation-dependent activation of numerous kinases and transcription factors that drive drug resistance and metastasis in breast cancer. A key signaling node activated by the Her2/Mapk/Erk pathway is Rsk2, which has been shown to induce numerous signaling pathways associated with the development of epithelial-to-mesenchymal transition (EMT) and metastasis including: Creb, Stat3, cSrc, Fak, Pax, Fascin, and actin polymerization. The data demonstrate that melatonin (both endogenous and exogenous) significantly represses this invasive/metastatic phenotype through a mechanism that involves the suppression of EMT, either by promoting mesenchymal-to-epithelial transition (MET), and/or by inhibiting key signaling pathways involved in later stages of metastasis. These data, combined with our earlier in vitro studies, support the concept that maintenance of elevated and extended duration of nocturnal melatonin levels plays a critical role in repressing the metastatic progression of breast cancer. PMID:27535706
Anti-Tumor Effects of Peptide Therapeutic and Peptide Vaccine Antibody Co-targeting HER-1 and HER-2 in Esophageal Cancer (EC) and HER-1 and IGF-1R in Triple-Negative Breast Cancer (TNBC).

PubMed

Overholser, Jay; Ambegaokar, Kristen Henkins; Eze, Siobhan M; Sanabria-Figueroa, Eduardo; Nahta, Rita; Bekaii-Saab, Tanios; Kaumaya, Pravin T P

2015-07-06

Despite the promise of targeted therapies, there remains an urgent need for effective treatment for esophageal cancer (EC) and triple-negative breast cancer (TNBC). Current FDA-approved drugs have significant problems of toxicity, safety, selectivity, efficacy and development of resistance. In this manuscript, we demonstrate that rationally designed peptide vaccines/mimics are a viable therapeutic strategy for blocking aberrant molecular signaling pathways with high affinity, specificity, potency and safety. Specifically, we postulate that novel combination treatments targeting members of the EGFR family and IGF-1R will yield significant anti-tumor effects in in vitro models of EC and TNBC possibly overcoming mechanisms of resistance. We show that the combination of HER-1 and HER-2 or HER-1 and IGF-1R peptide mimics/vaccine antibodies exhibited enhanced antitumor properties with significant inhibition of tumorigenesis in OE19 EC and MDA-MB-231 TNBC cell lines. Our work elucidates the mechanisms of HER-1/IGF-1R and HER-1/HER-2 signaling in these cancer cell lines, and the promising results support the rationale for dual targeting with HER-1 and HER-2 or IGF-1R as an improved treatment regimen for advanced therapy tailored to difference types of cancer.
Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

PubMed

Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

2013-05-28

Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ≥3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks
Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases.

PubMed

Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A; Frank, Richard T; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A; Kim, Julius W; Han, Yu; Yu, Dihua; Ahmed, Atique U; Aboody, Karen S; Lesniak, Maciej S

2015-10-01

The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation. © 2015 AlphaMed Press.
Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer.

PubMed

von Minckwitz, Gunter; Procter, Marion; de Azambuja, Evandro; Zardavas, Dimitrios; Benyunes, Mark; Viale, Giuseppe; Suter, Thomas; Arahmani, Amal; Rouchet, Nathalie; Clark, Emma; Knott, Adam; Lang, Istvan; Levy, Christelle; Yardley, Denise A; Bines, Jose; Gelber, Richard D; Piccart, Martine; Baselga, Jose

2017-07-13

Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or
Analysis of HER2 status in breast carcinoma by fully automated HER2 fluorescence in situ hybridization (FISH): comparison of two immunohistochemical tests and manual FISH.

PubMed

Yoon, Nara; Do, In-Gu; Cho, Eun Yoon

2014-09-01

Easy and accurate HER2 testing is essential when considering the prognostic and predictive significance of HER2 in breast cancer. The use of a fully automated, quantitative FISH assay would be helpful to detect HER2 amplification in breast cancer tissue specimens with reduced inter-laboratory variability. We compared the concordance of HER2 status as assessed by an automated FISH staining system to manual FISH testing. Using 60 formalin-fixed paraffin-embedded breast carcinoma specimens, we assessed HER2 immunoexpression with two antibodies (DAKO HercepTest and CB11). In addition, HER2 status was evaluated with automated FISH using the Leica FISH System for BOND and a manual FISH using the Abbott PathVysion DNA Probe Kit. All but one specimen were successfully stained using both FISH methods. When the data were divided into two groups according to HER2/CEP17 ratio, positive and negative, the results from both the automated and manual FISH techniques were identical for all 59 evaluable specimens. The HER2 and CEP17 copy numbers and HER2/CEP17 ratio showed great agreement between both FISH methods. The automated FISH technique was interpretable with signal intensity similar to those of the manual FISH technique. In contrast with manual FISH, the automated FISH technique showed well-preserved architecture due to low membrane digestion. HER2 immunohistochemistry and FISH results showed substantial significant agreement (κ = 1.0, p < 0.001). HER2 status can be reliably determined using a fully automated HER2 FISH system with high concordance to the well-established manual FISH method. Because of stable signal intensity and high staining quality, the automated FISH technique may be more appropriate than manual FISH for routine applications. © 2013 APMIS. Published by John Wiley & Sons Ltd.
Distinct apoptotic blocks mediate resistance to panHER inhibitors in HER2+ breast cancer cells.

PubMed

Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur

2018-05-04

Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2+ breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR-75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2+ breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells. Copyright © 2018 Elsevier B.V. All rights reserved.
Update on HER2 testing for breast and upper gastrointestinal tract cancers.

PubMed

Ross, Jeffrey S

2011-06-01

With the regulatory approvals in Europe and the USA of trastuzumab-based anti-HER2 targeted therapy for upper gastrointestinal cancers in 2010, HER2 testing has now become universal for newly diagnosed cases of both breast cancer and adenocarcinomas of esophagus, stomach and gastroesophageal origin. In the 12 years or more since the approval of trastuzumab for breast cancer, general refinements in approaches to HER2 testing, including a greater understanding of the implications of preanalytic factors impacting the test results and the application of standardization of reporting of HER2 test results, have taken place. There has also been continuing development in breast cancer with the introduction of new HER2 tests, including non-FISH tests, dimerization assays, phosphorylated HER2 receptor tests, mRNA-based tests, HER2 gene sequencing tests and the application of HER2 testing to circulating tumor cells. Most recently, the introduction of HER2 testing for upper gastrointentinal malignancies has emphasized the need for performing and interpreting slide-based assays in a manner unique to these specimens and not to apply the breast cancer testing protocols to esophageal and gastric adenocarcinomas.
Tumour Necrosis Factor-α Gene Polymorphism Is Associated with Metastasis in Patients with Triple Negative Breast Cancer.

PubMed

Li, Hui-Hui; Zhu, Hui; Liu, Li-Sheng; Huang, Yong; Guo, Jun; Li, Jie; Sun, Xin-Ping; Chang, Chun-Xiao; Wang, Zhe-Hai; Zhai, Kan

2015-07-13

Tumour necrosis factor-α (TNF-α) is critical in the regulation of inflammation and tumour progression. TNF-α-308G > A is associated with constitutively elevated TNF-α expression. The purpose of this study was to assess the association between TNF-α-308G > A and breast cancer (BC) risk by subtype and the connection between genotypes and clinical features of BC. A total of 768 patients and 565 controls were enrolled in this study, and genotypes were detected using the TaqMan assay. No effect on susceptibility for any BC subtype was found for the TNF-α-308 polymorphism in our study or in the pooled meta-analysis. This polymorphism was shown to be associated with age at menarche in all BC and in progesterone receptor-negative BC. Interestingly, triple negative breast cancer (TNBC) patients with TNF-α-308A had an increased risk of distant tumour metastasis (OR = 3.80, 95% CI: 1.31-11.02, P = 0.009). Multi-regression analysis showed that TNF-α-308A was also a risk factor for distant tumour metastasis after adjustment for tumour size and lymph node metastasis status (OR = 6.26, 95% CI: 1.88-20.87, P = 0.003). These findings indicate that TNF-α might play a distinct role in the progression of TNBC, especially in distant tumour metastasis of TNBC.
CRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation.

PubMed

Wang, Huajing; Sun, William

2017-01-28

With the discovery of the CRISPR/Cas9 technology, genome editing could be performed in a rapid, precise and effective manner. Its potential applications in functional interrogation of cancer-causing genes and cancer therapy have been extensively explored. In this study, we demonstrated the use of the CRISPR/Cas9 system to directly target the oncogene HER2. Directing Cas9 to exons of the HER2 gene inhibited cell growth in breast cancer cell lines that harbor amplification of the HER2 locus. The inhibitory effect was potentiated with the addition of PARP inhibitors. Unexpectedly, CRISPR-induced mutations did not significantly affect the level of HER2 protein expression. Instead, CRISPR targeting appeared to exert its effect through a dominant negative mutation. This HER2 mutant interfered with the MAPK/ERK axis of HER2 downstream signaling. Our work provides a novel mechanism underlying the anti-cancer effects of HER2-targeting by CRISPR/Cas9, which is distinct from the clinical drug Herceptin. In addition, it opens up the possibility that incomplete CRISPR targeting of certain oncogenes could still have therapeutic value by generation of dominant negative mutants. Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

ClinicalTrials.gov

2018-03-07

Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer
Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer.

PubMed

Duchnowska, Renata; Loibl, Sibylle; Jassem, Jacek

2018-06-01

Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients. Copyright © 2018 Elsevier Ltd. All rights reserved.
Predictive value of quantitative HER2, HER3 and p95HER2 levels in HER2-positive advanced breast cancer patients treated with lapatinib following progression on trastuzumab.

PubMed

Duchnowska, Renata; Sperinde, Jeff; Czartoryska-Arłukowicz, Bogumiła; Myśliwiec, Paulina; Winslow, John; Radecka, Barbara; Petropoulos, Christos; Demlova, Regina; Orlikowska, Marlena; Kowalczyk, Anna; Lang, Istvan; Ziółkowska, Barbara; Dębska-Szmich, Sylwia; Merdalska, Monika; Grela-Wojewoda, Aleksandra; Żawrocki, Anton; Biernat, Wojciech; Huang, Weidong; Jassem, Jacek

2017-11-28

Lapatinib is a HER1 and HER2 tyrosine kinase inhibitor (TKI) approved in second line treatment of advanced or metastatic breast cancer following progression on trastuzumab-containing therapy. Biomarkers for activity of lapatinib and other TKIs are lacking. Formalin-fixed, paraffin-embedded primary tumor samples were obtained from 189 HER2-positive patients treated with lapatinib plus capecitabine following progression on trastuzumab. The HERmark ® Breast Cancer Assay was used to quantify HER2 protein expression. HER3 and p95HER2 protein expression was quantified using the VeraTag ® technology. Overall survival (OS) was inversely correlated with HER2 (HR = 1.9/log; P = 0.009) for patients with tumors above the cut-off positivity level by the HERmark assay. OS was significantly shorter for those with above median HER2 levels (HR = 1.7; P = 0.015) and trended shorter for those below the cut-off level of positivity by the HERmark assay (HR = 1.7; P = 0.057) compared to cases with moderate HER2 overexpression. The relationship between HER2 protein expression and OS was best captured with a U-shaped parabolic function (P = 0.004), with the best prognosis at moderate levels of HER2 protein overexpression. In a multivariate model including HER2, increasing p95HER2 expression was associated with longer OS (HR = 0.35/log; P = 0.027). Continuous HER3 did not significantly correlate with OS. Patients with moderately overexpressed HER2 levels and high p95HER2 expression may have best outcomes while receiving lapatinib following progression on trastuzumab. Further study is warranted to explore the predictive utility of quantitative HER2 and p95HER2 in guiding HER2-directed therapies.
Impact of chemotherapy relative dose intensity on cause-specific and overall survival for stage I-III breast cancer: ER+/PR+, HER2- vs. triple-negative.

PubMed

Zhang, Lu; Yu, Qingzhao; Wu, Xiao-Cheng; Hsieh, Mei-Chin; Loch, Michelle; Chen, Vivien W; Fontham, Elizabeth; Ferguson, Tekeda

2018-05-01

To investigate the impact of chemotherapy relative dose intensity (RDI) on cause-specific and overall survival for stage I-III breast cancer: estrogen receptor or progesterone receptor positive, human epidermal-growth factor receptor negative (ER+/PR+ and HER2-) vs. triple-negative (TNBC) and to identify the optimal RDI cut-off points in these two patient populations. Data were collected by the Louisiana Tumor Registry for two CDC-funded projects. Women diagnosed with stage I-III ER+/PR+, HER2- breast cancer, or TNBC in 2011 with complete information on RDI were included. Five RDI cut-off points (95, 90, 85, 80, and 75%) were evaluated on cause-specific and overall survival, adjusting for multiple demographic variables, tumor characteristics, comorbidity, use of granulocyte-growth factor/cytokines, chemotherapy delay, chemotherapy regimens, and use of hormone therapy. Cox proportional hazards models and Kaplan-Meier survival curves were estimated and adjusted by stabilized inverse probability treatment weighting (IPTW) of propensity score. Of 494 ER+/PR+, HER2- patients and 180 TNBC patients, RDI < 85% accounted for 30.4 and 27.8%, respectively. Among ER+/PR+, HER2- patients, 85% was the only cut-off point at which the low RDI was significantly associated with worse overall survival (HR = 1.93; 95% CI 1.09-3.40). Among TNBC patients, 75% was the cut-off point at which the high RDI was associated with better cause-specific (HR = 2.64; 95% CI 1.09, 6.38) and overall survival (HR = 2.39; 95% CI 1.04-5.51). Higher RDI of chemotherapy is associated with better survival for ER+/PR+, HER2- patients and TNBC patients. To optimize survival benefits, RDI should be maintained ≥ 85% in ER+/PR+, HER2- patients, and ≥ 75% in TNBC patients.
Correlation Between Quantitative HER-2 Protein Expression and Risk for Brain Metastases in HER-2+ Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy

PubMed Central

Duchnowska, Renata; Biernat, Wojciech; Szostakiewicz, Barbara; Sperinde, Jeff; Piette, Fanny; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr; Jankowski, Tomasz; Radecka, Barbara; Foszczyńska-Kłoda, Małgorzata; Litwiniuk, Maria; Dȩbska, Sylwia; Weidler, Jodi; Huang, Weidong; Buyse, Marc; Bates, Michael

2012-01-01

Background. Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. Results. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). Conclusions. These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for
Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

PubMed

Duchnowska, Renata; Biernat, Wojciech; Szostakiewicz, Barbara; Sperinde, Jeff; Piette, Fanny; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Czartoryska-Arłukowicz, Bogumiła; Wysocki, Piotr; Jankowski, Tomasz; Radecka, Barbara; Foszczynska-Kłoda, Małgorzata; Litwiniuk, Maria; Debska, Sylwia; Weidler, Jodi; Huang, Weidong; Buyse, Marc; Bates, Michael; Jassem, Jacek

2012-01-01

Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this
Pertuzumab: a new targeted therapy for HER2-positive metastatic breast cancer.

PubMed

Malenfant, Stephanie J; Eckmann, Karen R; Barnett, Chad M

2014-01-01

Trastuzumab, a humanized monoclonal antibody, has become an important targeted therapy for patients with all stages of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. However, primary and acquired resistance to trastuzumab remains a significant problem. Pertuzumab, a humanized monoclonal antibody that binds to a domain of the HER2 receptor separate from trastuzumab, may have the potential to overcome trastuzumab resistance. Clinical trials have shown that pertuzumab can be effectively combined with other biologic therapy or chemotherapy in patients with metastatic HER2-positive breast cancer. Pertuzumab is relatively well tolerated with minimal increases in hematologic and cardiac toxicity observed when added to trastuzumab and/or docetaxel. In addition to becoming the standard of care in combination with docetaxel and trastuzumab in patients with newly diagnosed HER2-positive metastatic breast cancer, clinical trials continue to evaluate pertuzumab in combination with other targeted therapy, chemotherapy, and in patients with early stage breast cancer. These trials will help to further determine the role of pertuzumab in the treatment of HER2-positive breast cancer. © 2013 Pharmacotherapy Publications, Inc.
Importance of confirming HER2 overexpression of recurrence lesion in breast cancer patients.

PubMed

Nakamura, Rikiya; Yamamoto, Naohito; Onai, Yasuhide; Watanabe, Yoshihiro; Kawana, Hidetada; Miyazaki, Masaru

2013-10-01

The systemic management of metastatic breast cancer (MBC) is usually based on ER or HER2 status of the primary tumor. However, the hormonal status or the overexpression of human epidermal growth factor 2 (HER2) may change in every metastatic site because of the effects of the long-term treatment of metastatic cancer with endocrine therapy, chemotherapy, or biological agents. The purpose of this study was to investigate the frequency of change in HER2 expression in primary and distant metastatic tumors in breast cancer patients. Another objective of the study was to examine the effect of the clinical therapy on the basis of HER2 expression in a metastatic tumor. In our hospital between 1991 to December 2010, retrospectively, 156 patients had biopsy or surgical resection of their metastatic site. All sample were analyzed pathologically to confirm metastatic disease and, second, to evaluate HER2 status by immunohistochemistry or by FISH. The recurrence lesions were resected from the breast or lymph node (n = 67, local lesion), brain (n = 27), lung (n = 16), liver (n = 20), bone (n = 16), and from the stomach, intestine, ovary, and uterus (n = 10). Loss, increase, or no change in HER2 overexpression was observed in 3, 5, and 92%, respectively. Positive changes of HER2 in metastatic sites were 3 (4%) local lesion, 3 (11%) brain, 1 (7%) lung, 0 (0%) liver, 2 (17%) bone, and 0 (0%) others. In 3 of these 8 patients, trastuzumab was administered. In 2 of 3 patients, trastuzumab achieved long stable disease. The negative conversion rate of HER2 expression in metastatic lesions was 37% in patients treated with trastuzumab and 6% in those not treated with trastuzumab, a significant difference between the two groups (P < 0.05). The results of this study emphasize the significance of confirming HER2 expression in a recurrence lesion. For patients with positive conversion of HER2 status, more treatment options may be available. On the other hand, the rate of loss of
Determination of HER2 amplification status in breast cancer cells using Raman spectroscopy

NASA Astrophysics Data System (ADS)

Bi, Xiaohong; Rexer, Brent; Arteaga, Carlos L.; Guo, Mingsheng; Li, Ming; Mahadevan-Jansen, Anita

2010-02-01

The overexpression of HER2 (human epidermal growth factor receptor 2) in breast cancer is associated with increased disease recurrence and worse prognosis. Current diagnosis of HER2 positive breast cancer is time consuming with an estimated 20% inaccuracy. Raman spectroscopy is a proven method for pathological diagnosis based on the molecular composition of tissues. This study aimed to determine the feasibility of Raman spectroscopy to differentially identify the amplification of HER2 in cells. Three cell lines including BT474 (HER2 overexpressing breast cancer cell), MCF-10A (human breast epithelial cell), and MCF-10A with overexpressing HER2, were investigated using a bench top confocal Raman system. A diagnostic algorithm based on generalized linear model (GLM) with elastic-net penalties was established to discriminate 318 spectra collected from the cells, and to identify the spectra regions that differentiate the cell lines. The algorithm was able to differentially identify BT474 breast cancer cells with an overall sensitivity of 100% and specificity of 99%. The results demonstrate the capability of Raman spectroscopy to determine HER2 status in cells. Raman spectroscopy shows promise for application in the diagnosis of HER2 positive breast cancer in clinical practice.

Oestrogen receptor negative early operable primary breast cancer in older women-Biological characteristics and long-term clinical outcome.

PubMed

Syed, Binafsha Manzoor; Morgan, Dal; Setty, Tulassi; Green, Andrew R; Paish, Emma C; Ellis, Ian O; Cheung, K L

2017-01-01

Older women are at the greatest risk of breast cancer development and a considerable number present with comorbidities. Although the majority of breast cancers in this age group express oestrogen receptor (ER), which makes endocrine therapy (primary or adjuvant) feasible, given the huge size of the elderly population, there remains a significant number of patients, in absolute term, whose tumours do not express ER and their management is challenging. Of a consecutive series of 1,758 older (≥70 years) women with early operable primary breast cancer managed in a dedicated service from 1973-2010, 252(14.3%) had ER-negative (histochemical (H) score ≤50) tumours. Their clinical outcome was retrospectively reviewed and tumour samples collected from diagnostic core biopsies were analysed for progesterone receptor (PgR), HER2 and Ki67 using immunohistochemistry. The commonest primary treatment was surgery (N = 194, 77%) followed by primary endocrine therapy (14.3%), primary radiotherapy (5.6%) and supportive treatment only (3.1%). Among the patients undergoing surgery, most of them had grade 3 (78.1%) and node-negative disease (62.2%). Some of them (21.1%) received postoperative radiotherapy. At a median follow-up of 37.5 months, 117 patients had died, out of which 48.6% were due to breast cancer. For those who underwent surgery, the regional and local recurrence rates were 2% and 1.1% per annum respectively. For those who received primary endocrine therapy, 38% progressed at 6 months, however all patients who had primary radiotherapy achieved clinical benefit at 6 months. Regardless of treatment given, the 5-year breast cancer specific and overall survival rates were 70% and 50% respectively. Biological analysis based on good quality needle core biopsy specimensfrom181 patients showed that 26.8% (N = 49), 16.9% (N = 31) and 70.7% (N = 70)expressed positivity for PgR, HER2 and Ki67 respectively. No correlation between these biomarkers and breast cancer specific
Targeting Sirna Missiles to Her2+ Breast Cancer

DTIC Science & Technology

2008-06-01

intact and appears to be protected from serum nucleases (Fig. 1) . T7 -transcribed siRNA induces higher breast cancer cell cytotoxicity than synthetic...cytotoxicity of T7 transcribed vs s y n t h e t i c anti-HER2 siRNA on HER2+ cells. We acquired a 21 nucleotide (nt) s y n t h e t i c anti-HER2...ErbB2) siRNA and also produced a T7 -transcribed molecule (Silencer Principal Investigator: Medina-Kauwe, Lali K. 2 siRNA construction kit; Ambion) using
Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer.

PubMed

Bernhard, Helga; Neudorfer, Julia; Gebhard, Kerstin; Conrad, Heinke; Hermann, Christine; Nährig, Jörg; Fend, Falko; Weber, Wolfgang; Busch, Dirk H; Peschel, Christian

2008-02-01

The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated antigen by immunotherapeutical approaches based on HER2-directed monoclonal antibodies and cancer vaccines. We describe the adoptive transfer of autologous HER2-specific T-lymphocyte clones to a patient with metastatic HER2-overexpressing breast cancer. The HLA/multimer-based monitoring of the transferred T lymphocytes revealed that the T cells rapidly disappeared from the peripheral blood. The imaging studies indicated that the T cells accumulated in the bone marrow (BM) and migrated to the liver, but were unable to penetrate into the solid metastases. The disseminated tumor cells in the BM disappeared after the completion of adoptive T-cell therapy. This study suggests the therapeutic potential for HER2-specific T cells for eliminating disseminated HER2-positive tumor cells and proposes the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors.
HER2 copy number of circulating tumour DNA functions as a biomarker to predict and monitor trastuzumab efficacy in advanced gastric cancer.

PubMed

Wang, Haixing; Li, Beifang; Liu, Zhentao; Gong, Jifang; Shao, Lin; Ren, Jun; Niu, Yunyun; Bo, Shiping; Li, Zhongwu; Lai, Yumei; Lu, Sijia; Gao, Jing; Shen, Lin

2018-01-01

HER2 status is significant to trastuzumab therapy; however, it is difficult to determine HER2 status accurately with few pieces of biopsies from advanced gastric cancer (AGC) due to highly heterogeneity and invasive behaviour, which will be investigated in this study. Fifty-six patients with AGC were included in this study. Primary tumour tissues and matched plasmas before medication from 36 patients were retrospectively collected, and the other 20 patients with primary tumour tissues and paired plasmas were prospectively collected. HER2 expression and amplification in 56 tumour tissues were determined by immunohistochemistry (IHC) and dual in situ hybridisation (DISH), and HER2 copy number in 135 circulating tumour DNAs (ctDNAs) was judged by next-generation sequencing. For tumour tissues, HER2 amplification by DISH was most commonly found in patients with HER2 score 3+by IHC. For plasmas, HER2 amplification defined as HER2 copy number >2.22 was identified in 26 of 56 patients. There was a high concordance of HER2 amplification between ctDNA and tumour tissues, suggesting that ctDNA could function as an alternative to screen HER2-targeted population. Moreover, the changes of HER2 copy number in ctDNA could efficiently monitor trastuzumab efficacy, the power of which was superior to commonly used markers carcinoembryonic antigen (CEA) and CA199, suggesting its potential role in clinical practice. ctDNA for HER2 analysis was strongly recommended to serve as a surrogate to screen trastuzumab-suitable population and monitor trastuzumab efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.
BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer.

PubMed

Shields, Sarah; Conroy, Emer; O'Grady, Tony; McGoldrick, Alo; Connor, Kate; Ward, Mark P; Useckaite, Zivile; Dempsey, Eugene; Reilly, Rebecca; Fan, Yue; Chubb, Anthony; Matallanas, David Gomez; Kay, Elaine W; O'Connor, Darran; McCann, Amanda; Gallagher, William M; Coppinger, Judith A

2018-03-20

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.
BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer

PubMed Central

Shields, Sarah; Conroy, Emer; O’Grady, Tony; McGoldrick, Alo; Connor, Kate; Ward, Mark P.; Useckaite, Zivile; Dempsey, Eugene; Reilly, Rebecca; Fan, Yue; Chubb, Anthony; Matallanas, David Gomez; Kay, Elaine W.; O’Connor, Darran; McCann, Amanda; Gallagher, William M.; Coppinger, Judith A.

2018-01-01

Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC. PMID:29644001
Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer.

PubMed

Nahta, Rita; Yu, Dihua; Hung, Mien-Chie; Hortobagyi, Gabriel N; Esteva, Francisco J

2006-05-01

Trastuzumab is a monoclonal antibody targeted against the human epidermal growth factor receptor (HER) 2 tyrosine kinase receptor, which is overexpressed in approximately 25% of invasive breast cancers. The majority of patients with metastatic breast cancer who initially respond to trastuzumab, however, demonstrate disease progression within 1 year of treatment initiation. Preclinical studies have indicated several molecular mechanisms that could contribute to the development of trastuzumab resistance. Increased signaling via the phosphatidylinositol 3-kinase/Akt pathway could contribute to trastuzumab resistance because of activation of multiple receptor pathways that include HER2-related receptors or non-HER receptors such as the insulin-like growth factor 1 receptor, which appears to be involved in a cross-talk with HER2 in resistant cells. Additionally, loss of function of the tumor suppressor PTEN gene, the negative regulator of Akt, results in heightened Akt signaling that leads to decreased sensitivity to trastuzumab. Decreased interaction between trastuzumab and its target receptor HER2, which is due to steric hindrance of HER2 by cell surface proteins such as mucin-4 (MUC4), may block the inhibitory actions of trastuzumab. Novel therapies targeted against these aberrant molecular pathways offer hope that the effectiveness and duration of response to trastuzumab can be greatly improved.
Quantitative HER2 and p95HER2 levels in primary breast cancers and matched brain metastases.

PubMed

Duchnowska, Renata; Sperinde, Jeff; Chenna, Ahmed; Huang, Weidong; Weidler, Jodi M; Winslow, John; Haddad, Mojgan; Paquet, Agnes; Lie, Yolanda; Trojanowski, Tomasz; Mandat, Tomasz; Kowalczyk, Anna; Czartoryska-Arłukowicz, Bogumiła; Radecka, Barbara; Jarosz, Bożena; Staszkiewicz, Rafal; Kalinka-Warzocha, Ewa; Chudzik, Małgorzata; Biernat, Wojciech; Jassem, Jacek

2015-09-01

Patients with advanced breast cancer positive for human epidermal growth factor receptor 2 (HER2) are at high risk for brain metastasis (BM). The prevalence and significance of expression of HER2 and its truncated form p95HER2 (p95) in BM is unknown. Seventy-five pairs of formalin-fixed paraffin-embedded samples from matched primary breast cancers (PBCs) and BM were assayed for quantitative p95 and HER2-total (H2T) protein expression using the p95 VeraTag and HERmark assays, respectively. There was a net increase in p95 and H2T expression in BM relative to the matched PBC (median 1.5-fold, P = .0007 and 2.1-fold, P < .0001, respectively). Cases with H2T-positive tumors were more likely to have the largest (≥5-fold) increase in p95 (odds ratio = 6.3, P = .018). P95 positivity in PBC correlated with progression-free survival (hazard ratio [HR] = 2.2, P = .013), trended with shorter time to BM (HR = 1.8, P = .070), and correlated with overall survival (HR = 2.1, P = .042). P95 positivity in BM correlated with time to BM (HR = 2.0, P = .016) but did not correlate with overall survival from the time of BM diagnosis (HR = 1.2, P = .61). This is the first study of quantitative p95 and HER2 expression in matched PBC and BM. BM of breast cancer shows significant increases in expression of both biomarkers compared with matched PBC. These data provide a rationale for future correlative studies on p95 and HER2 levels in BM. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer

PubMed Central

Chow, L W-C; Xu, B; Gupta, S; Freyman, A; Zhao, Y; Abbas, R; Vo Van, M-L; Bondarenko, I

2013-01-01

Introduction: Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours. Methods: This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer. Results: Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m−2 on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1–147.3 weeks). Common treatment-emergent adverse events (all grades/grade ⩾3) included diarrhoea (92%/29% none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9–81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan–Meier median progression-free survival was 57
Treatment of advanced HER2-positive breast cancer: 2018 and beyond.

PubMed

Pondé, Noam; Brandão, Mariana; El-Hachem, Georges; Werbrouck, Emilie; Piccart, Martine

2018-05-02

In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer - HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including the "real-life" benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new imaging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER antibodies, which may, in coming years further push the boundaries of what we can do for our patients. Copyright © 2018 Elsevier Ltd. All rights reserved.
An acquired HER2 T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer

PubMed Central

Hanker, Ariella B.; Brewer, Monica Red; Sheehan, Jonathan H.; Koch, James P.; Sliwoski, Gregory R.; Nagy, Rebecca; Lanman, Richard; Berger, Michael F.; Hyman, David M.; Solit, David B.; He, Jie; Miller, Vincent; Cutler, Richard E.; Lalani, Alshad S.; Cross, Darren; Lovly, Christine M.; Meiler, Jens; Arteaga, Carlos L.

2017-01-01

We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. PMID:28274957
An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

PubMed

Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H; Koch, James P; Sliwoski, Gregory R; Nagy, Rebecca; Lanman, Richard; Berger, Michael F; Hyman, David M; Solit, David B; He, Jie; Miller, Vincent; Cutler, Richard E; Lalani, Alshad S; Cross, Darren; Lovly, Christine M; Meiler, Jens; Arteaga, Carlos L

2017-06-01

We report a HER2 T798I gatekeeper mutation in a patient with HER2 L869R -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2 L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3 E928G , also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2 T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 L869R but not HER2 L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2 L869R/T798I -induced signaling and cell growth. Acquisition of HER2 T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2 L869R is a driver mutation. HER2 T798I -mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2 -mutant breast cancer upon clinical progression on neratinib. We speculate that HER2 T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2 -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.
[Targeted detecting HER2 expression with recombinant anti HER2 ScFv-GFP fusion antibody].

PubMed

Gao, Guohui; Chen, Chong; Yang, Yanmei; Yang, Han; Wang, Jindan; Zheng, Yi; Huang, Qidi; Hu, Xiaoqu

2012-08-01

To verify the reliability of targeted detecting HER2 positive cancer cells and clinical pathological tissue specimens with a recombinant anti HER2 single chain antibody in single chain Fv fragment (scFv) format, we have constructed the fusion variable regions of the ScFv specific for HER2/neu. labeled a green-fluorescent protein(GFP). The humanized recombinant Anti HER2 ScFv-GFP gene was inserted into pFast Bac HT A, and expressed in insect cells sf9. Then the recombinant fusion protein Anti HER2 ScFv-GFP was properly purified with Ni2+-NTA affinity chromatography from the infected sf9 cells used to test the specificity of the fusion antibody for HER2 positive cancer cells. Firstly, the purified antibody incubated with HER2 positive breast cancer cells SKBR3, BT474 and HER2 negative breast cancer cells MCF7 for 12 h/24 h/48 h at 37 degrees C, in order to confirm targeted detecting HER2 positive breast cancer cells by Laser Confocal Microscopy. Furthermore, the same clinical pathological tissue samples were assessed by immunohistochemistry (IHC) and the fusion antibody Anti HER2 ScFv-GFP in the meanwhile. The data obtained indicated that the recombinant eukaryotic expression plasmid pFast Bac HT A/Anti HER2 ScFv-GFP was constructed successfully In addition, obvious green fluorescent was observed in insect cells sf9. When the purified fusion antibody was incubated with different cancer cells, much more green fluorescent was observed on the surface of the HER2 positive cancer cells SKBR3 and BT474. In contrast, no green fluorescent on the surface of the HER2 negative cancer cells MCF7 was detected. The concentration of the purified fusion antibody was 115.5 microg/mL, of which protein relative molecular weight was 60 kDa. The analysis showed the purity was about 97% and the titer was about 1:64. The detection results of IHC and fusion antibody testing indicated the conformity. In summary, the study showed that the new fusion antibody Anti HER2 ScFv-GFP can test HER2
Association between partial-volume corrected SUVmax and Oncotype DX recurrence score in early-stage, ER-positive/HER2-negative invasive breast cancer.

PubMed

Lee, Su Hyun; Ha, Seunggyun; An, Hyun Joon; Lee, Jae Sung; Han, Wonshik; Im, Seock-Ah; Ryu, Han Suk; Kim, Won Hwa; Chang, Jung Min; Cho, Nariya; Moon, Woo Kyung; Cheon, Gi Jeong

2016-08-01

Oncotype DX, a 21-gene expression assay, provides a recurrence score (RS) which predicts prognosis and the benefit from adjuvant chemotherapy in patients with early-stage, estrogen receptor-positive (ER-positive), and human epidermal growth factor receptor 2-negative (HER2-negative) invasive breast cancer. However, Oncotype DX tests are expensive and not readily available in all institutions. The purpose of this study was to investigate whether metabolic parameters on (18)F-FDG PET/CT are associated with the Oncotype DX RS and whether (18)F-FDG PET/CT can be used to predict the Oncotype DX RS. The study group comprised 38 women with stage I/II, ER-positive/HER2-negative invasive breast cancer who underwent pretreatment (18)F-FDG PET/CT and Oncotype DX testing. On PET/CT, maximum (SUVmax) and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis were measured. Partial volume-corrected SUVmax (PVC-SUVmax) determined using the recovery coefficient method was also evaluated. Oncotype DX RS (0 - 100) was categorized as low (<18), intermediate (18 - 30), or high (≥31). The associations between metabolic parameters and RS were analyzed. Multivariate logistic regression was used to identify significant independent predictors of low versus intermediate-to-high RS. Of the 38 patients, 22 (58 %) had a low RS, 13 (34 %) had an intermediate RS, and 3 (8 %) had a high RS. In the analysis with 38 index tumors, PVC-SUVmax was higher in tumors in patients with intermediate-to-high RS than in those with low RS (5.68 vs. 4.06; P = 0.067, marginally significant). High PVC-SUVmax (≥4.96) was significantly associated with intermediate-to-high RS (odds ratio, OR, 10.556; P = 0.004) in univariate analysis. In multivariate analysis with clinicopathologic factors, PVC-SUVmax ≥4.96 (OR 8.459; P = 0.013) was a significant independent predictor of intermediate-to-high RS. High PVC-SUVmax on (18)F-FDG PET/CT was significantly
Development of 99mTc-radiolabeled nanosilica for targeted detection of HER2-positive breast cancer

PubMed Central

Rainone, Paolo; Riva, Benedetta; Belloli, Sara; Sudati, Francesco; Ripamonti, Marilena; Verderio, Paolo; Colombo, Miriam; Colzani, Barbara; Gilardi, Maria Carla; Moresco, Rosa Maria; Prosperi, Davide

2017-01-01

The human epidermal growth factor receptor 2 (HER2) is normally associated with a highly aggressive and infiltrating phenotype in breast cancer lesions with propensity to spread into metastases. In clinic, the detection of HER2 in primary tumors and in their metastases is currently based on invasive methods. Recently, nuclear molecular imaging techniques, including positron emission tomography and single photon emission computed tomography (SPECT), allowed the detection of HER2 lesions in vivo. We have developed a 99mTc-radiolabeled nanosilica system, functionalized with a trastuzumab half-chain, able to act as drug carrier and SPECT radiotracer for the identification of HER2-positive breast cancer cells. To this aim, nanoparticles functionalized or not with trastuzumab half-chain, were radiolabeled using the 99mTc-tricarbonyl approach and evaluated in HER2 positive and negative breast cancer models. Cell uptake experiments, combined with flow cytometry and fluorescence imaging, suggested that active targeting provides higher efficiency and selectivity in tumor detection compared to passive diffusion, indicating that our radiolabeling strategy did not affect the nanoconjugate binding efficiency. Ex vivo biodistribution of 99mTc-nanosilica in a SK-BR-3 (HER2+) tumor xenograft at 4 h postinjection was higher in targeted compared to nontargeted nanosilica, confirming the in vitro data. In addition, viability and toxicity tests provided evidence on nanoparticle safety in cell cultures. Our results encourage further assessment of silica 99mTc-nanoconjugates to validate a safe and versatile nanoreporter system for both diagnosis and treatment of aggressive breast cancer. PMID:28496321
Long-term remission of a Her2/neu positive primary breast cancer under double monoclonal antibody therapy with trastuzumab and bevacizumab

PubMed Central

Königsberg, Robert; Maierhofer, Julia; Steininger, Tanja; Kienzer, Gabriele; Dittrich, Christian

2014-01-01

Background The attempt to act on several signalling pathways involved in tumour development simultaneously appears to be more attractive than attacking a single target structure alone. Vascular endothelial growth factor (VEGF) over-expression is frequently observed in human epidermal growth factor receptor 2 (Her2/neu) positive patients with breast cancer and over-expression of the proto-oncogene Her2/neu is associated with an up-regulation of VEGF. Case report The case of a Her2/neu positive patient with breast cancer who refused cytotoxic chemotherapy with its potential side effects as well as mastectomy is presented. Our patient has been receiving the combined double administration of bevacizumab and trastuzumab for more than 4 years. Conclusions This case report shows that (a) the combined double administration of bevacizumab and trastuzumab was be clinically effective. (b) The combination of bevacizumab and trastuzumab is safe and non-toxic. (c) Bevacizumab and trastuzumab can be used as a long-term application. PMID:24991208
Ex vivo expanded natural killer cells from breast cancer patients and healthy donors are highly cytotoxic against breast cancer cell lines and patient-derived tumours.

PubMed

Shenouda, Mira M; Gillgrass, Amy; Nham, Tina; Hogg, Richard; Lee, Amanda J; Chew, Marianne V; Shafaei, Mahsa; Aarts, Craig; Lee, Dean A; Hassell, John; Bane, Anita; Dhesy-Thind, Sukhbinder; Ashkar, Ali A

2017-07-01

Natural killer (NK) cells play a critical role in cancer immunosurveillance. Recent developments in NK cell ex-vivo expansion makes it possible to generate millions of activated NK cells from a small volume of peripheral blood. We tested the functionality of ex vivo expanded NK cells in vitro against breast cancer cell lines and in vivo using a xenograft mouse model. The study aim was to assess functionality and phenotype of expanded NK cells from breast cancer patients against breast cancer cell lines and autologous primary tumours. We used a well-established NK cell co-culture system to expand NK cells ex vivo from healthy donors and breast cancer patients and examined their surface marker expression. Moreover, we tested the ability of expanded NK cells to lyse the triple negative breast cancer and HER2-positive breast cancer cell lines MDA-MB-231 and MDA-MB-453, respectively. We also tested their ability to prevent tumour growth in vivo using a xenograft mouse model. Finally, we tested the cytotoxicity of expanded NK cells against autologous and allogeneic primary breast cancer tumours in vitro. After 3 weeks of culture we observed over 1000-fold expansion of NK cells isolated from either breast cancer patients or healthy donors. We also showed that the phenotype of expanded NK cells is comparable between those from healthy donors and cancer patients. Moreover, our results confirm the ability of ex vivo expanded NK cells to lyse tumour cell lines in vitro. While the cell lines examined had differential sensitivity to NK cell killing we found this was correlated with level of major histocompatibility complex (MHC) class I expression. In our in vivo model, NK cells prevented tumour establishment and growth in immunocompromised mice. Finally, we showed that NK cells expanded from the peripheral blood of breast cancer patients show high cytotoxicity against allogeneic and autologous patient-derived tumour cells in vitro. NK cells from breast cancer patients can be
miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer.

PubMed

Corcoran, Claire; Rani, Sweta; Breslin, Susan; Gogarty, Martina; Ghobrial, Irene M; Crown, John; O'Driscoll, Lorraine

2014-03-24

While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells
Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis.

PubMed

Zhang, Qian; Chen, Jian; Yu, Xiaoli; Cai, Gang; Yang, Zhaozhi; Cao, Lu; Hu, Chaosu; Guo, Xiaomao; Sun, Jing; Chen, Jiayi

2016-09-01

We aimed to assess the survival benefit of epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT) in combination with systemic treatments, especially anti-HER2 therapy. This retrospective study analyzed the overall survival (OS) of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received chemotherapy while 18 patients did not receive after WBRT. With regard to anti-HER2 therapy, after WBRT, 17 patients received anti-HER2 treatment without prior adjuvant trastuzumab-based therapy, 7 patients received anti-HER2 treatment with prior adjuvant trastuzumab-based therapy, and 36 patients did not receive further anti-HER2 treatment. All patients were followed up regularly until January 23, 2013. The median OS of patients with BM was 12 months. Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment. Patients who received anti-HER2 treatment after WBRT but did not receive adjuvant trastuzumab-based therapy for early breast cancer had better OS, followed by patients who received anti-HER2 agent both in adjuvant treatment and after WBRT and patients who did not receive anti-HER2 treatment. Multivariate analysis showed that Karnofsky Performance Status, control of extracranial metastases, chemotherapy after WBRT, and anti-HER2 therapy combined with WBRT were all independent predictors for OS. Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure.
Racial disparities in breast cancer diagnosis and treatment by hormone receptor and HER2 status

PubMed Central

Chen, Lu; Li, Christopher I.

2015-01-01

Background African American and Hispanic women are more likely to be diagnosed with aggressive forms of breast cancer. Disparities within each subtype of breast cancer have not been well documented. Methods Using data from 18 SEER cancer registries, we identified 102,064 women aged 20 years or older, diagnosed with invasive breast cancer in 2010–2011, and with known stage, hormone receptor (HR) and HER2 status. Associations between race/ethnicity and cancer stage and receipt of guideline concordant treatment were evaluated according to HR/HER2 status. Results Overall, African American and Hispanic women were 30–60% more likely to be diagnosed with stage II–IV breast cancer compared to Non-Hispanic whites. African American women had 40–70% higher risks of stage IV breast cancer across all four subtypes. American Indian/Alaska Native women had a 3.9-fold higher risk of stage IV triple negative breast cancer. African American and Hispanic whites were 30–40% more likely to receive non-guideline concordant treatment for breast cancer overall and across subtypes. Conclusions Women in several racial/ethnic groups are more likely to be diagnosed with more advanced stage breast cancer. African American and American Indian/Alaska native women in particular had the highest risk of being diagnosed with stage IV triple negative breast cancer. African American and Hispanic women were also consistently at higher risk of not receiving guideline concordant treatment across subtypes. Impact These findings provide important characterization of which subtypes of breast cancer racial/ethnic disparities in stage and treatment persist. PMID:26464428

Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib.

PubMed

Kourie, Hampig Raphael; El Rassy, Elie; Clatot, Florian; de Azambuja, Evandro; Lambertini, Matteo

2017-01-01

Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.
Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

PubMed Central

Kourie, Hampig Raphael; El Rassy, Elie; Clatot, Florian; de Azambuja, Evandro; Lambertini, Matteo

2017-01-01

Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib. PMID:28744140
Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer - Results from the prospective German TMK cohort study.

PubMed

Fietz, Thomas; Tesch, Hans; Rauh, Jacqueline; Boller, Emil; Kruggel, Lisa; Jänicke, Martina; Marschner, Norbert

2017-08-01

Data on treatment and outcome of advanced breast cancer in routine practice are rare, especially concerning recurrent disease, but important to complement the results from clinical trials and to improve the standard of care. We present data on choice of systemic first-line treatment, number of treatment lines, and survival of patients treated by medical oncologists in Germany. 1395 patients recruited by 124 sites at start of first-line therapy into the ongoing, prospective German clinical cohort study TMK (Tumour Registry Breast Cancer) between February 2007 and October 2015 were analysed. The median OS was 33.8 months (95% CI 30.2-40.2) for HR-positive/HER2-negative, 38.2 months (95% CI 31.3-43.0) for HER2-positive and 16.8 months (95% CI 11.5-22.0) for triple negative breast cancer. Patients with triple negative tumours more often died before start of a third-line therapy than patients with HR-positive or HER2-positive tumours (44% vs. 25%). Use of taxane-based chemotherapies has increased since 2007, with 65% of all first-line chemotherapy-treatments containing taxanes in 2013-15 (60% HR-positive/HER2-negative, 75% HER2-positive, 56% triple negative). 52% of the patients with HR-positive/HER2-negative tumours received first-line endocrine therapy in 2013-15; when restricted to patients with only non-visceral metastases this percentage increased to 63%. To our knowledge, this is the first cohort study showing systemic first-line therapy for all subtypes of advanced breast cancer. Overall survival in the TMK is comparable to that reported by clinical trials despite the inclusion of older and comorbid patients. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma.

PubMed

Tokunaga, Eriko; Oki, Eiji; Kimura, Yasue; Yamanaka, Takeharu; Egashira, Akinori; Nishida, Kojiro; Koga, Tadashi; Morita, Masaru; Kakeji, Yoshihiro; Maehara, Yoshihiko

2007-03-01

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.
(64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

PubMed

Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; Yonemori, Kan; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro; Tamura, Kenji

2015-01-01

The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. UMIN000004170.
Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azuma, Koichi; Tsurutani, Junji, E-mail: tsurutani_j@dotd.med.kindai.ac.jp; Sakai, Kazuko

2011-04-01

Highlights: {yields} A lapatinib-resistant breast cancer cell line, UACC812 (UACC812/LR), was found to harbor amplification of the FGFR2 gene. {yields} Inhibition of the molecule by a specific inhibitor of FGFR dramatically induced growth inhibition accompanied by cell death. {yields} Immunohistochemical analysis of patients with HER2-positive breast cancer demonstrated an association between FGFR2 expression and poor outcome for lapatinib-containing chemotherapy. -- Abstract: Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cellsmore » (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGFR2 and reduced expression of HER2, and a cell proliferation assay showed that the IC{sub 50} of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that FGFR-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer.« less
A definition for aggressive disease in patients with HER-2 negative metastatic breast cancer: an expert consensus of the Spanish Society of Medical Oncology (SEOM).

PubMed

González, A; Lluch, A; Aba, E; Albanell, J; Antón, A; Álvarez, I; Ayala, F; Barnadas, A; Calvo, L; Ciruelos, E; Cortés, J; de la Haba, J; López-Vega, J M; Martínez, E; Muñoz, M; Peláez, I; Redondo, A; Rodríguez, Á; Rodríguez, C A; Ruíz, A; Llombart, A

2017-05-01

To converge on an expert opinion to define aggressive disease in patients with HER2-negative mBC using a modified Delphi methodology. A panel of 21 breast cancer experts from the Spanish Society of Medical Oncology agreed upon a survey which comprised 47 questions that were grouped into three sections: relevance for defining aggressive disease, aggressive disease criteria and therapeutic goals. Answers were rated using a 9-point Likert scale of relevance or agreement. Among the 88 oncologists that were invited to participate, 81 answered the first round (92%), 70 answered the second round (80%), and 67 answered the third round (76%) of the survey. There was strong agreement regarding the fact that identifying patients with aggressive disease needs to be adequately addressed to help practitioners to decide the best treatment options for patients with HER2-negative mBC. The factors that were considered to be strongly relevant to classifying patients with aggressive HER2-negative mBC were a high tumor burden, a disease-free interval of less than 12-24 months after surgery, the presence of progressive disease during adjuvant or neoadjuvant chemotherapy and having a triple-negative phenotype. The main therapeutic goals were controlling symptoms, improving quality of life and increasing the time to progression and overall survival. High tumor burden, time to recurrence after prior therapy and having a triple-negative phenotype were the prognostic factors for which the greatest consensus was found for identifying patients with aggressive HER2-negative mBC. Identifying patients with aggressive disease leads to different therapeutic approaches.
H2Mab-77 is a Sensitive and Specific Anti-HER2 Monoclonal Antibody Against Breast Cancer.

PubMed

Itai, Shunsuke; Fujii, Yuki; Kaneko, Mika K; Yamada, Shinji; Nakamura, Takuro; Yanaka, Miyuki; Saidoh, Noriko; Chang, Yao-Wen; Handa, Saori; Takahashi, Maki; Suzuki, Hiroyoshi; Harada, Hiroyuki; Kato, Yukinari

2017-08-01

Human epidermal growth factor receptor 2 (HER2) plays a critical role in the progression of breast cancers, and HER2 overexpression is associated with poor clinical outcomes. Trastuzumab is an anti-HER2 humanized antibody that leads to significant survival benefits in patients with HER2-positive metastatic breast cancers. In this study, we developed novel anti-HER2 monoclonal antibodies (mAbs) and characterized their efficacy in flow cytometry, Western blot, and immunohistochemical analyses. Initially, we expressed the full length or ectodomain of HER2 in LN229 glioblastoma cells and then immunized mice with ectodomain of HER2 or LN229/HER2, and performed the first screening by enzyme-linked immunosorbent assays using ectodomain of HER2. Subsequently, we selected mAbs according to their efficacy in flow cytometry (second screening), Western blot (third screening), and immunohistochemical analyses (fourth screening). Among 100 mAb clones, only three mAbs reacted with HER2 in Western blot, and clone H 2 Mab-77 (IgG 1 , kappa) was selected. Finally, immunohistochemical analyses with H 2 Mab-77 showed sensitive and specific reactions against breast cancer cells, warranting the use of H 2 Mab-77 to detect HER2 in pathological analyses of breast cancers.
The extracellular domain of Her2 in serum as a biomarker of breast cancer.

PubMed

Perrier, Alexandre; Gligorov, Joseph; Lefèvre, Guillaume; Boissan, Mathieu

2018-02-28

Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.
Updated 2013 College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) guideline recommendations for human epidermal growth factor receptor 2 (HER2) fluorescent in situ hybridization (FISH) testing increase HER2 positive and HER2 equivocal breast cancer cases; retrospective study of HER2 FISH results of 836 invasive breast cancers.

PubMed

Singh, Kamaljeet; Tantravahi, Umadevi; Lomme, Michele M; Pasquariello, Terese; Steinhoff, Margaret; Sung, C James

2016-06-01

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2-), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2- tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.
Preoperative serum HER2 extracellular domain levels in primary invasive breast cancer.

PubMed

Lee, Sae Byul; Lee, Jong Won; Yu, Jong Han; Ko, Beom Seok; Kim, Hee Jeong; Son, Byung Ho; Gong, Gyungyub; Lee, Hee Jin; Kim, Sung-Bae; Jung, Kyung Hae; Ahn, Jin-Hee; Lee, Woochang; Sung, Joohon; Ahn, Sei-Hyun

2014-12-10

Despite the preclinical outcomes and biologic significance of the presence of the human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD), there is little evidence supporting the measurement of ECD levels in any clinical setting. The aim of this study was to determine the prevalence of elevated serum HER2 ECD levels, the association between these levels and tissue HER2 overexpression, and the potential clinical prognostic value of HER2 ECD in primary invasive breast cancer. Serum HER2 ECD levels were examined preoperatively in 2,862 consecutive stage I-III primary breast cancer patients between 2007 and 2009. Serum HER2 ECD levels were measured by chemiluminescence immunoassay (ADVIA Centaur), and the tissue HER2 status was assessed by immunohistochemistry and fluorescence in situ hybridization. The cutoff value for the serum level of HER2 ECD was set at 15.2 ng/ml. Among the 2,862 patients, 126 (4.4%) had elevated serum HER2 ECD levels, and HER2 was overexpressed in the tumor tissue of 692 patients (24.2%), with a concordance of 78.7%. Multivariate analysis revealed that elevated serum HER2 ECD was a significant independent prognostic factor for worse distant-metastasis-free survival [DMFS; hazard ratio (HR) = 2.50, 95% confidence interval (CI) = 1.5-4.3, P = 0.001] and breast-cancer-specific survival (BCSS; HR = 2.0, 95% CI = 1.1-3.8, P = 0.036), which were much stronger in patients with tissue HER2-positive tumors (DMFS: HR = 3.8, 95% CI = 2.0-7.0, P < 0.001; BCSS: HR = 2.6, 95% CI = 1.2-5.3, P = 0.012). Given the prevalence of HER2 expression, its measurement as an independent prognostic factor can be clinically useful, particularly in patients with tissue HER2-positive tumors.
Using antibody directed phototherapy to target oesophageal adenocarcinoma with heterogeneous HER2 expression

PubMed Central

Pye, Hayley; Butt, Mohammed Adil; Funnell, Laura; Reinert, Halla W.; Puccio, Ignazio; Rehman Khan, Saif U.; Saouros, Savvas; Marklew, Jared S.; Stamati, Ioanna; Qurashi, Maryam; Haidry, Rehan; Sehgal, Vinay; Oukrif, Dahmane; Gandy, Michael; Whitaker, Hayley C.; Rodriguez-Justo, Manuel; Novelli, Marco; Hamoudi, Rifat; Yahioglu, Gokhan; Deonarain, Mahendra P.; Lovat, Laurence B.

2018-01-01

Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an in vivo mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. In vitro we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent in vitro was observed. In an in vivo OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA. PMID:29796164
Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer

PubMed Central

Li, Jianzong; Wang, Haiyang; Li, Junjie; Bao, Jinku; Wu, Chuanfang

2016-01-01

Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor. PMID:27376283
Pembrolizumab in Treating Patients With Triple-Negative Breast Cancer

ClinicalTrials.gov

2018-06-28

Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage 0 Breast Cancer AJCC v6 and v7; Stage I Breast Cancer AJCC v7; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Triple-Negative Breast Carcinoma
Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes: a population-based study and first report.

PubMed

Lund, Mary Jo; Butler, Ebonee N; Hair, Brionna Y; Ward, Kevin C; Andrews, Judy H; Oprea-Ilies, Gabriella; Bayakly, A Rana; O'Regan, Ruth M; Vertino, Paula M; Eley, J William

2010-06-01

Although US year 2000 guidelines recommended characterizing breast cancers by human epidermal growth factor receptor 2 (HER2), national cancer registries do not collect HER2, rendering a population-based understanding of HER2 and clinical "triple subtypes" (estrogen receptor [ER] / progesterone receptor [PR] / HER2) largely unknown. We document the population-based prevalence of HER2 testing / status, triple subtypes and present the first report of subtype incidence rates. Medical records were searched for HER2 on 1842 metropolitan Atlanta females diagnosed with breast cancer during 2003-2004. HER2 testing/status and triple subtypes were analyzed by age, race/ethnicity, tumor factors, socioeconomic status, and treatment. Age-adjusted incidence rates were calculated. Over 90% of cases received HER2 testing: 12.6% were positive, 71.7% negative, and 15.7% unknown. HER2 testing compliance was significantly better for women who were younger, of Caucasian or African-American descent, or diagnosed with early stage disease. Incidence rates (per 100,000) were 21.1 for HER2+ tumors and 27.8 for triple-negative tumors, the latter differing by race (36.3 and 19.4 for black and white women, respectively). HER2 recommendations are not uniformly adhered to. Incidence rates for breast cancer triple subtypes differ by age/race. As biologic knowledge is translated into the clinical setting eg, HER2 as a biomarker, it will be incumbent upon national cancer registries to report this information. Incidence rates cautiously extrapolate to an annual burden of 3000 and 17,000 HER2+ tumors for black and white women, respectively, and triple-negative tumors among 5000 and 16,000 respectively. Testing, rate, and burden variations warrant population-based in-depth exploration and clinical translation. (c) 2010 American Cancer Society.
Role of PTP1B in HER2 Signaling in Breast Cancer

DTIC Science & Technology

2012-10-01

AD_________________ Award Number: W81XWH-10-1-1005 TITLE: Role of PTP1B in HER2 Signaling in...AND SUBTITLE 5a. CONTRACT NUMBER Role of PTP1B in HER2 Signaling in Breast Cancer 5b. GRANT NUMBER W81XWH-10-1-1005 5c. PROGRAM ELEMENT NUMBER...2009, Postdoctoral Fellowship Award W81XWH-10-1-1005, “Role of PTP1B in HER2 Signaling in Breast Cancer" INTRODUCTION The receptor tyrosine
Pembrolizumab and Ruxolitinib Phosphate in Treating Patients With Metastatic Stage IV Triple Negative Breast Cancer

ClinicalTrials.gov

2018-03-05

Breast Carcinoma Metastatic in the Bone; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma
Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

PubMed

Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel; Domchek, Susan M; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J; Robson, Mark; Sherman, Mark; Spurdle, Amanda B; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M; Janavicius, Ramunas; Hansen, Thomas vO; Nielsen, Finn C; Ejlertsen, Bent; Osorio, Ana; Muñoz-Repeto, Iván; Durán, Mercedes; Godino, Javier; Pertesi, Maroulio; Benítez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E J; Wijnen, Juul; Gómez García, Encarna B; Nelen, Marcel R; Kets, C Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M A; van der Luijt, Rob B; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J Louise; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K; Schmutzler, Rita K; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schäfer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, François; Mazoyer, Sylvie; Léoné, Mélanie; Boutry-Kryza, Nadia; Hardouin, Agnès; Berthet, Pascaline; Muller, Danièle; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo; Weitzel, Jeffrey N; Lynch, Henry T; Ganz, Patricia A; Tomlinson, Gail E; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Lindor, Noralane M; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L; Greene, Mark H; Imyanitov, Evgeny; O'Malley, Frances P; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L; Beattie, Mary; Pharoah, Paul D P; Moysich, Kirsten B; Nathanson, Katherine L; Karlan, Beth Y; Gross, Jenny; John, Esther M; Daly, Mary B; Buys, Saundra M; Southey, Melissa C; Hopper, John L; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F; Andrulis, Irene L; Antoniou, Antonis C

2011-01-01

Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for
Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

PubMed Central

2011-01-01

Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models
Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: polyploidization can lead to diagnostic pitfalls with potential impact for clinical management.

PubMed

Valent, Alexander; Penault-Llorca, Frédérique; Cayre, Anne; Kroemer, Guido

2013-01-01

The status of the HER2 (ERBB2) gene in breast cancer is not static and may change among the primary tumor, lymph node metastases, and distant metastases. This status change can be a consequence of the natural evolution of the tumor or can be induced by therapy. The HER2 gene status is, in the majority of cases, established at the moment of diagnosis. After chemotherapy, monitoring HER2 status can be a challenge because of ploidy changes induced by drugs. The cytogeneticist or the pathologist can face real difficulties in distinguishing between a true HER2 amplification and HER2 copy number increase by polyploidization. We performed a HER2 genetic examination by fluorescence in situ hybridization (FISH) of invasive breast cancers before and after taxane treatment. The majority of patients (91%) were HER2-negative both at diagnosis and after treatment. Thirty of 344 patients (9%) whose tumors were initially HER2-negative were found by FISH to have supernumerary HER2 gene copies (up to 15 copies) after neoadjuvant chemotherapy. This HER2 copy increase could not be attributed to true gene amplifications and instead reflected polyploidization events, which presumably affected all chromosomes. Indeed, when we used other FISH probes, we found other gene copy numbers to parallel those of HER2. We recommend careful checking of invasive breast carcinomas by supplementary FISH probes if the copy number of the HER2 gene is >6. This procedure allows the discrimination of specific HER2 gene amplifications and global increases in ploidy. Copyright © 2013 Elsevier Inc. All rights reserved.

miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer

PubMed Central

2014-01-01

Background While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods We investigated the levels of intra- and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate- or acquired- resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630’s regulation of mRNA, proteins and their phosphorylated forms. Results We established that introducing miR-630 into cells with innate- or acquired- resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630’s regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby
Trastuzumab Emtansine for HER2-Positive Breast Cancer

Cancer.gov

An NCI Cancer Currents blog on results from the TH3RESA and EMILIA clinical trials showing trastuzumab emtansine (T-DM1) improved overall survival in patients with previously treated metastatic HER2-positive breast cancer.
XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

PubMed

Chen, Xi; Iliopoulos, Dimitrios; Zhang, Qing; Tang, Qianzi; Greenblatt, Matthew B; Hatziapostolou, Maria; Lim, Elgene; Tam, Wai Leong; Ni, Min; Chen, Yiwen; Mai, Junhua; Shen, Haifa; Hu, Dorothy Z; Adoro, Stanley; Hu, Bella; Song, Minkyung; Tan, Chen; Landis, Melissa D; Ferrari, Mauro; Shin, Sandra J; Brown, Myles; Chang, Jenny C; Liu, X Shirley; Glimcher, Laurie H

2014-04-03

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer

PubMed Central

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M.; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W. Y.; Marass, Francesco; Gale, Davina; Ali, H. Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P.; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-01-01

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution. PMID:26530965
Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer.

PubMed

Murtaza, Muhammed; Dawson, Sarah-Jane; Pogrebniak, Katherine; Rueda, Oscar M; Provenzano, Elena; Grant, John; Chin, Suet-Feung; Tsui, Dana W Y; Marass, Francesco; Gale, Davina; Ali, H Raza; Shah, Pankti; Contente-Cuomo, Tania; Farahani, Hossein; Shumansky, Karey; Kingsbury, Zoya; Humphray, Sean; Bentley, David; Shah, Sohrab P; Wallis, Matthew; Rosenfeld, Nitzan; Caldas, Carlos

2015-11-04

Circulating tumour DNA analysis can be used to track tumour burden and analyse cancer genomes non-invasively but the extent to which it represents metastatic heterogeneity is unknown. Here we follow a patient with metastatic ER-positive and HER2-positive breast cancer receiving two lines of targeted therapy over 3 years. We characterize genomic architecture and infer clonal evolution in eight tumour biopsies and nine plasma samples collected over 1,193 days of clinical follow-up using exome and targeted amplicon sequencing. Mutation levels in the plasma samples reflect the clonal hierarchy inferred from sequencing of tumour biopsies. Serial changes in circulating levels of sub-clonal private mutations correlate with different treatment responses between metastatic sites. This comparison of biopsy and plasma samples in a single patient with metastatic breast cancer shows that circulating tumour DNA can allow real-time sampling of multifocal clonal evolution.
Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients: a study of the Southeast Netherlands Breast Cancer Consortium.

PubMed

van Kampen, R J W; Ramaekers, B L T; Lobbezoo, D J A; de Boer, M; Dercksen, M W; van den Berkmortel, F; Smilde, T J; van de Wouw, A J; Peters, F P J; van Riel, J M G; Peters, N A J B; Tjan-Heijnen, V C G; Joore, M A

2017-07-01

The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario. Copyright © 2017 Elsevier Ltd. All rights reserved.
Response evaluation after primary systemic therapy of Her2 positive breast cancer – an observational cross-sectional study.

PubMed

Tőkés, Tímea; Szentmártoni, Gyöngyvér; Torgyík, László; Kajáry, Kornélia; Lengyel, Zsolt; Györke, Tamás; Molnár, Béla Á; Tőkés, Anna-Mária; Kulka, Janina; Dank, Magdolna

2015-04-01

To evaluate (I) trastuzumab-containing primary systemic therapy (PST) in human epidermal growth factor receptor 2 (Her2) overexpressing breast carcinomas.; (II) compare the patients who achieved and those who did not achieve pathological complete remission (pCR), and (III) analyze the accuracy of different clinical-imaging modalities in tumor response monitoring. 188 patients who received PST between 2008 and 2014 were reviewed and 43 Her2 overexpressing breast cancer patients (28 Luminal B/Her2-positive and 15 Her2-positive) were enrolled. 26 patients received mostly taxane-based PST without trastuzumab (Group 1) and 17 patients received trastuzumab-containing PST (Group 2). We compared the concordance between pCR and complete remission (CR) defined by breast-ultrasound, CR defined by standard 18F-fluoro-deoxy-glucose positron emission tomography and computerized tomography (FDG-PET/CT) criteria (Method 1) and CR defined by a novel, breast cancer specific FDG-PET/CT criteria (Method 2). Sensitivity (sens), specificity (spec), and positive (PPV) and negative predictive values (NPV) were calculated. Ten patients (38.5%) in Group 1 and eight (47%) in Group 2 achieved pCR. pCR was significantly more frequent in Her2-positive than in Luminal B/Her2-positive tumors in both Group 1: (P=0.043) and Group 2: (P=0.029). PET/CT evaluated by the breast cancer specific criteria (Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1: sens=77.8%, spec=%, PPV=100%, NPV=71.4%; Group 2: sens=87.5%, spec=62.5%, PPV=70%, NPV=83.3%) than standard PET/CT criteria (Method 1) (Group 1: sens=22.2% spec=100% PPV=100% NPV=41.7%; in Group 2: sens=37.5%, spec=87.5%, PPV=75% NPV=58.3%) or breast ultrasound (Group 1, sens=83.3% spec=25% PPV=62.5% NPV=50%; Group 2, sens=100% spec=12.5% PPV=41.6% NPV=100%). The benefit of targeted treatment with trastuzumab-containing PST in Her2 overexpressing breast cancer was defined in terms of pCR rate. Luminal B/Her2-positive
Effect of neoadjuvant chemotherapy on HER-2 expression in surgically treated gastric and oesophagogastric junction carcinoma: a multicentre Italian study.

PubMed

Chiari, Damiano; Orsenigo, Elena; Guarneri, Giovanni; Baiocchi, Gian Luca; Mazza, Elena; Albarello, Luca; Bissolati, Massimiliano; Molfino, Sarah; Staudacher, Carlo

2017-03-01

Predictors of response to neoadjuvant chemotherapy are not available for gastric and oesophago-gastric junction carcinoma. HER-2 over-expression in breast cancer correlates with poor prognosis and high incidence of recurrence. First aim of this study was to evaluate if the HER-2 expression/amplification is predictive of response to neoadjuvant chemotherapy in terms of pathologic regression. Secondary aim was to evaluate if HER-2 expression varies after neoadjuvant treatment. Thirty-five patients with locally advanced gastric or oesophago-gastric junction carcinoma underwent preoperative chemotherapy and surgical resection at San Raffaele Scientific Institute and Spedali Civili of Brescia. HER-2 expression/amplification was evaluated on every biopsy at diagnosis time and on every surgical sample after neoadjuvant chemotherapy. Pathologic response to chemotherapy was evaluated according to TNM classification (ypT status and ypN status) and Mandard's tumour regression grade classification. In our series 10 patients (28.6%) showed a reduction in HER-2 overexpression and in 6 of them (17.1%) HER-2 expression completely disappeared. Only three of the six patients with HER-2 disappearance had a complete pathological response to neoadjuvant chemotherapy. There was a strong correlation between HER-2 negativity on biopsy and absence of lymph node metastasis in surgical samples after neoadjuvant chemotherapy, irrespective of nodal status before chemotherapy. A direct correlation between HER-2 reduction after neoadjuvant chemotherapy and pathologic regression (primary tumour and lymph nodes) in surgical samples was found. HER-2 negativity may represent a predictor of pathologic response to neoadjuvant chemotherapy for gastric and oesophago-gastric junction adenocarcinoma. Neoadjuvant treatment can reduce HER-2 overexpression.
Clinical Practice Patterns and Cost-Effectiveness of HER2 Testing Strategies in Breast Cancer Patients

PubMed Central

Phillips, Kathryn A.; Marshall, Deborah A.; Haas, Jennifer S.; Elkin, Elena B.; Liang, Su-Ying; Hassett, Michael J.; Ferrusi, Ilia; Brock, Jane E.; Van Bebber, Stephanie L

2009-01-01

Background Testing technologies are increasingly used to target cancer therapies. Human epidermal growth factor receptor 2 (HER2) testing to target trastuzumab for patients with breast cancer provides insights into the evidence needed for emerging testing technologies. Methods We reviewed literature on HER2 test utilization and cost-effectiveness of HER2 testing for patients with breast cancer. We examined available evidence on: percentage of eligible patients tested for HER2; test methods used; concordance of test results between community and central/reference laboratories; use of trastuzumab by HER2 test result; and cost-effectiveness of testing strategies. Results Little evidence is available to determine whether all eligible patients are tested; how many are retested to confirm results; and how many with negative HER2 test results still receive trastuzumab. Studies suggest that up to 66% of eligible patients had no documentation of testing in claims records; up to 20% of patients receiving trastuzumab were not tested or had no documentation of a positive test; and 20% of HER2 results may be incorrect. Few cost-effectiveness analyses of trastuzumab explicitly considered the economic implications of various testing strategies. Conclusions There is little information about the actual use of HER2 testing in clinical practice, but evidence suggests important variations in testing practices and key gaps in knowledge exist. Given the increasing use of targeted therapies, it is critical to build an evidence base that supports informed decision-making on emerging testing technologies in cancer care. PMID:19753618
ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

PubMed Central

Feldinger, Katharina; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Ng, Tzi Bun; Wong, Jack Ho; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Li, Ji-Liang; Bridges, Esther; Turley, Helen; Leek, Russell; Roxanis, Ioannis; Capala, Jacek; Murphy, Gillian; Harris, Adrian L.; Kong, Anthony

2014-01-01

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p≤0.001 in BT474; p≤0.01 in SKBR3) and in vivo (p≤0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p≤0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p≤0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p≤0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients. PMID:24952873
Pembrolizumab and Enobosarm in Treating Patients With Androgen Receptor Positive Metastatic Triple Negative Breast Cancer

ClinicalTrials.gov

2018-04-05

Androgen Receptor Positive; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma
Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours.

PubMed

Yan, Benedict; Choo, Shoa Nian; Mulyadi, Patricia; Srivastava, Supriya; Ong, Chee Wee; Yong, Kol Jia; Putti, Thomas; Salto-Tellez, Manuel; Lim, Gkeok Stzuan Diana

2011-12-01

Ovarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment. The authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay. The authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001). The results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm.
Neratinib Approved for HER2+ Breast Cancer.

PubMed

2017-09-01

The FDA approved the tyrosine kinase inhibitor neratinib for extended adjuvant treatment of early-stage HER2-positive breast cancer. The decision adds another treatment option to help prevent recurrence, but its relatively small potential benefit must be weighed against the risk of serious side effects. ©2017 American Association for Cancer Research.
Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

PubMed

Tan, A R; Johannes, H; Rastogi, P; Jacobs, S A; Robidoux, A; Flynn, P J; Thirlwell, M P; Fehrenbacher, L; Stella, P J; Goel, R; Julian, T B; Provencher, L; Bury, M J; Bhatt, K; Geyer, C E; Swain, S M; Mamounas, E P; Wolmark, N

2015-01-01

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.
Effects of childhood body size on breast cancer tumour characteristics

PubMed Central

2010-01-01

Introduction Although a role of childhood body size in postmenopausal breast cancer risk has been established, less is known about its influence on tumour characteristics. Methods We studied the relationships between childhood body size and tumour characteristics in a Swedish population-based case-control study consisting of 2,818 breast cancer cases and 3,111 controls. Our classification of childhood body size was derived from a nine-level somatotype. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from fitting unconditional logistic regression models. Association between somatotype at age 7 and tumour characteristics were evaluated in a case-only analysis where P values for heterogeneity were obtained by performing one degree of freedom trend tests. Results A large somatotype at age 7 was found to be associated with decreased postmenopausal breast cancer risk. Although strongly associated with other risk factors such as age of menarche, adult body mass index and mammographic density, somatotype at age 7 remained a significant protective factor (odds ratio (OR) comparing large to lean somatotype at age 7 = 0.73, 95% confidence interval (CI) = 0.58-0.91, P trend = 0.004) after adjustment. The significant protective effect was observed within all subgroups defined by estrogen receptor (ER) and progesterone receptor (PR) status, with a stronger effect for ER-negative (0.40, 95% CI = 0.21-0.75, P trend = 0.002), than for ER-positive (0.80, 95% CI = 0.62-1.05, P trend = 0.062), tumours (P heterogeneity = 0.046). Somatotype at age 7 was not associated with tumour size, histology, grade or the presence or absence of metastatic nodes. Conclusions Greater body size at age 7 is associated with a decreased risk of postmenopausal breast cancer, and the associated protective effect is stronger for the ER-negative breast cancer subtype than for the ER-positive subtype. PMID:20398298
Targeting siRNA Missiles to Her2+ Breast Cancer

DTIC Science & Technology

2009-06-01

that HerPBK10 protects siRNA from serum nuclease-mediated degradation, T7 transcribed siRNA is more cytotoxic than synthetic siRNA when delivered to...nuclease-mediated degradation, T7 transcribed siRNA is more cytotoxic than synthetic siRNA when delivered to HER2+ breast cancer cells by HerPBK10...produced either synthetically by a commercial vendor (Dharmacon), or from a T7 transcription kit (Ambion), and shRNA, which is reportedly a more effective
Limitations in predicting PAM50 intrinsic subtype and risk of relapse score with Ki67 in estrogen receptor-positive HER2-negative breast cancer

PubMed Central

Fernand ez-Martinez, Aranzazu; Pascual, Tomás; Perrone, Giuseppe; Morales, Serafin; de la Haba, Juan; González-Rivera, Milagros; Galván, Patricia; Zalfa, Francesca; Amato, Michela; Gonzalez, Lucia; Prats, Miquel; Rojo, Federico; Manso, Luis; Paré, Laia; Alonso, Immaculada; Albanell, Joan; Vivancos, Ana; González, Antonio; Matito, Judit; González, Sonia; Fernandez, Pedro; Adamo, Barbara; Muñoz, Montserrat; Viladot, Margarita; Font, Carme; Aya, Francisco; Vidal, Maria; Caballero, Rosalía; Carrasco, Eva; Altomare, Vittorio; Tonini, Giuseppe; Prat, Aleix; Martin, Miguel

2017-01-01

PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%. PMID:28423537
19p13.1 is a triple-negative-specific breast cancer susceptibility locus.

PubMed

Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans-Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K; Meindl, Alfons; Bartram, Claus R; Schott, Sarah; Engel, Christoph; Godwin, Andrew K; Weaver, Joellen; Pathak, Harsh B; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen J; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L; Benítez, Javier; Zamora, María Pilar; Pérez, José Ignacio Arias; Bojesen, Stig E; Nielsen, Sune F; Nordestgaard, Børge G; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Cordina-Duverger, Emilie; Burwinkel, Barbara; Marmé, Frederick; Schneeweiss, Andreas; Sohn, Christof; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; Dos Santos Silva, Isabel; Fasching, Peter A; Beckmann, Matthias W; Hartmann, Arndt; Ekici, Arif B; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K; Broeks, Annegien; Braaf, Linde M; Rosenberg, Efraim H; Hopper, John L; Apicella, Carmel; Park, Daniel J; Southey, Melissa C; Swerdlow, Anthony J; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hsiung, Chia-Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul P; Dunning, Alison M; Humphreys, Manjeet K; Wang, Qin; Cox, Angela; Cross, Simon S; Reed, Malcom W; Hall, Per; Czene, Kamila; Ambrosone, Christine B; Ademuyiwa, Foluso; Hwang, Helena; Eccles, Diana M; Garcia-Closas, Montserrat; Figueroa, Jonine D; Sherman, Mark E; Lissowska, Jolanta; Devilee, Peter; Seynaeve, Caroline; Tollenaar, Rob A E M; Hooning, Maartje J; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M; Miron, Alexander; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Giles, Graham G; Baglietto, Laura; McLean, Catriona A; Severi, Gianluca; Kosel, Matthew L; Pankratz, V S; Slager, Susan; Olson, Janet E; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne-Sophie; Christiaens, Marie-Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M; Soini, Ylermi; Easton, Douglas F; Couch, Fergus J

2012-04-01

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. ©2012 AACR.
Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer.

PubMed

Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

2012-06-15

Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs
Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

PubMed Central

2012-01-01

Background Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0

Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy.

PubMed

Li, Bian; Tao, Wang; Shao-Hua, Zhang; Ze-Rui, Qu; Fu-Quan, Jin; Fan, Li; Ze-Fei, Jiang

2018-04-03

In clinical practice, one subgroup patients of breast cancer might have developed resistance to multi-anti-HER2 targeted drugs(trastuzumab, lapatinib and/or T-DM1) and can not benefit from the anti-HER2 targeted therapy continuously. We attempt to change the next therapic way for these patients. Two patients with metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy were treated with pembrolizumab (2 mg/Kg, day1) plus albumin-bound paclitaxel (125 mg/m 2 , day1,8) every 3 weeks. CT evaluation and HER2 ECD test were performed every 2 cycles. Both of the two patients achieved remarkable response with Partial Remission (PR), meanwhile serum HER2 ECD levels (the upper normal limit is 15 ng/ml) showed a remarkable decreases(compared to the base line decreases 75% and 60% respectively). The results indicate that regimen of pembrolizumab combination with albumin-bound paclitaxel might produce response in patients with HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy.
Immunohistochemistry and alternative FISH testing in breast cancer with HER2 equivocal amplification.

PubMed

Agersborg, Sally; Mixon, Christopher; Nguyen, Thanh; Aithal, Sramila; Sudarsanam, Sucha; Blocker, Forrest; Weiss, Lawrence; Gasparini, Robert; Jiang, Shiping; Chen, Wayne; Hess, Gregory; Albitar, Maher

2018-03-22

While HER2 testing is well established in directing appropriate treatment for breast cancer, a small percentage of cases show equivocal results by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Alternative probes may be used in equivocal cases. We present a single community-based institution's experience in further evaluating these cases. Between 2014 and 2016, 4255 samples were submitted for HER2 amplification testing by alternative probes, TP53, RAI1, and RARA. Of the patients tested by FISH, 505/3908 (12.9%) also had IHC data. Most (73.9%) FISH equivocal cases remained equivocal after IHC testing. However, 50.5% of equivocal cases were classified as HER2 amplified by alternative probes. Most cases were positive by more than one probe: 78% of positive cases by RAI1 and 73.9% by TP53. There was a significant difference between IHC and FISH alternative testing (p < 0.0001) among the equivocal cases by conventional FISH testing, 44% of IHC negative cases became positive while 36% of the positive IHC cases became negative by alternative FISH testing. Available data showed that 41% of patients were treated with palbociclib and were positive by alternative FISH. The prevalence of double HER2 equivocal cases and the discrepancy between IHC and alternative FISH testing suggest that FISH alternative testing using both RAI1 and TP53 probes is necessary for conclusive classification. Because almost half of FISH equivocal cases converted to HER2 amplified upon alternative testing, clinical studies to determine the benefit of anti-HER2 therapy in these patients are urgently needed.
Advantages and disadvantages of technologies for HER2 testing in breast cancer specimens.

PubMed

Furrer, Daniela; Sanschagrin, François; Jacob, Simon; Diorio, Caroline

2015-11-01

Human epidermal growth factor receptor 2 (HER2) plays a central role as a prognostic and predictive marker in breast cancer specimens. Reliable HER2 evaluation is central to determine the eligibility of patients with breast cancer to targeted anti-HER2 therapies such as trastuzumab and lapatinib. Presently, several methods exist for the determination of HER2 status at different levels (protein, RNA, and DNA level). In this review, we discuss the main advantages and disadvantages of the techniques developed so far for the evaluation of HER2 status in breast cancer specimens. Each technique has its own advantages and disadvantages. It is therefore not surprising that no consensus has been reached so far on which technique is the best for the determination of HER2 status. Currently, emphasis must be put on standardization of procedures, internal and external quality control assessment, and competency evaluation of already existing methods to ensure accurate, reliable, and clinically meaningful test results. Development of new robust and accurate diagnostic assays should also be encouraged. In addition, large clinical trials are warranted to identify the technique that most reliably predicts a positive response to anti-HER2 drugs. Copyright© by the American Society for Clinical Pathology.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

PubMed

Slamon, D J; Leyland-Jones, B; Shak, S; Fuchs, H; Paton, V; Bajamonde, A; Fleming, T; Eiermann, W; Wolter, J; Pegram, M; Baselga, J; Norton, L

2001-03-15

The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that
Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function.

PubMed

Garrett, Joan T; Sutton, Cammie R; Kuba, María Gabriela; Cook, Rebecca S; Arteaga, Carlos L

2013-02-01

Dual blockade of HER2 with trastuzumab and lapatinib or with pertuzumab is a superior treatment approach compared with single-agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphoinositide 3-kinase (PI3K)/AKT causes a transcriptional and posttranslational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Inhibition of HER2/HER3 in HER2(+) breast cancer cell lines was evaluated by Western blotting. We analyzed drug-induced apoptosis and two- and three-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3-neutralizing monoclonal antibody U3-1287. Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the antitumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2(+) xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival than mice treated with lapatinib and trastuzumab. Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers.
Evaluation of human epidermal growth factor receptor 2 (HER2) single nucleotide polymorphisms (SNPs) in normal and breast tumor tissues and their link with breast cancer prognostic factors.

PubMed

Furrer, Daniela; Lemieux, Julie; Côté, Marc-André; Provencher, Louise; Laflamme, Christian; Barabé, Frédéric; Jacob, Simon; Michaud, Annick; Diorio, Caroline

2016-12-01

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with worse prognosis and decreased overall survival in breast cancer patients. The HER2 gene contains several polymorphisms; two of the best-characterized HER2 polymorphisms are Ile655Val and Ala1170Pro. The aim of this study was to evaluate the association between these two HER2 polymorphisms in normal breast and breast cancer tissues and known breast cancer prognostic factors in a retrospective cohort study of 73 women with non-metastatic HER2-positive breast cancer. HER2 polymorphisms were assessed in breast cancer tissue and normal breast tissue using TaqMan assay. Ala1170Pro polymorphism in normal breast tissue was associated with age at diagnosis (p = 0.007), tumor size (p = 0.004) and lymphovascular invasion (p = 0.06). Similar significant associations in cancer tissues were observed. No association between the Ile655Val polymorphism and prognostic factors were observed. However, we found significant differences in the distribution of Ile655Val (p = 0.03) and Ala1170Pro (p = 0.01) genotypes between normal breast and breast tumor tissues. This study demonstrates that only the Ala1170Pro polymorphism is associated with prognostic factors in HER2-positive breast cancer patients. Moreover, our results suggest that both HER2 polymorphisms could play a significant role in carcinogenesis in non-metastatic HER2-positive breast cancer women. Copyright © 2016 Elsevier Ltd. All rights reserved.
Establishment of two new cell lines derived from human breast carcinomas with HER-2/neu amplification.

PubMed Central

Meltzer, P.; Leibovitz, A.; Dalton, W.; Villar, H.; Kute, T.; Davis, J.; Nagle, R.; Trent, J.

1991-01-01

Two human cell lines (UACC-812 and 893), both containing significant amplification of the HER-2/neu gene, were established from biopsy specimens of breast carcinomas. One patient had Stage II breast carcinoma; the other had metastatic disease. Characterisation of these lines has revealed that both are highly aneuploid containing multiple clonal chromosome alterations, have doubling times near 100 h, and are oestrogen and progesterone receptor negative. Electron microscopy demonstrates that both lines contain numerous microvilli, cytoplasmic filaments, multivesicular bodies, and desmosomes. Immunoblot analysis for P-glycoprotein using the monoclonal antibody C219 was negative for both patient cell lines. These relatively rare cell lines may represent a useful model to investigate human breast carcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:1674877
A prognostic factor index for overall survival in patients receiving first-line chemotherapy for HER2-negative advanced breast cancer: an analysis of the ATHENA trial.

PubMed

Llombart-Cussac, Antonio; Pivot, Xavier; Biganzoli, Laura; Cortes-Funes, Hernan; Pritchard, Kathleen I; Pierga, Jean-Yves; Smith, Ian; Thomssen, Christoph; Srock, Stefanie; Sampayo, Miguel; Cortes, Javier

2014-10-01

Evidence-based definitions of 'poor-prognosis' or 'aggressive' advanced breast cancer are lacking. We developed a prognostic factor index using data from 2203 patients treated with first-line chemotherapy plus bevacizumab for HER2-negative advanced breast cancer. The risk factors most closely associated with worse OS were: disease-free interval ≤24 months; liver metastases or ≥3 involved organ sites; prior anthracycline and/or taxane therapy; triple-negative breast cancer (TNBC); and performance status 2 or prior analgesic/corticosteroid treatment. Risk of death was increased threefold in patients with ≥3 versus ≤1 risk factors (hazard ratio 3.0 [95% CI 2.6-3.4; p < 0.001]; median 16.0 vs 38.8 months, respectively). This prognostic index may enable identification of patients with a poorer prognosis in whom more intensive systemic regimens may be appropriate. The index may also be considered in designing new trials, although it requires validation in other datasets before extrapolation to non-bevacizumab-containing therapy. ClinicalTrials.gov identifier: NCT00448591. Copyright © 2014 Elsevier Ltd. All rights reserved.
Cooperation of neurotrophin receptor TrkB and Her2 in breast cancer cells facilitates brain metastases.

PubMed

Choy, Cecilia; Ansari, Khairul I; Neman, Josh; Hsu, Sarah; Duenas, Matthew J; Li, Hubert; Vaidehi, Nagarajan; Jandial, Rahul

2017-04-26

Patients with primary breast cancer that is positive for human epidermal growth factor receptor 2 (Her2+) have a high risk of developing metastases in the brain. Despite gains with systemic control of Her2+ disease using molecular therapies, brain metastases remain recalcitrant to therapeutic discovery. The clinical predilection of Her2+ breast cancer cells to colonize the brain likely relies on paracrine mechanisms. The neural niche poses unique selection pressures, and neoplastic cells that utilize the brain microenvironment may have a survival advantage. Tropomyosin-related kinase B (TrkB), Her2, and downstream targets were analyzed in primary breast cancer, breast-to-brain metastasis (BBM) tissues, and tumor-derived cell lines using quantitative real-time PCR, western blot, and immunohistochemical assessment. TrkB function on BBM was confirmed with intracranial, intracardiac, or mammary fat pad xenografts in non-obese diabetic/severe combined immunodeficiency mice. The function of brain-derived neurotrophic factor (BDNF) on cell proliferation and TrkB/Her2 signaling and interactions were confirmed using selective shRNA knockdown and selective inhibitors. The physical interaction of Her2-TrkB was analyzed using electron microscopy, co-immunoprecipitation, and in silico analysis. Dual targeting of Her2 and TrkB was analyzed using clinically utilized treatments. We observed that patient tissues and cell lines derived from Her2+ human BBM displayed increased activation of TrkB, a neurotrophin receptor. BDNF, an extracellular neurotrophin, with roles in neuronal maturation and homeostasis, specifically binds to TrkB. TrkB knockdown in breast cancer cells led to decreased frequency and growth of brain metastasis in animal models, suggesting that circulating breast cancer cells entering the brain may take advantage of paracrine BDNF-TrkB signaling for colonization. In addition, we investigated a possible interaction between TrkB and Her2 receptors on brain metastatic
Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

PubMed

Shak, S

1999-08-01

The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. Clinical experience with this novel biologic has been obtained in more than 1,000 women with HER2-overexpressing metastatic breast cancer. Two pivotal trials were performed to evaluate trastuzumab efficacy and safety: (1) trastuzumab in combination with chemotherapy as first-line therapy and (2) trastuzumab as a single agent in second- and third-line chemotherapy. Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.
HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy.

PubMed

Stocker, Albina; Hilbers, Marie-Luise; Gauthier, Claire; Grogg, Josias; Kullak-Ublick, Gerd A; Seifert, Burkhardt; Varga, Zsuzsanna; Trojan, Andreas

2016-01-01

Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS). Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression. A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact
Role of PTP1B in HER2 Signaling in Breast Cancer

DTIC Science & Technology

2011-10-01

AD_________________ Award Number: W81XWH-10-1-1005 TITLE: Role of PTP1B in HER2 Signaling in...AND SUBTITLE 5a. CONTRACT NUMBER Role of PTP1B in HER2 Signaling in Breast Cancer 5b. GRANT NUMBER W81XWH-10-1-1005 5c. PROGRAM ELEMENT...pathways. Recent reports have shown that Protein Tyrosine Phosphatase 1B ( PTP1B ) plays a positive role in ErbB2-induced breast cancer in vitroand
Neratinib for the treatment of HER2-positive early stage breast cancer.

PubMed

Echavarria, Isabel; López-Tarruella, Sara; Márquez-Rodas, Iván; Jerez, Yolanda; Martin, Miguel

2017-08-01

Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.
19p13.1 is a triple negative-specific breast cancer susceptibility locus

PubMed Central

Stevens, Kristen N.; Fredericksen, Zachary; Vachon, Celine M.; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans-Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K.; Meindl, Alfons; Bartram, Claus R.; Schott, Sarah; Engel, Christof; Godwin, Andrew K.; Weaver, JoEllen; Pathak, Harsh B.; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen J.; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L.; Benítez, Javier; Zamora, M Pilar; Pérez, José Ignacio Arias; Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Børge G; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Cordina-Duverger, Emilie; Burwinkel, Barbara; Marmé, Frederick; Schneeweiss, Andreas; Sohn, Christof; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; Silva, Isabel dos Santos; Fasching, Peter A.; Beckmann, Matthias W.; Hartmann, Arndt; Ekici, Arif B.; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K; Broeks, Annegien; Braaf, Linde M; Rosenberg, Efraim H; Hopper, John L.; Apicella, Carmel; Park, Daniel J.; Southey, Melissa C.; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J.; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hsiung, Chia-Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul P.; Dunning, Alison M; Humphreys, Manjeet K.; Wang, Qin; Cox, Angela; Cross, Simon S.; Reed, Malcom W.; Hall, Per; Czene, Kamila; Ambrosone, Christine B.; Ademuyiwa, Foluso; Hwang, Helena; Eccles, Diana M.; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Sherman, Mark E.; Lissowska, Jolanta; Devilee, Peter; Seynaeve, Caroline; Tollenaar, R.A.E.M.; Hooning, Maartje J.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M.; Miron, Alexander; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Giles, Graham G.; Baglietto, Laura; McLean, Catriona A; Severi, Gianluca; Kosel, Matthew L.; Pankratz, V.S.; Slager, Susan; Olson, Janet E.; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne-Sophie; Christiaens, Marie-Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Soini, Ylermi; Easton, Douglas F.; Couch, Fergus J.

2012-01-01

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways. PMID:22331459
Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

PubMed Central

Law, Mary E.; Davis, Bradley J.; Bartley, Ashton N.; Higgins, Paul J.; Kilberg, Michael S.; Santostefano, Katherine E.; Terada, Naohiro; Heldermon, Coy D.; Castellano, Ronald K.; Law, Brian K.

2017-01-01

Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and “Triple-Negative” Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance. PMID:28423644
Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab.

PubMed

Yao, Evelyn; Zhou, Wei; Lee-Hoeflich, Si Tuen; Truong, Tom; Haverty, Peter M; Eastham-Anderson, Jeffrey; Lewin-Koh, Nicholas; Gunter, Bert; Belvin, Marcia; Murray, Lesley J; Friedman, Lori S; Sliwkowski, Mark X; Hoeflich, Klaus P

2009-06-15

Oncogenic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is prevalent in breast cancer and has been associated with resistance to HER2 inhibitors in the clinic. We therefore investigated the combinatorial activity of GDC-0941, a novel class I PI3K inhibitor, with standard-of-care therapies for HER2-amplified breast cancer. Three-dimensional laminin-rich extracellular matrix cultures of human breast cancer cells were utilized to provide a physiologically relevant approach to analyze the efficacy and molecular mechanism of combination therapies ex vivo. Combination studies were done using GDC-0941 with trastuzumab (Herceptin), pertuzumab, lapatinib (Tykerb), and docetaxel, the principal therapeutic agents that are either approved or being evaluated for treatment of early HER2-positive breast cancer. Significant GDC-0941 activity (EC(50) <1 micromol/L) was observed for >70% of breast cancer cell lines that were examined in three-dimensional laminin-rich extracellular matrix culture. Differential responsiveness to GDC-0941 as a single agent was observed for luminal breast cancer cells upon stimulation with the HER3 ligand, heregulin. Combined treatment of GDC-0941, trastuzumab, and pertuzumab resulted in growth inhibition, altered acinar morphology, and suppression of AKT mitogen-activated protein kinase (MAPK) / extracellular signed-regulated kinase (ERK) kinase and MEK effector signaling pathways for HER2-amplified cells in both normal and heregulin-supplemented media. The GDC-0941 and lapatinib combination further showed that inhibition of HER2 activity was essential for maximum combinatorial efficacy. PI3K inhibition also rendered HER2-amplified BT-474M1 cells and tumor xenografts more sensitive to docetaxel. GDC-0941 is efficacious in preclinical models of breast cancer. The addition of GDC-0941 to HER2-directed treatment could augment clinical benefit in breast cancer patients.
Potential use of COX-2–aromatase inhibitor combinations in breast cancer

PubMed Central

Bundred, N J; Barnes, N L P

2005-01-01

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer. PMID:16100520
HER2-positive breast cancer: Current and new therapeutic strategies.

PubMed

Escrivá-de-Romaní, Santiago; Arumí, Miriam; Bellet, Meritxell; Saura, Cristina

2018-06-01

Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far. Copyright © 2018 Elsevier Ltd. All rights reserved.
Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy

PubMed Central

Giuliano, Mario; Hu, Huizhong; Wang, Yen-Chao; Fu, Xiaoyong; Nardone, Agostina; Herrera, Sabrina; Mao, Sufeng; Contreras, Alejandro; Gutierrez, Carolina; Wang, Tao; Hilsenbeck, Susan G.; De Angelis, Carmine; Wang, Nicholas J.; Heiser, Laura M.; Gray, Joe W.; Lopez-Tarruella, Sara; Pavlick, Anne C.; Trivedi, Meghana V.; Chamness, Gary C.; Chang, Jenny C.; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel

2015-01-01

Purpose To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples. Experimental design Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies, and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 post treatment), were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and western blot. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro. Results Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy, compared with untreated tumors, in both preclinical models (UACC812: ER p=0.0014; Bcl2 p<0.001. MCF7/HER2-18: ER p=0.0007; Bcl2 p=0.0306). In the neoadjuvant clinical study, lapatinib treatment for two weeks was associated with parallel upregulation of ER and Bcl2 (Spearman’s coefficient: 0.70; p=0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER re-expression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (p=0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (p<0.0001). Conclusion HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. PMID:26015514
HER2-positive male breast cancer with thyroid cancer: an institutional report and review of literature.

PubMed

Bardhan, Pooja; Bui, Marilyn M; Minton, Susan; Loftus, Loretta; Carter, W Bradford; Laronga, Christine; Ismail-Khan, Roohi

2012-01-01

We report a rare finding of two male breast cancer patients with HER2-positive breast cancer who also developed thyroid cancer. We reviewed 45 male breast cancer patients treated in our institution from 2003 to 2008. Only five male breast cancer patients were HER2-positive. In reviewing the published data, we found no cases of thyroid cancer and concurrent breast cancer in men. However, breast cancer and thyroid cancer have shown close association in women. This finding therefore provokes speculation as to whether we should investigate whether women with HER2-positive breast cancer are at a higher risk for thyroid cancer. Although this observation seems to be clinically prevalent, publications are sparse in clinical research areas linking thyroid cancer to breast cancer.

The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours.

PubMed

Varley, J M; Armour, J; Swallow, J E; Jeffreys, A J; Ponder, B A; T'Ang, A; Fung, Y K; Brammar, W J; Walker, R A

1989-06-01

We have analysed the organisation of the retinoblastoma (RB1) gene in 77 primary breast carcinomas, in metastatic tissue derived from 16 of those primary tumours, and in a variety of benign breast lesions. Expression of RB1 was also assessed in most samples by immunohistochemical detection of the RB1 protein in tissue sections. Structural abnormalities to RB1 were detected in DNA from 15/77 (19%) of primary breast carcinomas examined. Where DNA was available from metastatic tissue derived from such primary tumours, the same aberration could be detected. No alterations were seen in benign breast lesions. 16/56 (29%) of tumours examined for expression by immunohistochemical methods showed a proportion of tumour cells to be completely negative for the RB1 protein. All tumours in which a structural alteration to RB1 was detected had a proportion of negative cells, except for one case where all cells were positive. Several primary tumour samples were identified where there was no detectable structural change to the gene, but there was loss of expression in some tumour cells. The data presented here demonstrate that changes to the RB1 gene leading to loss of expression of both alleles are frequent in primary human breast tumours.
A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.

PubMed

Risi, Emanuela; Grilli, Andrea; Migliaccio, Ilenia; Biagioni, Chiara; McCartney, Amelia; Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo; Vitale, Stefania; Biganzoli, Laura; Bicciato, Silvio; Di Leo, Angelo; Malorni, Luca

2018-07-01

HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.
ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer.

PubMed

Paplomata, Elisavet; Nahta, Rita

2018-03-01

Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for 'ABP 980' or 'trastuzumab biosimilar'. 'ABP 980 and breast cancer' or 'trastuzumab biosimilar and breast cancer' were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included. Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.
Utility of the CPS+EG staging system in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated with neoadjuvant chemotherapy.

PubMed

Marmé, Frederik; Lederer, Bianca; Blohmer, Jens-Uwe; Costa, Serban Dan; Denkert, Carsten; Eidtmann, Holger; Gerber, Bernd; Hanusch, Claus; Hilfrich, Jörn; Huober, Jens; Jackisch, Christian; Kümmel, Sherko; Loibl, Sibylle; Paepke, Stefan; Untch, Michael; von Minckwitz, Gunter; Schneeweiss, Andreas

2016-01-01

Pathologic complete response after neoadjuvant chemotherapy (NACT) correlates with overall survival (OS) in primary breast cancer. A recently described staging system based on pre-treatment clinical stage (CS), final pathological stage (PS), estrogen receptor (ER) status and nuclear grade (NG) leads to a refined estimation of prognosis in unselected patients. Its performance in luminal type breast cancers has not been determined. This study investigates the clinical utility of this CPS+EG score when restricted to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients and compares the results to a cohort of unselected patients. The CPS+EG score was calculated for 6637 unselected patients and 2454 patients with HR+/HER2- tumours who received anthracycline/taxane-based NACT within 8 prospective German trials. Five-year disease-free survival (DFS) and OS were 75.6% and 84.1% for the unselected cohort and 80.6% and 87.8% for the HR+/HER2- subgroup, respectively. The CPS+EG system distinguished different prognostic groups with 5-year DFS ranging from 0% to 91%. The CPS+EG system leads to an improved categorisation of patients by outcome compared to CS, PS, ER or NG alone. When applying the CPS+EG score to the HR+/HER2- subgroup, a shift to lower scores was observed compared to the overall population, but 5-year DFS and OS for the individual scores were identical to that observed in the overall population. In HR+/HER2- patients, the CPS+EG staging system retains its ability to facilitate a refined stratification of patients according to outcome. It can help to select candidates for post-neoadjuvant clinical trials in luminal breast cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
Oestrogen receptor negativity in breast cancer: a cause or consequence?

PubMed Central

Gajulapalli, Vijaya Narasihma Reddy; Malisetty, Vijaya Lakshmi; Chitta, Suresh Kumar; Manavathi, Bramanandam

2016-01-01

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers. PMID:27884978
Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers

PubMed Central

Ghosh, Ritwik; Narasanna, Archana; Wang, Shizhen Emily; Liu, Shuying; Chakrabarty, Anindita; Balko, Justin M.; González-Angulo, Ana María; Mills, Gordon B.; Penuel, Elicia; Winslow, John; Sperinde, Jeff; Dua, Rajiv; Pidaparthi, Sailaja; Mukherjee, Ali; Leitzel, Kim; Kostler, Wolfgang J.; Lipton, Allan; Bates, Michael; Arteaga, Carlos L.

2011-01-01

In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925
Could HER2 heterogeneity open new therapeutic options in patients with HER2- primary breast cancer

DTIC Science & Technology

is an initial proof-of-concept that targeted imaging may help identify patients eligible for targeted therapies. However, six of nine patients have...needed. A first-in-human trial of 89Zr-pertuzumab PET/CT was performed in six patients with HER2-positive metastatic breast cancer, demonstrating
HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy

PubMed Central

Stocker, Albina; Hilbers, Marie-Luise; Gauthier, Claire; Grogg, Josias; Kullak-Ublick, Gerd A.; Seifert, Burkhardt; Varga, Zsuzsanna

2016-01-01

Background Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS). Methods Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007–2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression. Results A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23–89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy
Tumour location within the breast: Does tumour site have prognostic ability?

PubMed

Rummel, Seth; Hueman, Matthew T; Costantino, Nick; Shriver, Craig D; Ellsworth, Rachel E

2015-01-01

Tumour location within the breast varies with the highest frequency in the upper outer quadrant (UOQ) and lowest frequency in the lower inner quadrant (LIQ). Whether tumour location is prognostic is unclear. To determine whether tumour location is prognostic, associations between tumour site and clinicopathological characteristics were evaluated. All patients enrolled in the Clinical Breast Care Project whose tumour site-UOQ, upper inner quadrant (UIQ), central, LIQ, lower outer quadrant (LOQ)-was determined by a single, dedicated breast pathologist were included in this study. Patients with multicentric disease (n = 122) or tumours spanning multiple quadrants (n = 381) were excluded from further analysis. Clinicopathological characteristics were analysed using chi-square tests for univariate analysis with multivariate analysis performed using principal components analysis (PCA) and multiple logistic regression. Significance was defined as P < 0.05. Of the 980 patients with defined tumour location, 30 had bilateral disease. Tumour location in the UOQ (51.5%) was significantly higher than in the UIQ (15.6%), LOQ (14.2%), central (10.6%), or LIQ (8.1%). Tumours in the central quadrant were significantly more likely to have higher tumour stage (P = 0.003) and size (P < 0.001), metastatic lymph nodes (P < 0.001), and mortality (P = 0.011). After multivariate analysis, only tumour size and lymph node status remained significantly associated with survival. Evaluation of tumour location as a prognostic factor revealed that although tumours in the central region are associated with less favourable outcome, these associations are not independent of location but rather driven by larger tumour size. Tumours in the central region are more difficult to detect mammographically, resulting in larger tumour size at diagnosis and thus less favourable prognosis. Together, these data demonstrate that tumour location is not an independent prognostic factor.
Integrin Alpha-v and HER2 in Breast Cancer Brain Metastasis

DTIC Science & Technology

2015-10-01

ZOOM live cell imaging machine (ESSEN Bioscience; Figure 2). c. Interactions of αv integrin and HER2 in breast cancer brain metastases. We found...HCC1954 breast cancer cells. C) Real time live cell imaging of MM2BH cells treated with cilengitide (0, .3, 1, 3, and 10 µg/mL) using IncuCyte ZOOM
Her2Net: A Deep Framework for Semantic Segmentation and Classification of Cell Membranes and Nuclei in Breast Cancer Evaluation.

PubMed

Saha, Monjoy; Chakraborty, Chandan

2018-05-01

We present an efficient deep learning framework for identifying, segmenting, and classifying cell membranes and nuclei from human epidermal growth factor receptor-2 (HER2)-stained breast cancer images with minimal user intervention. This is a long-standing issue for pathologists because the manual quantification of HER2 is error-prone, costly, and time-consuming. Hence, we propose a deep learning-based HER2 deep neural network (Her2Net) to solve this issue. The convolutional and deconvolutional parts of the proposed Her2Net framework consisted mainly of multiple convolution layers, max-pooling layers, spatial pyramid pooling layers, deconvolution layers, up-sampling layers, and trapezoidal long short-term memory (TLSTM). A fully connected layer and a softmax layer were also used for classification and error estimation. Finally, HER2 scores were calculated based on the classification results. The main contribution of our proposed Her2Net framework includes the implementation of TLSTM and a deep learning framework for cell membrane and nucleus detection, segmentation, and classification and HER2 scoring. Our proposed Her2Net achieved 96.64% precision, 96.79% recall, 96.71% F-score, 93.08% negative predictive value, 98.33% accuracy, and a 6.84% false-positive rate. Our results demonstrate the high accuracy and wide applicability of the proposed Her2Net in the context of HER2 scoring for breast cancer evaluation.
Paraneoplastic cerebellar degeneration with anti-Yo antibody in a patient with HER2/neu overexpressing breast cancer: a case report with a current literature review.

PubMed

Ogita, Shin; Llaguna, Omar H; Feldman, Sheldon M; Blum, Ronald

2008-01-01

Paraneoplastic cerebellar degeneration (PCD) is a rare paraneoplastic syndrome, occurring in <1% of breast cancers. We describe a 32-year-old female presenting with ataxia subsequently diagnosed with poorly differentiated breast cancer. She was serum anti-Yo antibody positive, with estrogen/progesterone receptor negative and HER2/neu receptor positive breast cancer. Neurological symptoms progressed despite modified radical mastectomy, supraclavicular lymphadenectomy, intravenous immunoglobulin, corticosteroids, transtuzumab, and combination chemotherapy. We performed a literature search, which found a possible association between anti-Yo positive PCD and HER2/neu-expressing breast cancer.
Breast tumour visualization using 3D quantitative ultrasound methods

NASA Astrophysics Data System (ADS)

Gangeh, Mehrdad J.; Raheem, Abdul; Tadayyon, Hadi; Liu, Simon; Hadizad, Farnoosh; Czarnota, Gregory J.

2016-04-01

Breast cancer is one of the most common cancer types accounting for 29% of all cancer cases. Early detection and treatment has a crucial impact on improving the survival of affected patients. Ultrasound (US) is non-ionizing, portable, inexpensive, and real-time imaging modality for screening and quantifying breast cancer. Due to these attractive attributes, the last decade has witnessed many studies on using quantitative ultrasound (QUS) methods in tissue characterization. However, these studies have mainly been limited to 2-D QUS methods using hand-held US (HHUS) scanners. With the availability of automated breast ultrasound (ABUS) technology, this study is the first to develop 3-D QUS methods for the ABUS visualization of breast tumours. Using an ABUS system, unlike the manual 2-D HHUS device, the whole patient's breast was scanned in an automated manner. The acquired frames were subsequently examined and a region of interest (ROI) was selected in each frame where tumour was identified. Standard 2-D QUS methods were used to compute spectral and backscatter coefficient (BSC) parametric maps on the selected ROIs. Next, the computed 2-D parameters were mapped to a Cartesian 3-D space, interpolated, and rendered to provide a transparent color-coded visualization of the entire breast tumour. Such 3-D visualization can potentially be used for further analysis of the breast tumours in terms of their size and extension. Moreover, the 3-D volumetric scans can be used for tissue characterization and the categorization of breast tumours as benign or malignant by quantifying the computed parametric maps over the whole tumour volume.
Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy

PubMed Central

Floros, Konstantinos V.; Hu, Bin; Monterrubio, Carles; Hughes, Mark T.; Wells, Jason D.; Morales, Cristina Bernadó; Ghotra, Maninderjit S.; Costa, Carlotta; Souers, Andrew J.; Boikos, Sosipatros A.; Leverson, Joel D.; Tan, Ming; Serra, Violeta; Koblinski, Jennifer E.; Arribas, Joaquin; Prat, Aleix; Paré, Laia; Miller, Todd W.; Harada, Hisashi; Windle, Brad E.; Scaltriti, Maurizio; Faber, Anthony C.

2018-01-01

HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes. PMID:29476008
Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization.

PubMed

Pauletti, G; Godolphin, W; Press, M F; Slamon, D J

1996-07-04

Amplification and overexpression of the HER-2/neu gene occurs in 25-30% of human breast cancers. This genetic alteration is associated with a poor clinical prognosis in women with either node negative or node positive breast cancers. The initial studies testing this association were somewhat controversial and this controversy was due in large part to significant heterogeneity in both the methods and/or reagents used in testing archival material for the presence of the alteration. These methods included a number of solid matrix blotting techniques for DNA, RNA and protein as well as immunohistochemistry. Fluorescence in situ hybridization (FISH) represents the newest methodologic approach for testing for this genetic alteration. In this study, FISH is compared to Southern, Northern and Western blot analyses as well as immunohistochemistry in a large cohort of archival human breast cancer specimens. FISH was found to be superior to all other methodologies tested in assessing formalin fixed, paraffin embedded material for HER-2/neu amplification. The results from this study also confirm that overexpression of HER-2/neu rarely occurs in the absence of gene amplification in breast cancer (approximately 3% of cases). This method of analysis is rapid, reproducible and extremely reliable in detecting presence of HER-2/neu gene amplification and should have clinical utility.
Prevention of ER-Negative Breast Cancer

PubMed Central

Li, Yuxin

2014-01-01

The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer. PMID:19213564
Local recurrence of a phyllodes tumour of the breast presenting with widespread differentiation to a telangiectatic osteosarcoma.

PubMed Central

Graadt van Roggen, J F; Zonderland, H M; Welvaart, K; Peterse, J L; Hogendoorn, P C

1998-01-01

Osteogenic sarcomas of the breast are extremely rare and need to be distinguished from a variety of breast lesions producing metaplastic bone. A 50 year old patient presented with a painless lump in her right breast after twice previously having undergone local excision of a phyllodes tumour at this site. Following radiological and cytological investigation, excision was advised. Histology showed focal remnants of the previously excised phyllodes tumour in continuity with areas of widespread differentiation towards a telangiectatic osteosarcoma. So far this is a unique morphological endpoint. Images PMID:9930079
Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67.

PubMed

Xu, Junnan; Guo, Xiangyu; Jing, Mingxi; Sun, Tao

2018-01-01

Cancer immunoediting is the process of eliminating highly immunogenic tumor cells by somatic evolution and protecting the host from tumor development in the host immune system. Frequencies of somatic mutations or tumor mutation burden (TMB) were associated with immunogenicity of breast cancer. This study aimed to predict the level of TMB in patients with breast cancer by the expression of estrogen (ER), progesterone (PR), HER-2, and Ki-67, thereby anticipating the prognosis of patients and the possible response to immunotherapy. In 53 patients with breast cancer, the 453 multigenes panel based on NGS was used to determine the TMB value of breast cancer in the patient's primary tumor tissues. The predicted TMB value was divided into 4 groups: A (0-3.33), B (3.33-5.56), C (5.56-8.89), and D (>8.89), according to the quartile method, with group A as reference level. Logistic regression was used to analyze the risk ratio of each molecule type, and the prediction model was established. Survival probabilities by covariates were assessed using Kaplan-Meier estimator survival analysis and Cox's proportional hazards models. In 53 patients, the TMB value measured by the NGS polygenic panel was between 0 and 14.4/Mb. TMB distribution in 53 cases of breast cancer tissue: 18 cases in A group, 22 cases in B group, 10 cases in C group, and 3 cases in D group. HER-2 expression positivity was significantly associated with TMB (HER-2 positive vs HER-2 negative, odds ratio [OR] =34.81, 95% confidence interval [CI]: 3.711-821.689, P =0.0065). Higher TMB was distributed in the patients who were Ki-67 expression positive (>14%) than those who were Ki-67 expression negative (≤14%) (OR =0.217, 95% CI: 0.054-0.806, P =0.0242). However, no significant differences of TMB were found between ER-positive group and ER-negative group (OR =3.133, 95% CI: 0.124-127.687, P =0.4954) and between PR-positive group and PR-negative group in terms of TMB (OR =1.702, 95% CI: 0.162-20.335, P =0.6492). The
HER-2 as a Progression Factor and Therapeutic Target in Breast Cancer.

DTIC Science & Technology

1999-06-01

used gene specific targeting of HER-2 with hammerhead - ribozyme expression constructs, a technology which we have applied successfully in the...2 in MCF-7 cells by ribozyme -targeting estradiol lost its ability to induce anchorage- independent colony formation in soft agar of the tumor cells...between estrogen and HER-2 signal transduction is ongoing. 14. SUBJECT TERMS Breast Cancer HER-2, estradiol, ribozymes , apoptosis, cell cycle, cDNA
Lymphangiogenesis assessed using three methods is related to tumour grade, breast cancer subtype and expression of basal marker.

PubMed

Niemiec, Joanna; Adamczyk, Agnieszka; Ambicka, Aleksandra; Mucha-Małecka, Anna; Wysocki, Wojciech; Mituś, Jerzy; Ryś, Janusz

2012-11-01

Lymphangiogenesis is a potential indicator of cancer patients' survival. However, there is no standardisation of methodologies applied to the assessment of lymphatic vessel density. In 156 invasive ductal breast cancers (T  1/N+/M0), lymphatic and blood vessels were visualised using podoplanin and CD34, respectively. Based on these markers expression, four parameters were assessed: (i) distribution of podoplanin-stained vessels (DPV) - the percentage of fields with at least one lymphatic vessel (a simple method proposed by us), (ii) lymphatic vessel density (LVD), (iii) LVD to microvessel density ratio (LVD/MVD) and (iv) the expression of podoplanin in cancer-associated fibroblasts. Next, we estimated relations between the above-mentioned parameters and: (i) breast cancer subtype, (ii) tumour grade, and (iii) basal markers expression. We found that intensive lymphangiogenesis, assessed using all studied methods, is positively related to high tumour grade, triple negative or HER2 subtype and expression of basal markers. Whereas, the absence of podoplanin expression in fibroblasts of cancer stroma is related to luminal A subtype, low tumour grade or lack of basal markers expression. Distribution of podoplanin-stained vessels, assessed by a simple method proposed by us (indicating the percentage of fields with at least one lymphatic vessel), might be used instead of the "hot-spot" method.

Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

ClinicalTrials.gov

2016-10-04

Breast Adenocarcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma
Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial.

PubMed

Goss, Paul E; Smith, Ian E; O'Shaughnessy, Joyce; Ejlertsen, Bent; Kaufmann, Manfred; Boyle, Frances; Buzdar, Aman U; Fumoleau, Pierre; Gradishar, William; Martin, Miguel; Moy, Beverly; Piccart-Gebhart, Martine; Pritchard, Kathleen I; Lindquist, Deborah; Chavarri-Guerra, Yanin; Aktan, Gursel; Rappold, Erica; Williams, Lisa S; Finkelstein, Dianne M

2013-01-01

Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis. This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 [corrected] centres in 33 countries [corrected] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322. Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4-60·0) in the lapatinib group and 48·3 (0·7-61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70-1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67-1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3-4 diarrhoea (97 [6%] vs nine [<1%]), rash (72 [5%] vs three
Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.

PubMed

Taskar, Kunal S; Rudraraju, Vinay; Mittapalli, Rajendar K; Samala, Ramakrishna; Thorsheim, Helen R; Lockman, Julie; Gril, Brunilde; Hua, Emily; Palmieri, Diane; Polli, Joseph W; Castellino, Stephen; Rubin, Stephen D; Lockman, Paul R; Steeg, Patricia S; Smith, Quentin R

2012-03-01

Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. (14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains. Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.
Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy

PubMed Central

Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

2018-01-01

The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1/PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients. PMID:29662653
Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy.

PubMed

Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

2018-03-27

The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1 / PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients.
Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

Doi, Toshihiko; Shitara, Kohei; Naito, Yoichi; Shimomura, Akihiko; Fujiwara, Yasuhiro; Yonemori, Kan; Shimizu, Chikako; Shimoi, Tatsunori; Kuboki, Yasutoshi; Matsubara, Nobuaki; Kitano, Atsuko; Jikoh, Takahiro; Lee, Caleb; Fujisaki, Yoshihiko; Ogitani, Yusuke; Yver, Antoine; Tamura, Kenji

2017-11-01

Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they
Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer.

PubMed

Pérez-Gómez, Eduardo; Andradas, Clara; Blasco-Benito, Sandra; Caffarel, María M; García-Taboada, Elena; Villa-Morales, María; Moreno, Estefanía; Hamann, Sigrid; Martín-Villar, Ester; Flores, Juana M; Wenners, Antonia; Alkatout, Ibrahim; Klapper, Wolfram; Röcken, Christoph; Bronsert, Peter; Stickeler, Elmar; Staebler, Annette; Bauer, Maret; Arnold, Norbert; Soriano, Joaquim; Pérez-Martínez, Manuel; Megías, Diego; Moreno-Bueno, Gema; Ortega-Gutiérrez, Silvia; Artola, Marta; Vázquez-Villa, Henar; Quintanilla, Miguel; Fernández-Piqueras, José; Canela, Enric I; McCormick, Peter J; Guzmán, Manuel; Sánchez, Cristina

2015-06-01

Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with
Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL INVESTIGATOR...Elizabeth A. Mittendorf, MD, PhD CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX 77030 REPORT DATE: October...CONTRACT NUMBER Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer 5b. GRANT NUMBER W81XWH-14-1-0109 5c. PROGRAM
[Her2 testing in gastric cancer. What is different in comparison to breast cancer?].

PubMed

Rüschoff, J; Nagelmeier, I; Baretton, G; Dietel, M; Höfler, H; Schildhaus, H U; Büttner, R; Schlake, W; Stoss, O; Kreipe, H H

2010-05-01

Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values of > or =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.
Adjuvant trastuzumab in HER2-positive breast cancer.

PubMed

Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; von Minckwitz, Gunter; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John

2011-10-06

Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).
Platinum Based Chemotherapy or Capecitabine in Treating Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy

ClinicalTrials.gov

2017-12-07

Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma
Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.

PubMed

De Mattos-Arruda, Leticia; Ng, Charlotte K Y; Piscuoglio, Salvatore; Gonzalez-Cao, Maria; Lim, Raymond S; De Filippo, Maria R; Fusco, Nicola; Schultheis, Anne M; Ortiz, Carolina; Viteri, Santiago; Arias, Alexandra; Macedo, Gabriel S; Oliveira, Mafalda; Gomez, Patricia; Teixidó, Cristina; Nuciforo, Paolo; Peg, Vicente; Saura, Cristina; Ramon Y Cajal, Santiago; Casas, Francesc Tresserra; Weigelt, Britta; Cortes, Javier; Seoane, Joan; Reis-Filho, Jorge S

2018-04-17

Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR , homozygous deletion in CDKN2A and amplification in KRAS . Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53 . Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.
Clinical utility of serum HER-2/neu testing on the Bayer Immuno 1 automated system in breast cancer.

PubMed

Cook, G B; Neaman, I E; Goldblatt, J L; Cambetas, D R; Hussain, M; Lüftner, D; Yeung, K K; Chan, D W; Schwartz, M K; Allard, W J

2001-01-01

The clinical utility of automated serum HER-2/neu measurements in breast cancer run on the Bayer random analyzer Immuno 1 was analyzed in several steps: [a] The reference interval was determined for 242 normal healthy pre- and postmenopausal females. [b] The clinical specificity of serum HER-2/neu to separate healthy controls from 210 patients with non-malignant breast--and non-breast diseases was calculated. [c] The clinical sensitivity of cross-sectional serum HER-2/neu values for 204 patients (pts) with stage I-IV breast cancer was established. [d] Specimens from 103 stage IV breast cancer pts were tested for their parallel between serial serum HER-2/neu results and disease course. [a] The value of 13.03 ng/ml exceeded 95% of the results from the healthy female population. Based on the mean +2 standard deviations value of 14.7 ng/dl, the upper limit of normal was established at 15 ng/ml. [b] The specificity for benign breast diseases and other benign non-breast diseases was 98.0% and 94.6%, respectively. [c] The correlation of increased serum HER-2/neu levels and stage of breast cancer revealed the best sensitivity of 40% for stage IV disease. [4] Thirty-eight (36.9%) of 103 stage IV patients had initial HER-2/neu values > 15 ng/ml, 33 of whom showed longitudinal HER-2/neu concentrations which paralleled the clinical course of the disease giving a sensitivity of 86.8%.
Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

PubMed

Oliveira, Mafalda; Braga, Sofia; Passos-Coelho, José Luís; Fonseca, Ricardo; Oliveira, João

2011-06-01

Trastuzumab, a monoclonal antibody against the HER2 receptor, is a major breakthrough in the treatment of HER2+ breast cancer. However, its high molecular weight precludes it from crossing the intact blood-brain barrier, making the central nervous system a sanctuary to HER2+ breast cancer metastases. We prospectively assessed functional outcome and toxicity of administering trastuzumab directly into the cerebrospinal fluid of a patient with leptomeningeal carcinomatosis (LC) and brain metastases from HER2+ breast cancer that had already been treated with other intrathecal chemotherapy, with no benefit. Upon signed informed consent, weekly lumbar puncture with administration of trastuzumab 25 mg was begun to a 44 year-old women with metastatic breast cancer (lymph node, bone, lung, and liver involvement) previously treated with tamoxifen, letrozole, anthracyclines, taxanes, capecitabine, intravenous trastuzumab, and lapatinib. She received 67 weekly administrations of intrathecal trastuzumab with marked clinical improvement and no adverse events. She survived 27 months after LC diagnosis. A complete leptomeningeal response, with no evidence of leptomeningeal metastasis at necropsy, was achieved. We believe that intrathecal trastuzumab administration should be prospectively evaluated to confirm clinical activity and optimize dose, schedule, and duration of treatment.
Primary mucinous cystadenocarcinoma of the breast with amplification of the HER2 gene confirmed by FISH - case report and review of the literature.

PubMed

Kucukzeybek, Betul Bolat; Yigit, Seyran; Sari, Ayşegul Akder; Rezanko, Turkan; Durak, Evren; Sadullahoglu, Canan

2014-03-01

Fifty five-years-old woman was presented to the general surgery upon the palpation of a mass in her left breast. In the excisional biopsy performed, partially cystic tumor of 2 × 1 cm with solid areas was macroscopically observed. After through microscopic examination, the patient was diagnosed as invasive mucinous cystadenocarcinoma and the tumor was found to be ER- and PR-negative and C-erbB2 (2+). In the fluorescent in situ hybridization, HER2/neu gene amplification was observed. Here, we present the clinical, cytological, morphological and immunohistochemical features of a very rare type of breast carcinoma, mucinous cystadenocarcinoma of the breast, with the review of the relevant literature.
Probing HER2-PUMA and EGFR-PUMA Crosstalks in Aggressive Breast Cancer

DTIC Science & Technology

2013-09-01

malignant biology and drug-resistant phenotype of EGFR- and/or HER2-overexpressing breast cancer and to use the acquired knowledge for the development...with PUMA, we first assessed whether HER2 can physically interact with PUMA using immunoprecipitation/western blotting (IP/WB). We used SK-BR3 and BT...activate HER2. We subjected the cell lysates to IP/WB using a PUMA antibody for IP and immunoblotted with anti-phospho-tyrosine antibodies. As shown
Surgery of primary tumour has survival benefit in metastatic breast cancer with single-organ metastasis, especially bone.

PubMed

Rhu, Jinsoo; Lee, Se Kyung; Kil, Won Ho; Lee, Jeong Eon; Nam, Seok Jin

2015-04-01

Surgery for the primary breast tumour is usually not recommended in metastatic breast cancer (MBC); however, some reports have suggested a benefit of locoregional treatment. We designed this study to evaluate the efficacy of locoregional surgery in MBC. Data for patients diagnosed with MBC at Samsung Medical Center between 1995 and 2011 were retrospectively collected. We compared the survival benefit of all treatment modalities using Cox regression analysis. Subgroup analyses based on number of metastases were performed to delineate the indication for each treatment. Among 262 patients, 40 (15.3%) underwent surgery. Other treatments included chemotherapy (n = 213, 81.3%), radiotherapy (n = 138, 52.7%), hormone therapy (n = 118, 45.0%) and HER2/neu receptor (HER2)-targeted therapy (n = 37, 14.1%). Cox regression analysis showed that surgery (hazard ratios (HR) = 0.51, P < 0.01), hormone therapy (HR = 0.31, P < 0.01) and HER2-targeted therapy (HR = 0.33, P < 0.01) were associated with improved survival, whereas presence of three or more metastatic organs (HR = 1.62, P = 0.03) was associated with poor survival. In patients with metastasis to a single organ, surgery (HR = 0.43, P < 0.01), chemotherapy (HR = 0.62, P = 0.05), hormone therapy (HR = 0.39, P < 0.01) and HER2-targeted therapy (HR = 0.39, P = 0.02) had a survival benefit. Furthermore, for patients with bone-only metastasis, surgery (HR = 0.37, P = 0.02), chemotherapy (HR = 0.42, P < 0.01), hormone therapy (HR = 0.22, P < 0.01) and HER2-targeted therapy (HR = 0.09, P = 0.02) showed a survival benefit. However, only hormone therapy and HER2-targeted therapy had a survival benefit in MBC with metastasis to multiple organs. Surgical control of the primary breast tumour should be considered as a locoregional therapy in combination with systemic therapy in MBC with metastasis to a single organ, especially bone-only metastasis.
Development of a Targeted anti-HER2 scFv Chimeric Peptide for Gene Delivery into HER2-Positive Breast Cancer Cells.

PubMed

Cheraghi, Roya; Nazari, Mahboobeh; Alipour, Mohsen; Majidi, Asia; Hosseinkhani, Saman

2016-12-30

Chimeric polymers are known as suitable carriers for gene delivery. Certain properties are critical for a polymer to be used as a gene delivery vector. A new polymer was designed for the targeted delivery of genes into breast cancer cell lines, based on MPG peptide. It is composed of different functional domains, including HIV gp41, nuclear localization sequence of SV40 T-antigen, two C-terminus repeats of histone H1, and the scFv of anti-HER2 antibody. The results demonstrated that the vector can effectively condense plasmid DNA into nanoparticles with an average size of 250nm. Moreover, fusion of the scFv portion to the carrier brought about the specific recognition of HER2. Overall, the transfection efficiency of the vector demonstrated that it could deliver the desired gene into BT-474 HER2-positive breast cancer cells. Copyright Â© 2016 Elsevier B.V. All rights reserved.
Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions

PubMed Central

Recondo, Gonzalo Jr; Dìaz Canton, Enrique; de la Vega, Màximo; Greco, Martin; Recondo, Gonzalo Sr; Valsecchi, Matias E

2014-01-01

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2 (HER-2) positive breast cancer. Trastuzumab, pertuzumab, ado-trastuzumab emtansine and lapatinib are currently food and drug administration (FDA)-approved for the treatment of breast cancer patients with HER-2 over-expressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated information related to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available. PMID:25114858
Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor.

PubMed

Andreani, Cristina; Bartolacci, Caterina; Wijnant, Kathleen; Crinelli, Rita; Bianchi, Marzia; Magnani, Mauro; Hysi, Albana; Iezzi, Manuela; Amici, Augusto; Marchini, Cristina

2017-02-26

The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice. This in vivo tumor-promoting effect of resveratrol was associated with up-regulation of Δ16HER2 and down-regulation of ERα protein levels and was recapitulated in vitro by murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Δ16HER2 accumulation which favors the formation of Δ16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models.

Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer

ClinicalTrials.gov

2017-02-28

Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer
Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma.

PubMed

Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

2017-01-01

Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER.
Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

PubMed

Yang, Yun; Guo, Rui; Tian, Xiaoting; Zhang, Ziheng; Zhang, Pengfei; Li, Changzheng; Feng, Zhiwei

2017-08-05

Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.
Carboplatin and Paclitaxel Albumin-Stabilized Nanoparticle Formulation Before Surgery in Treating Patients With Locally Advanced or Inflammatory Triple Negative Breast Cancer

ClinicalTrials.gov

2018-05-04

Inflammatory Breast Cancer; Stage IIA Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer; Stage IIB Breast Cancer; Estrogen Receptor Negative; Progesterone Receptor Negative; HER2/Neu Negative
ABO and Rh blood groups frequency in women with HER2 positive breast cancer.

PubMed

Urun, Y; Utkan, G; Altundag, K; Arslan, O; Onur, H; Arslan, U Y; Kocer, M; Dogan, I; Senler, F C; Yalcin, B; Demirkazik, A; Akbulut, H; Icli, F

2012-01-01

The role of genetic factors in the development of cancer is widely accepted. Data on the role of ABO blood group and Rh factor in breast cancer is inconclusive. The aim of this study was to investigate the presence of a possible association between HER2 (+) breast cancer in Turkish women and ABO blood groups and Rh factor. In 294 female patients with HER2 (+) breast cancer, ABO blood groups and Rh factor were examined. The relationship of blood groups with age, menopausal status, and family history of cancer, estrogen receptor (ER), progesterone receptor (PR) and HER2 status of these patients was evaluated. Blood groups distribution of 22,821 healthy blood donors was also assessed and compared with the patients' blood groups distribution. The median patient age was 47 years (range 20-80) and 56% of the patients were premenopausal. ER and PR were positive in 50 and 60% of the patients, respectively. Overall, the ABO blood group distribution of the 294 HER2 (+) breast cancer patients was similar to that of the healthy blood donors (p=0.36). Likewise there was no correlation between blood type and ER, PR and menopausal status. Rh (-) patients had more frequent family cancer history and this difference was significant for patients with blood group B Rh (-) and O Rh (-) (p = 0.04). In the present study we didn't find any relationship between HER2 status and ABO blood group and Rh factor. However, further studies with larger number of patients are needed to establish the role (if any) of blood groups in patients with breast cancer.
Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

PubMed Central

Moreno-Bueno, Gema; Salvador, Fernando; Martín, Alberto; Floristán, Alfredo; Cuevas, Eva P; Santos, Vanesa; Montes, Amalia; Morales, Saleta; Castilla, Maria Angeles; Rojo-Sebastián, Alejandro; Martínez, Alejandra; Hardisson, David; Csiszar, Katalin; Portillo, Francisco; Peinado, Héctor; Palacios, José; Cano, Amparo

2011-01-01

Basal-like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR−, PR−, Her2neu−). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl-oxidase-like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Breast carcinoma cell lines with basal-like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal-like breast carcinomas. LOXL2 silencing in basal-like carcinoma cells induces a mesenchymal-epithelial transition (MET) associated with a decrease of tumourigenicity and suppression of metastatic potential. Mechanistic studies indicate that LOXL2 maintains the mesenchymal phenotype of basal-like carcinoma cells by a novel mechanism involving transcriptional downregulation of Lgl2 and claudin1 and disorganization of cell polarity and tight junction complexes. Therefore, intracellular LOXL2 is a new candidate marker of basal-like carcinomas and a target to block metastatic dissemination of this aggressive breast tumour subtype. PMID:21732535
Overexpression of HER2 signaling to WAVE2-Arp2/3 complex activates MMP-independent migration in breast cancer.

PubMed

Yokotsuka, Mayumi; Iwaya, Keiichi; Saito, Tsuyoshi; Pandiella, Atanasio; Tsuboi, Ryoji; Kohno, Norio; Matsubara, Osamu; Mukai, Kiyoshi

2011-04-01

The final signal for triggering the formation of lamellipodia that initiate directional migration of mammalian cells is binding of the Wiskott-Aldrich syndrome (WASP)/WASP family verproline-homologous protein 2 (WAVE2) to the actin-related protein 2 and 3 (Arp2/3) complex. This WAVE2-Arp2/3 signal is suggested to be enhanced in some breast cancers, facilitating invasion, and/or metastasis. Here, we demonstrated one cause of the enhanced signal using four breast cancer cell lines (SKBR3, AU565, MCF7, and MDA-MB-231). The WAVE2-Arp2/3 signal was estimated semi-quantitatively by counting the number of lamellipodia expressing both WAVE2 and Arp2 using high-power confocal laser microscopy. Higher expression of the WAVE2-Arp2/3 signal was detected in SKBR3 and AU565, which have HER2 gene amplification, than in the other two cell lines that lack HER2 gene amplification. Trastuzumab suppressed both the formation of lamellipodia and migration in a Boyden chamber experiment in SKBR3 and AU565. When the HER2 gene was transfected into MCF7, the number of both lamellipodia and migrated cells was increased. This enhancement of migration did not occur in the presence of extracellular matrix, and zymographic analysis showed no clear difference between HER2 gene-transfected cells and MCF7 cells. Immunohistochemical analysis of 115 cases of breast cancer revealed that coexpression of WAVE2 and Arp2 was significantly correlated with HER2-overexpression (P < 0.0001). These data indicate that an abnormal signal resulting from HER2 gene amplification activates lamellipodia formation in breast cancer cells, which initiates their metalloproteinase-independent migration.
Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells.

PubMed

Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M M; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

2015-01-01

In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of "de novo" FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA.
Docosahexaenoic Acid Modulates a HER2-Associated Lipogenic Phenotype, Induces Apoptosis, and Increases Trastuzumab Action in HER2-Overexpressing Breast Carcinoma Cells

PubMed Central

Ravacci, Graziela Rosa; Brentani, Maria Mitzi; Tortelli, Tharcisio Citrângulo; Torrinhas, Raquel Suzana M. M.; Santos, Jéssica Reis; Logullo, Angela Flávia; Waitzberg, Dan Linetzky

2015-01-01

In breast cancer, lipid metabolic alterations have been recognized as potential oncogenic stimuli that may promote malignancy. To investigate whether the oncogenic nature of lipogenesis closely depends on the overexpression of HER2 protooncogene, the normal breast cell line, HB4a, was transfected with HER2 cDNA to obtain HER2-overexpressing HB4aC5.2 cells. Both cell lines were treated with trastuzumab and docosahexaenoic acid. HER2 overexpression was accompanied by an increase in the expression of lipogenic genes involved in uptake (CD36), transport (FABP4), and storage (DGAT) of exogenous fatty acids (FA), as well as increased activation of “de novo” FA synthesis (FASN). We further investigate whether this lipogenesis reprogramming might be regulated by mTOR/PPARγ pathway. Inhibition of the mTORC1 pathway markers, p70S6 K1, SREBP1, and LIPIN1, as well as an increase in DEPTOR expression (the main inhibitor of the mTOR) was detected in HB4aC5.2. Based on these results, a PPARγ selective antagonist, GW9662, was used to treat both cells lines, and the lipogenic genes remained overexpressed in the HB4aC5.2 but not HB4a cells. DHA treatment inhibited all lipogenic genes (except for FABP4) in both cell lines yet only induced death in the HB4aC5.2 cells, mainly when associated with trastuzumab. Neither trastuzumab nor GW9662 alone was able to induce cell death. In conclusion, oncogenic transformation of breast cells by HER2 overexpression may require a reprogramming of lipogenic genetic that is independent of mTORC1 pathway and PPARγ activity. This reprogramming was inhibited by DHA. PMID:26640797
Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer.

PubMed

Schramm, Amelie; Schochter, Fabienne; Friedl, Thomas W P; de Gregorio, Nikolaus; Andergassen, Ulrich; Alunni-Fabbroni, Marianna; Trapp, Elisabeth; Jaeger, Bernadette; Heinrich, Georg; Camara, Oumar; Decker, Thomas; Ober, Angelika; Mahner, Sven; Fehm, Tanja N; Pantel, Klaus; Fasching, Peter A; Schneeweiss, Andreas; Janni, Wolfgang; Rack, Brigitte K

2017-07-01

Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary
Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status.

PubMed

Jiang, X P; Yang, D C; Elliott, R L; Head, J F

2000-05-01

Elevated serum IL-6 concentrations have been associated with poor prognosis in a variety of cancers, and decreases in serum IL-6 concentrations have been reported after chemotherapy. We have demonstrated that serum IL-6 concentrations are elevated in breast cancer patients [normal women 0.7 +/- 2.5 pg/ml (n=36), breast cancer patients 38.3 +/- 138.7 pg/ml (n = 111)]. After vaccination of breast cancer patients with a combination of tumour-associated antigens and biological adjuvants (IL-2 and GM-CSF), the concentration of IL-6 decreased significantly (P<0.05) to 8.1 +/- 14.6 pg/ml (n=85). Other studies have shown that oestrogen suppresses IL-6 production in oestrogen receptor positive breast cancer cells. We have demonstrated that the decrease in IL-6 associated with vaccination is related to the oestrogen receptor status of the tumours from breast cancer patients, as a decrease in IL-6 from 124.0 +/- 267.5 pg/ml (n=26) to 6.2 +/- 11.0 pg/ml (n=34) only occurs in patients with oestrogen receptor negative tumours. The IL-6 concentration in breast cancer patients with oestrogen receptor positive tumours remained unchanged (9.5 pg/ml before vaccination, and 9.3 pg/ml after vaccination). These results suggest that postmenopausal women with oestrogen receptor negative breast cancers, who do not respond well to either hormonal therapy with tamoxifen or adjuvant chemotherapy, may have a significant response to vaccination with autologous tumour-associated antigens.
PTK6 inhibition promotes apoptosis of Lapatinib-resistant Her2(+) breast cancer cells by inducing Bim.

PubMed

Park, Sun Hee; Ito, Koichi; Olcott, William; Katsyv, Igor; Halstead-Nussloch, Gwyneth; Irie, Hanna Y

2015-06-19

Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2(+) (Her2(+)) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibition is an effective strategy to inhibit growth and survival of Her2(+) breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2(+) breast cancer, either intrinsically or acquired after continuous drug exposure. To determine the effects of PTK6 inhibition on Lapatinib-resistant Her2(+) breast cancer cell lines (UACC893R1 and MDA-MB-453), we used short hairpin ribonucleic acid (shRNA) vectors to downregulate PTK6 expression. We determined the effects of PTK6 downregulation on growth and survival in vitro and in vivo, as well as the mechanisms responsible for these effects. Lapatinib treatment of "sensitive" Her2(+) cells induces apoptotic cell death and enhances transcript and protein levels of Bim, a pro-apoptotic Bcl2 family member. In contrast, treatment of relatively "resistant" Her2(+) cells fails to induce Bim or enhance levels of cleaved, poly-ADP ribose polymerase (PARP). Downregulation of PTK6 expression in these "resistant" cells enhances Bim expression, resulting in apoptotic cell death. PTK6 downregulation impairs growth of these cells in in vitro 3-D Matrigel(TM) cultures, and also inhibits growth of Her2(+) primary tumor xenografts. Bim expression is critical for apoptosis induced by PTK6 downregulation, as co-expression of Bim shRNA rescued these cells from PTK6 shRNA-induced death. The regulation of Bim by PTK6 is not via changes in Erk/MAPK or Akt signaling, two pathways known to regulate Bim expression. Rather, PTK6 downregulation activates p38, and pharmacological inhibition of p38 activity prevents PTK6 shRNA-induced Bim expression and partially rescues cells from apoptosis. PTK6 downregulation
A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK

PubMed Central

Dey, Nandini; Williams, Casey; Leyland-Jones, Brain; De, Pradip

2015-01-01

ERBB3/HER3 is the most intriguing RTK by virtue of its ability to transduce multiple cytosolic signals for the proliferation and growth of tumor cells in spite of being a “kinase dead” receptor that binds to its true ligand, heregulin. Although other members of the HER3 family like EGFR and HER2 have long been recognized to be associated with breast tumorigenesis and studied because of their predictive and prognostic value, the significance of HER3 as an irrefutable component of HER family signalosome is a relatively new development. The recent understanding of signals originating from the oncogenic partnership of HER3 with HER2 in the context of HER2 amplification/overexpression showed the critical clinical value for the treatment of HER2+BC. The downstream signaling cascade (included but not limited to the PI3K signaling) associated with signals originating from HER2:HER3 dimers play a vital role in the tumorigenesis, drug-resistance and tumor progression of HER2+BC. The upregulation of HER3 activity provides an alternate “escape route” via which tumor cells bypass either the inhibition of the HER family RTKs or the inhibition of the downstream PI3K-AKT-mTOR signaling pathway. By understanding the signaling that provides this “escape route” for these tumor cells treated with a targeted therapy (HER2 inhibitors or inhibitors of downstream PI3K-AKT-mTOR signaling pathway), we are just beginning to appreciate the prognostic value of HER3 in breast cancer. In this review, we will discuss the relevance of HER3 signaling in the context of, (1) downstream oncogenic signals and (2) therapeutic options in HER2 amplified BC. PMID:26064441
Veliparib and Atezolizumab Either Alone or in Combination in Treating Patients With Stage III-IV Triple Negative Breast Cancer

ClinicalTrials.gov

2018-03-20

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma
Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival.

PubMed

Baker, Andrew; Wyatt, Debra; Bocchetta, Maurizio; Li, Jun; Filipovic, Aleksandra; Green, Andrew; Peiffer, Daniel S; Fuqua, Suzanne; Miele, Lucio; Albain, Kathy S; Osipo, Clodia

2018-05-10

Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.
PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia.

PubMed

Banh, Robert S; Iorio, Caterina; Marcotte, Richard; Xu, Yang; Cojocari, Dan; Rahman, Anas Abdel; Pawling, Judy; Zhang, Wei; Sinha, Ankit; Rose, Christopher M; Isasa, Marta; Zhang, Shuang; Wu, Ronald; Virtanen, Carl; Hitomi, Toshiaki; Habu, Toshiyuki; Sidhu, Sachdev S; Koizumi, Akio; Wilkins, Sarah E; Kislinger, Thomas; Gygi, Steven P; Schofield, Christopher J; Dennis, James W; Wouters, Bradly G; Neel, Benjamin G

2016-07-01

Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.
Patient-reported Quality of Life and Treatment Satisfaction in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer.

PubMed

Wood, Robert; Mitra, Debanjali; de Courcy, Jonathan; Iyer, Shrividya

2017-08-01

Globally, around 1.67 million new cases of breast cancer are diagnosed each year, with advanced breast cancer (ABC-Stage III) and metastatic breast cancer (MBC-Stage IV) together accounting for up to 22% of incident cases. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer comprises 66% of ABC/MBC. Understanding disease-specific health-related quality of life and patient satisfaction with treatments currently available for HR + /HER2 - ABC/MBC in clinical practice is essential for assessing potential unmet need in this patient population. Data on treatment patterns in patients with HR + /HER2 - ABC/MBC were collected from oncology practices across the United States and Europe in a cross-sectional study in a clinical practice setting, the Adelphi Real World Advanced Breast Cancer Disease Specific Programme. A subset of patients included in the study completed several self-reported tools, including the Functional Assessment of Cancer Therapy-Breast and the Cancer Therapy Satisfaction Questionnaire. Analyses were conducted using data from the overall cohort and stratified by current treatment, metastatic sites, and number of prior therapy lines. Overall, 739 patients were recruited by 173 oncologists; 83% of patients had MBC, with the balance having ABC. The majority of patients with MBC had visceral metastases without bone metastases, and similar percentages of the total study population (≈40%) were receiving chemotherapy and endocrine therapy. Patients receiving only endocrine therapy had significantly better cancer-specific quality of life than did those receiving chemotherapy. Endocrine therapy also associated with fewer concerns about side effects and higher treatment satisfaction than chemotherapy. Statistically lower scores, indicating poorer well-being, were observed in patients with both bone and visceral metastases compared with those with either bone-only or visceral-only metastases for all but the
HER-3 peptide vaccines/mimics: Combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells.

PubMed

Miller, Megan Jo; Foy, Kevin C; Overholser, Jay P; Nahta, Rita; Kaumaya, Pravin Tp

2014-11-01

The human epidermal growth factor receptor 3 (HER-3/ErbB3) is a unique member of the human epidermal growth factor family of receptors, because it lacks intrinsic kinase activity and ability to heterodimerize with other members. HER-3 is frequently upregulated in cancers with epidermal growth factor receptor (EGFR/HER-1/ErbB1) or human epidermal growth factor receptor 2 (HER-2/ErBB2) overexpression, and targeting HER-3 may provide a route for overcoming resistance to agents that target EGFR or HER-2. We have previously developed vaccines and peptide mimics for HER-1, HER-2 and vascular endothelial growth factor (VEGF). In this study, we extend our studies by identifying and evaluating novel HER-3 peptide epitopes encompassing residues 99-122, 140-162, 237-269 and 461-479 of the HER-3 extracellular domain as putative B-cell epitopes for active immunotherapy against HER-3 positive cancers. We show that the HER-3 vaccine antibodies and HER-3 peptide mimics induced antitumor responses: inhibition of cancer cell proliferation, inhibition of receptor phosphorylation, induction of apoptosis and antibody dependent cellular cytotoxicity (ADCC). Two of the HER-3 epitopes 237-269 (domain II) and 461-479 (domain III) significantly inhibited growth of xenografts originating from both pancreatic (BxPC3) and breast (JIMT-1) cancers. Combined therapy of HER-3 (461-471) epitope with HER-2 (266-296), HER-2 (597-626), HER-1 (418-435) and insulin-like growth factor receptor type I (IGF-1R) (56-81) vaccine antibodies and peptide mimics show enhanced antitumor effects in breast and pancreatic cancer cells. This study establishes the hypothesis that combination immunotherapy targeting different signal transduction pathways can provide effective antitumor immunity and long-term control of HER-1 and HER-2 overexpressing cancers.
Neratinib: Inching up on the cure rate of HER2+ breast cancer?

PubMed

Unni, Nisha; Sudhan, Dhivya R; Arteaga, Carlos L

2018-05-25

Neratinib was recently approved by FDA for extended adjuvant treatment of HER-2 positive breast cancer. ExteNET trial showed improvement in invasive disease-free survival (iDFS) in the neratinib arm compared to placebo. The benefit was more pronounced in patients with ER+/HER2+ tumors, suggesting bidirectional crosstalk between the two pathways. Copyright ©2018, American Association for Cancer Research.
Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A; Moy, Beverly; Iwata, Hiroji; Harvey, Vernon J; Robert, Nicholas J; Silovski, Tajana; Gokmen, Erhan; von Minckwitz, Gunter; Ejlertsen, Bent; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Buyse, Marc; Gore, Ira; Smith, John; Harker, Graydon; Masuda, Norikazu; Petrakova, Katarina; Zotano, Angel Guerrero; Iannotti, Nicholas; Rodriguez, Gladys; Tassone, Pierfrancesco; Wong, Alvin; Bryce, Richard; Ye, Yining; Yao, Bin; Martin, Miguel

2016-03-01

Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70

Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

ClinicalTrials.gov

2017-11-15

Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer
Adjuvant Trastuzumab in HER2-Positive Breast Cancer

PubMed Central

Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; von Minckwitz, Gunter; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John

2011-01-01

BACKGROUND Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. METHODS We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. RESULTS At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. CONCLUSIONS The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006
Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor

PubMed Central

Wijnant, Kathleen; Crinelli, Rita; Bianchi, Marzia; Magnani, Mauro; Hysi, Albana; Iezzi, Manuela

2017-01-01

The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice. This in vivo tumor-promoting effect of resveratrol was associated with up-regulation of Δ16HER2 and down-regulation of ERα protein levels and was recapitulated in vitro by murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Δ16HER2 accumulation which favors the formation of Δ16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models. PMID:28238967
Interlaboratory comparison of immunohistochemical testing for HER2: results of the 2004 and 2005 College of American Pathologists HER2 Immunohistochemistry Tissue Microarray Survey.

PubMed

Fitzgibbons, Patrick L; Murphy, Douglas A; Dorfman, David M; Roche, Patrick C; Tubbs, Raymond R

2006-10-01

Correct assessment of human epidermal growth factor receptor 2 (HER2) status is essential in managing patients with invasive breast carcinoma, but few data are available on the accuracy of laboratories performing HER2 testing by immunohistochemistry (IHC). To review the results of the 2004 and 2005 College of American Pathologists HER2 Immunohistochemistry Tissue Microarray Survey. The HER2 survey is designed for laboratories performing immunohistochemical staining and interpretation for HER2. The survey uses tissue microarrays, each consisting of ten 3-mm tissue cores obtained from different invasive breast carcinomas. All cases are also analyzed by fluorescence in situ hybridization. Participants receive 8 tissue microarrays (80 cases) with instructions to perform immunostaining for HER2 using the laboratory's standard procedures. The laboratory interprets the stained slides and returns results to the College of American Pathologists for analysis. In 2004 and 2005, a core was considered "graded" when at least 90% of laboratories agreed on the result--negative (0, 1+) versus positive (2+, 3+). This interlaboratory comparison survey included 102 laboratories in 2004 and 141 laboratories in 2005. Of the 160 cases in both surveys, 111 (69%) achieved 90% consensus (graded). All 43 graded cores scored as IHC-positive were fluorescence in situ hybridization-positive, whereas all but 3 of the 68 IHC-negative graded cores were fluorescence in situ hybridization-negative. Ninety-seven (95%) of 102 laboratories in 2004 and 129 (91%) of 141 laboratories in 2005 correctly scored at least 90% of the graded cores. Performance among laboratories performing HER2 IHC in this tissue microarray-based survey was excellent. Cores found to be IHC-positive or IHC-negative by participant consensus can be used as validated benchmarks for interlaboratory comparison, allowing laboratories to assess their performance and determine if improvements are needed.
Analysis of molecular subtypes for the increased HER2 equivocal cases caused by application of the updated 2013 ASCO/CAP HER2 testing guidelines in breast cancer.

PubMed

Guo, Lei; Yuan, Pei; Zhang, Jing; Ling, Yun; Li, Wenbin; Zhao, Bohui; Ying, Jianming; Xuan, Lixue

2017-11-01

Accurate testing of the status of human epidermal growth factor receptor type 2 (HER2) is a prerequisite for HER2-directed therapy. The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) published joint guideline recommendations for HER2 testing in breast cancer in 2007 and it was updated in 2013. We compared the HER2 gene amplification status based on these two guidelines and analyzed the molecular characteristics of the equivocal cases. A total of 1894 patient samples were analyzed for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). HER2 FISH amplification was examined and re-assessed using 2013 guidelines. According to the 2013 ASCO/CAP recommendations, 763 (40.3%) cases were classified as HER2 positive compared with 729 (38.5%) cases defined by 2007 guidelines. There was a significant increase of 6.1% in the proportion of HER2 FISH equivocal cases that were interpreted using ASCO/CAP 2013 (7.3%) compared with 2007 (1.2%) guidelines (P < 0.001). Of 138 FISH equivocal cases defined by 2013 guidelines, 125 cases were IHC2+ and 13 cases were IHC1+. These 125 cases included 4 double equivocal cases which were defined as equivocal by both 2007 and 2013 guidelines and 121 cases whose status was changed from negative defined by 2007 guidelines to equivocal defined by 2013 guidelines. Compared with luminal A type and luminal B type respectively, these 121 equivocal cases demonstrated no significant difference with luminal B type in T stage and N stage (P = 0.192, P = 0.421). When we divided the luminal B type into two parts that included HER2 negative cases and HER2 positive cases, the equivocal cases also showed no significant difference with these two subtypes in T stage and N stage. Our study suggested that implementation of the revised ASCO/CAP 2013 guidelines resulted in an increase of 1.7% in overall HER2 positivity rate and of 6.1% in equivocal cases. Pathological analysis revealed that
Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial.

PubMed

Sonke, Gabe S; Hart, Lowell L; Campone, Mario; Erdkamp, Frans; Janni, Wolfgang; Verma, Sunil; Villanueva, Cristian; Jakobsen, Erik; Alba, Emilio; Wist, Erik; Favret, Anne M; Bachelot, Thomas; Hegg, Roberto; Wheatley-Price, Paul; Souami, Farida; Sutradhar, Santosh; Miller, Michelle; Germa, Caroline; Burris, Howard A

2018-02-01

Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer. 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was PFS, which was evaluated in elderly (≥ 65 years) and younger (< 65 years) patients. Secondary endpoints included response rates and safety. Ribociclib plus letrozole significantly improved PFS vs placebo plus letrozole in elderly (hazard ratio: 0.608; 95% CI 0.394-0.937) and younger patients (hazard ratio: 0.523; 95% CI 0.378-0.723). Overall response rates were numerically higher in the ribociclib vs placebo arm, regardless of age. Ribociclib plus letrozole was well tolerated in elderly patients, with the safety profile similar to the overall study population. Nausea, vomiting, alopecia, and diarrhea were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm in both subgroups; most events were grade 1/2. In elderly patients, grade 1/2 anemia and fatigue were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm and discontinuation rates were similar in both arms. Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2- advanced breast cancer in the first-line setting.
Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients.

PubMed

Mosalpuria, Kailash; Hall, Carolyn; Krishnamurthy, Savitri; Lodhi, Ashutosh; Hallman, D Michael; Baraniuk, Mary S; Bhattacharyya, Anirban; Lucci, Anthony

2014-09-01

Triple-negative breast cancer (TNBC) is characterised by lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)2/neu gene amplification. TNBC patients typically present at a younger age, with a larger average tumor size, higher grade and higher rates of lymph node positivity compared to patients with ER/PR-positive tumors. Cyclooxygenase (COX)-2 regulates the production of prostaglandins and is overexpressed in a variety of solid tumors. In breast cancer, the overexpression of COX-2 is associated with indicators of poor prognosis, such as lymph node metastasis, poor differentiation and large tumor size. Since both TNBC status and COX-2 overexpression are known poor prognostic markers in primary breast cancer, we hypothesized that the COX-2 protein is overexpressed in the primary tumors of TNBC patients. The purpose of this study was to determine whether there exists an association between TNBC status and COX-2 protein overexpression in primary breast cancer. We prospectively evaluated COX-2 expression levels in primary tumor samples obtained from 125 patients with stage I-III breast cancer treated between February, 2005 and October, 2007. Information on clinicopathological factors was obtained from a prospective database. Baseline tumor characteristics and patient demographics were compared between TNBC and non-TNBC patients using the Chi-square and Fisher's exact tests. In total, 60.8% of the patients were classified as having ER-positive tumors, 51.2% were PR-positive, 14.4% had HER-2/neu amplification and 28.0% were classified as TNBC. COX-2 overexpression was found in 33.0% of the patients. TNBC was associated with COX-2 overexpression (P=0.009), PR expression (P=0.048) and high tumor grade (P=0.001). After adjusting for age, menopausal status, body mass index (BMI), lymph node status and neoadjuvant chemotherapy (NACT), TNBC was an independent predictor of COX-2 overexpression (P=0.01). In conclusion, the
Activation of mammalian target of rapamycin (mTOR) in triple negative feline mammary carcinomas

PubMed Central

2013-01-01

Background Triple negative breast cancer (TNBC) in humans is defined by the absence of oestrogen receptor (ER), progesterone receptor (PR) and HER2 overexpression. Mammalian target of rapamycin (mTOR) is overexpressed in TNBC and it represents a potential target for the treatment of this aggressive tumour. Feline mammary carcinoma (FMC) is considered to be a model for hormone-independent human breast cancer. This study investigated mTOR and p-mTOR expression in FMC in relation to triple negative (TN) phenotype. Results The expression of mTOR, p-mTOR, ERα, PR and HER2 was evaluated in 58 FMCs by immunohistochemistry and in six FMC cell lines by Western blot analysis. 53.5% of FMC analyzed were ER, PR, HER2 negative (TN-FMC) while 56.9% and 55.2% of cases expressed mTOR and p-mTOR respectively. In this study we found that m-TOR and p-mTOR were more frequently detected in TN-FMC and in HER2 negative samples. Conclusions In this study, we demonstrate that there is also a FMC subset defined as TN FMC, which is characterised by a statistically significant association with m-TOR and p-mTOR expression as demonstrated in human breast cancer. PMID:23587222
Improved survival of HER2+ breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain

PubMed Central

Knutson, Keith L.; Clynes, Raphael; Shreeder, Barath; Yeramian, Patrick; Kemp, Kathleen P.; Ballman, Karla; Tenner, Kathleen S.; Erskine, Courtney L.; Norton, Nadine; Northfelt, Donald; Tan, Winston; Calfa, Carmen; Pegram, Mark; Mittendorf, Elizabeth A.; Perez, Edith A.

2016-01-01

The addition of trastuzumab to chemotherapy extends survival among patients with HER2+ breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The present study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pre-treatment and post-treatment sera were obtained from 48 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically-resected HER2+ patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically-resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved PFS (HR 0.5, p=0.0042) and OS (HR=0.7, p=0.038). Augmented antibody responses to HER2-ICD also correlated (p=0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer progression free (PFS, HR=1.6, p<0.0001) and overall survival (OS, HR=1.4, p=0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. PMID:27197192
Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature.

PubMed

Petrelli, Fausto; Tomasello, Gianluca; Barni, Sandro; Lonati, Veronica; Passalacqua, Rodolfo; Ghidini, Michele

2017-11-01

HER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling. We have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported). We retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive. We have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.
Cytologic assessment of estrogen receptor, progesterone receptor, and HER2 status in metastatic breast carcinoma

PubMed Central

Pareja, Fresia; Murray, Melissa P; Jean, Ryan Des; Konno, Fumiko; Friedlander, Maria; Lin, Oscar; Edelweiss, Marcia

2016-01-01

BACKGROUND Discordance in the receptor status between primary breast carcinomas (PBC) and corresponding metastasis is well documented. Interrogation of the receptor status of metastatic breast carcinoma (MBC) in cytology material is common practice; however, its utility has not been thoroughly validated. We studied patients with MBC, and evaluated the concordance rates of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between PBC surgical specimens and corresponding MBC cell blocks (CBs). We correlated the findings with clinicopathologic variables and with the fixation methods used. METHODS We searched for patients with MBC diagnosed on cytology from 2007 to 2009 and selected those with ER, PR and HER2 tested in both the PBC surgical specimens and the MBC CBs. We included CBs fixed in formalin and methanol based solution (CytoLyt®). All slides were reevaluated by cytopathologists. Clinical information was retrieved from the medical records. RESULTS We studied 65 patients with PBC and MBC paired specimens. The concordance rates between PBC and MBC were 78.5%, 58.5% and 96.9%, for ER, PR and HER2, respectively. When discordant, PR status switched from positive (PBC) to negative (MBC) in most cases (23/27). The PR concordance rate was 45.2% for CBs fixed in formalin and 70.6% for those fixed with CytoLyt® (p=0.047). CONCLUSION The ER, PR and HER2 concordance rates between the PBC and MBC CBs are similar to those reported in paired surgical specimens. PR status was the most prevalent discordance and was not accompanied by a switch in ER. PMID:28529880
A phase II, multicenter, single-arm trial of eribulin as first- or second-line chemotherapy for HER2-negative advanced or metastatic breast cancer: evaluation of efficacy, safety, and patient-reported outcomes.

PubMed

Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Yamamoto, Daigo; Yoshidome, Katsuhide; Ogura, Hiroyuki; Terasawa, Risa; Matsunami, Nobuki; Takahashi, Yuko; Nitta, Toshikatsu; Morimoto, Takashi; Fujioka, Hiroya; Kawaguchi, Kanako; Uchiyama, Kazuhisa

2018-05-01

Although eribulin is a suitable option for early-line treatment of metastatic breast cancer (MBC), data on first- or second-line use of eribulin for human epidermal growth factor receptor 2 (HER2)-negative MBC are still limited. Therefore, we conducted a phase II trial to investigate the efficacy and safety of eribulin for first- or second-line chemotherapy for HER2-negative MBC. We performed a phase II, open-label, single-arm, multicenter study in Japan. Eligible patients were women with histologically confirmed HER2-negative MBC without chemotherapy or only one chemotherapy line for MBC. The primary endpoint was the overall response rate (ORR) and the secondary endpoints included the clinical benefit rate (ORR + stable disease for 6 months; CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and health-related quality of life (HRQoL). A total of 35 patients with HER2-negative MBC were enrolled between March 2013 and February 2017 (data cut-off July 31, 2017). The ORR was 37.1% (95% CI 21.1-53.2%). The CBR was 54.3% (95% CI 37.8-70.8%). The median PFS was 6.2 months (95% CI 2.7-9.4 months) and median OS was 21.4 months (95% CI 11.5-32.9 months). Common grade 3/4 adverse events were neutropenia (42.9%) but febrile neutropenia (2.9%). Although the majority of non-hematological adverse events were mild in severity, one patient died of pneumonitis. In HRQoL analysis, eribulin appeared to maintain HRQoL of many patients. Eribulin as first- or second-line chemotherapy is effective and has manageable toxicity for patients with HER2-negative MBC.
Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.

PubMed

Slamon, D J; Godolphin, W; Jones, L A; Holt, J A; Wong, S G; Keith, D E; Levin, W J; Stuart, S G; Udove, J; Ullrich, A

1989-05-12

Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.
Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sambade, Maria J.; Kimple, Randall J.; Camp, J. Terese

2010-06-01

Purpose: To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. Methods and Materials: Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. Results: Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period.more » In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. Conclusion: Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.« less
Dissecting GRB7-mediated signals for proliferation and migration in HER2 overexpressing breast tumor cells: GTP-ase rules.

PubMed

Pradip, De; Bouzyk, Mark; Dey, Nandini; Leyland-Jones, Brian

2013-01-01

Amplification of human Her2 and its aberrant signaling in 20-30% of early breast cancer patients is responsible for highly aggressive tumors with poor outcome. Grb7 is reported to be co-amplified with Her2. We report a concurrent high expression of mRNA (from FFPE tumor samples; mRNA correlation, Pearson r(2)= 0.806), and high levels of GRB7 protein (immunoblot) in HER2+ breast cancer cell lines. We demonstrated the signaling mechanism of HER2 and downstream effectors that contributes to proliferation and migration. Using HER2+ and trastuzumab-resistant breast cancer cell lines, we identified the interaction between GRB7 and HER2 in the control of HER2+ cell proliferation. Our co-IP data show that GRB7 recruits SHC into the HER2-GRB7 signaling complex. This complex formation leads to activation of RAS-GTP. We also observed that following integrin engagement, GRB7 is phosphorylated at tyrosine in a p-FAK (Y397) dependent manner. This FAK-GRB7 complex leads to downstream activation of RAC1-GTP (responsible for migration) probably through the recruitment of VAV2. Our CO-IP data demonstrate that GRB7 directly binds with VAV2 following fibronectin engagement in HER2+ cells. To address whether GRB7 could serve as a pathway specific therapeutic target, we used siRNA to suppress GRB7 expression. Knockdown of GRB7 expression in the HER2+ breast cancer cell lines decreases RAS activation, cell proliferation, 2D and 3D colony formation and also blocked integrin-mediated RAC1 activation along with integrin-directed cell migration. These findings dissected the HER2-mediated signaling cascade into (1) HER2+ cell proliferation (HER2-GRB7-SHC-RAS) and (2) HER2+ cell migration (alpha5 beta1/alpha4 beta1-FAK-GRB7-VAV2-RAC1). Our data clearly demonstrate that a coupling of GRB7 with HER2 is required for the proliferative and migratory signals in HER2+ breast tumor cells.
Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients

PubMed Central

Heestand, Gregory M.; Schwaederle, Maria; Gatalica, Zoran; Arguello, David; Kurzrock, Razelle

2017-01-01

Background Topoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well. Summary of methods We analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well. Results Overexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer. Conclusion Our data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co-alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation. PMID:28728050
Characterization of patient-derived tumor xenografts (PDXs) as models for estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers.

PubMed

Kanaya, Noriko; Somlo, George; Wu, Jun; Frankel, Paul; Kai, Masaya; Liu, Xueli; Wu, Shang Victoria; Nguyen, Duc; Chan, Nymph; Hsieh, Meng-Yin; Kirschenbaum, Michele; Kruper, Laura; Vito, Courtney; Badie, Behnam; Yim, John H; Yuan, Yuan; Hurria, Arti; Peiguo, Chu; Mortimer, Joanne; Chen, Shiuan

2017-06-01

The research was to appraise the utility of the patient-derived tumor xenografts (PDXs) as models of estrogen receptor positive (ER+HER2- and ER+HER2+) breast cancers. We compared protein expression profiles by Reverse Phase Protein Array (RPPA) in tumors that resulted in PDXs compared to those that did not. Our overall PDX intake rate for ER+ breast cancer was 9% (9/97). The intake rate for ER+HER2+ tumors (3/16, 19%) was higher than for ER+HER2- tumors (6/81, 7%). Heat map analyses of RPPA data showed that ER+HER2- tumors were divided into 2 groups by luminal A/B signature [protein expression of ER, AR, Bcl-2, Bim (BCL2L11), GATA3 and INPP4b], and this expression signature was also associated with the rate of PDX intake. Cell survival pathways such as the PI3K/AKT signaling and RAS/ERK pathways were more activated in the specimens that could be established as PDX in both classes. Expression of the ER protein itself may have a bearing on the potential success of an ER+ PDX model. In addition, HER2 and its downstream protein expressions were up-regulated in the ER+HER2+ patient tumors that were successfully established as PDX models. Moreover, the comparison of RPPA data between original and PDX tumors suggested that the selection/adaptation process required to grow the tumors in mice is unavoidable for generation of ER+ PDX models, and we identified differences between patient tumor samples and paired PDX tumors. A better understanding of the biological characteristics of ER+PDX would be the key to using PDX models in assessing treatment strategies in a preclinical setting. Copyright © 2016 Elsevier Ltd. All rights reserved.
Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.

PubMed

Park, Youngmok; Kim, Hyemin; Kim, Eui-Hyun; Suh, Chang-Ok; Lee, Soohyeon

2016-01-01

Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.
HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

PubMed

Ingthorsson, S; Andersen, K; Hilmarsdottir, B; Maelandsmo, G M; Magnusson, M K; Gudjonsson, T

2016-08-11

The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492
HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR

PubMed Central

Ingthorsson, S; Andersen, K; Hilmarsdottir, B; Maelandsmo, G M; Magnusson, M K; Gudjonsson, T

2016-01-01

The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492HER2) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492HER2 (D492HER2/EGFR) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492HER2/EGFR xenografts grow slower than the D492HER2 tumors, while overexpression of EGFR alone (D492EGFR) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492HER2 xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can

In vivo examination of (188)Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer.

PubMed

Chen, Kuo-Ting; Lee, Te-Wei; Lo, Jem-Mau

2009-05-01

Trastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with beta- or alpha emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect. In this study, trastuzumab was labeled with (188)Re for radioimmunotherapy of HER2/neu-positive breast cancer. (188)Re(I)-tricarbonyl ion, [(188)Re(OH(2))(3)(CO)(3)](+), was employed as a precursor for directly labeling the monoclonal antibody with (188)Re. The immunoreactivity of (188)Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of (188)Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated. When incubated with human serum albumin and histidine at 25 degrees C, (188)Re(I)-trastuzumab was found to be stable within 24 h. The IC(50) of (188)Re(I)-trastuzumab was found to be 22.63+/-4.57 nM. (188)Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of (188)Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, (188)Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the (188)Re image at the localization of the tumor was dim. These results reveal that (188)Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.
Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab.

PubMed

Todeschini, P; Cocco, E; Bellone, S; Varughese, J; Lin, K; Carrara, L; Guzzo, F; Buza, N; Hui, P; Silasi, D-A; Ratner, E; Azodi, M; Schwartz, P E; Rutherford, T J; Pecorelli, S; Santin, A D

2011-10-11

We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo.
The Role of Novel Substituted Diindolyl Methane Analogues in the Treatment of Triple-Negative and ErbB2-Positive Breast Cancer

DTIC Science & Technology

2016-05-01

patients are diagnosed with TNBC, which do not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2...and EPBC are high risk breast cancers and the choice of orally available chemotherapeutic agents is limited. Hormonal therapy (ER modulators) and HER...antibody based therapy are far safer than cytotoxic drug based regimens. But triple negative breast cancers are not responsive to hormonal or HER
Anti-HER2 antibody and ScFvEGFR-conjugated antifouling magnetic iron oxide nanoparticles for targeting and magnetic resonance imaging of breast cancer

PubMed Central

Chen, Hongwei; Wang, Liya; Yu, Qiqi; Qian, Weiping; Tiwari, Diana; Yi, Hong; Wang, Andrew Y; Huang, Jing; Yang, Lily; Mao, Hui

2013-01-01

Antifouling magnetic iron oxide nanoparticles (IONPs) coated with block copolymer poly(ethylene oxide)-block-poly(γ-methacryloxypropyltrimethoxysilane) (PEO-b-PγMPS) were investigated for improving cell targeting by reducing nonspecific uptake. Conjugation of a HER2 antibody, Herceptin®, or a single chain fragment (ScFv) of antibody against epidermal growth factor receptor (ScFvEGFR) to PEO-b-PγMPS-coated IONPs resulted in HER2-targeted or EGFR-targeted IONPs (anti-HER2-IONPs or ScFvEGFR-IONPs). The anti-HER2-IONPs bound specifically to SK-BR-3, a HER2-overexpressing breast cancer cell line, but not to MDA-MB-231, a HER2-underexpressing cell line. On the other hand, the ScFvEGFR-IONPs showed strong reactivity with MDA-MB-231, an EGFR-positive human breast cancer cell line, but not with MDA-MB-453, an EGFR-negative human breast cancer cell line. Transmission electron microscopy revealed internalization of the receptor-targeted nanoparticles by the targeted cancer cells. In addition, both antibody-conjugated and non-antibody-conjugated IONPs showed reduced nonspecific uptake by RAW264.7 mouse macrophages in vitro. The developed IONPs showed a long blood circulation time (serum half-life 11.6 hours) in mice and low accumulation in both the liver and spleen. At 24 hours after systemic administration of ScFvEGFR-IONPs into mice bearing EGFR-positive breast cancer 4T1 mouse mammary tumors, magnetic resonance imaging revealed signal reduction in the tumor as a result of the accumulation of the targeted IONPs. PMID:24124366
Evaluation of Intratumoral HER-2 Heterogeneity by Fluorescence In Situ Hybridization in Invasive Breast Cancer: A Single Institution Study

PubMed Central

Lee, Sarah; Jung, Woohee; Hong, Soon-Won

2011-01-01

This study aimed to determine the incidence and characteristics of HER-2 gene heterogeneity in invasive breast cancer in a single institution. Included were 971 cases of primary invasive breast cancer diagnosed between 2008 and 2010. Fluorescence in situ hybridization (FISH) image files were retrospectively reviewed and HER-2 gene heterogeneity was defined as more than 5% but less than 50% of analyzed invasive tumor cells with a HER-2/Chr17 ratio higher than 2.2, according to the College of American Pathologists guidelines. HER-2 gene heterogeneity was identified in 24 (2.5%) cases. The mean proportion of invasive tumor cells with a HER-2/chromosome 17 ratio higher than 2.2 was 11.6% (range: 5%-25%). Of 24 cases, HER-2 gene status was not amplified in 8, showed borderline amplification in 2, and amplification in 14. All HER-2 amplification cases were low-grade. In conclusion, HER-2 gene heterogeneity of invasive breast cancer is identified in routine FISH examination. This may affect the results of HER-2 gene amplification status in FISH studies. PMID:21860549
Evaluation of intratumoral HER-2 heterogeneity by fluorescence in situ hybridization in invasive breast cancer: a single institution study.

PubMed

Lee, Sarah; Jung, Woohee; Hong, Soon-Won; Koo, Ja Seung

2011-08-01

This study aimed to determine the incidence and characteristics of HER-2 gene heterogeneity in invasive breast cancer in a single institution. Included were 971 cases of primary invasive breast cancer diagnosed between 2008 and 2010. Fluorescence in situ hybridization (FISH) image files were retrospectively reviewed and HER-2 gene heterogeneity was defined as more than 5% but less than 50% of analyzed invasive tumor cells with a HER-2/Chr17 ratio higher than 2.2, according to the College of American Pathologists guidelines. HER-2 gene heterogeneity was identified in 24 (2.5%) cases. The mean proportion of invasive tumor cells with a HER-2/chromosome 17 ratio higher than 2.2 was 11.6% (range: 5%-25%). Of 24 cases, HER-2 gene status was not amplified in 8, showed borderline amplification in 2, and amplification in 14. All HER-2 amplification cases were low-grade. In conclusion, HER-2 gene heterogeneity of invasive breast cancer is identified in routine FISH examination. This may affect the results of HER-2 gene amplification status in FISH studies.
RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland

PubMed Central

McDonald, Laura; Ferrari, Nicola; Terry, Anne; Bell, Margaret; Mohammed, Zahra M.; Orange, Clare; Jenkins, Alma; Muller, William J.; Gusterson, Barry A.; Neil, James C.; Edwards, Joanne; Morris, Joanna S.; Cameron, Ewan R.; Blyth, Karen

2014-01-01

RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer. PMID:24626992
CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells

PubMed Central

Wu, Chenglin; Fu, Kaifei; Wang, Yuxiao; Zhang, Yan; Liu, Yan; Zhou, Lijun

2016-01-01

Trastuzumab is widely used in the clinical treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer, but the patient response rate is low. CD147 stimulates cancer cell proliferation, migration, metastasis and differentiation and is involved in chemoresistance in many types of cancer cells. Whether CD147 alters the effect of trastuzumab on HER2-positive breast cancer cells has not been previously reported. Our study confirmed that CD147 suppression enhances the effects of trastuzumab both in vitro and in vivo. CD147 suppression increased the inhibitory rate of trastuzumab and cell apoptosis in SKBR3, BT474, HCC1954 and MDA-MB453 cells compared with the controls. Furthermore, CD147 knockdown increased expression of cleaved Caspase-3/9 and poly (ADP-ribose) polymerase (PARP) and decreased both mitogen-activated protein kinase (MAPK) and Akt phosphorylation in the four cell lines. In an HCC1954 xenograft model, trastuzumab achieved greater suppression of tumor growth in the CD147-knockdown group than in the shRNA negative control (NC) group. These data indicated that enhancement of the effect of trastuzumab on HER2-positive cells following CD147 knockdown might be attributed to increased apoptosis and decreased phosphorylation of signaling proteins. CD147 may be a key protein for enhancing the clinical efficacy of trastuzumab. PMID:27363028
CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells.

PubMed

Xiong, Lijuan; Ding, Li; Ning, Haoyong; Wu, Chenglin; Fu, Kaifei; Wang, Yuxiao; Zhang, Yan; Liu, Yan; Zhou, Lijun

2016-09-06

Trastuzumab is widely used in the clinical treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer, but the patient response rate is low. CD147 stimulates cancer cell proliferation, migration, metastasis and differentiation and is involved in chemoresistance in many types of cancer cells. Whether CD147 alters the effect of trastuzumab on HER2-positive breast cancer cells has not been previously reported. Our study confirmed that CD147 suppression enhances the effects of trastuzumab both in vitro and in vivo. CD147 suppression increased the inhibitory rate of trastuzumab and cell apoptosis in SKBR3, BT474, HCC1954 and MDA-MB453 cells compared with the controls. Furthermore, CD147 knockdown increased expression of cleaved Caspase-3/9 and poly (ADP-ribose) polymerase (PARP) and decreased both mitogen-activated protein kinase (MAPK) and Akt phosphorylation in the four cell lines. In an HCC1954 xenograft model, trastuzumab achieved greater suppression of tumor growth in the CD147-knockdown group than in the shRNA negative control (NC) group. These data indicated that enhancement of the effect of trastuzumab on HER2-positive cells following CD147 knockdown might be attributed to increased apoptosis and decreased phosphorylation of signaling proteins. CD147 may be a key protein for enhancing the clinical efficacy of trastuzumab.
TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

PubMed

Mercogliano, María F; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Proietti, Cecilia J; Inurrigarro, Gloria; Frahm, Isabel; Allemand, Daniel H; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-02-01

Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. �
HER-2 Pulsed Dendritic Cell Vaccine Can Eliminate HER-2 Expression and Impact DCIS

PubMed Central

Sharma, Anupama; Koldovsky, Ursula; Xu, Shuwen; Mick, Rosemarie; Roses, Robert; Fitzpatrick, Elizabeth; Weinstein, Susan; Nisenbaum, Harvey; Levine, Bruce L; Fox, Kevin; Zhang, Paul; Koski, Gary; Czerniecki, Brian J

2011-01-01

Background HER-2/neu over-expression plays a critical role in breast cancer development and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. Methods A HER-2/neu dendritic cell (DC) vaccine was administered to 27 patients with HER-2/neu over-expressing DCIS. The HER-2/neu vaccine was administered prior to surgical resection and pre- and post-vaccination analysis was conducted to assess clinical results. Results At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, while among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing ERneg with ERpos DCIS lesions, vaccination was more effective in hormone-independent DCIS. Following vaccination, no residual DCIS was found in 40% of ERneg subjects compared to 5.9% in ERpos subject. Sustained HER-2/neu expression was found in 10% of ERneg subjects compared to 47.1% in ERpos subjects (p=0.04). Post-vaccination phenotypes were significantly different between ERpos and ERneg subjects (p=0.01), with 7 of 16 (43.8%) initially presenting with ERpos HER-2/neupos Luminal B phenotype finishing with the ERpos HER-2/neuneg Luminal A phenotype, and 3 of 6 (50%) with the ERneg HER-2/neupos phenotype changing to the ERneg HER-2/neuneg phenotype. Conclusions Results suggest vaccination against HER-2/neu is safe, well-tolerated and induces decline and or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor associated antigens and pathways. PMID:22252842
Trastuzumab after Chemotherapy Is Effective in HER2-Positive Breast Cancer

Cancer.gov

Treatment with trastuzumab for 1 year following standard chemotherapy improved disease-free survival in women with HER2-positive early breast cancer, according to 4-year follow-up results of the Herceptin Adjuvant (HERA) trial reported February 25, 2011,
Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.

PubMed

Norton, Nadine; Fox, Nicholas; McCarl, Christie-Ann; Tenner, Kathleen S; Ballman, Karla; Erskine, Courtney L; Necela, Brian M; Northfelt, Donald; Tan, Winston W; Calfa, Carmen; Pegram, Mark; Colon-Otero, Gerardo; Perez, Edith A; Clynes, Raphael; Knutson, Keith L

2018-06-14

Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. ClinicalTrials.gov, NCT00005970 . Registered on July
C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

PubMed

Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

2018-05-02

Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

PubMed Central

Baselga, José; Bradbury, Ian; Eidtmann, Holger; Di Cosimo, Serena; de Azambuja, Evandro; Aura, Claudia; Gómez, Henry; Dinh, Phuong; Fauria, Karine; Van Dooren, Veerle; Aktan, Gursel; Goldhirsch, Aron; Chang, Tsai-Wang; Horváth, Zsolt; Coccia-Portugal, Maria; Domont, Julien; Tseng, Ling-Min; Kunz, Georg; Sohn, Joo Hyuk; Semiglazov, Vladimir; Lerzo, Guillermo; Palacova, Marketa; Probachai, Volodymyr; Pusztai, Lajos; Untch, Michael; Gelber, Richard D; Piccart-Gebhart, Martine

2017-01-01

Summary Background The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. Methods In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. Findings 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1–59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4–37·5]; difference 21·1%, 9·1–34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1–32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus
HER2-family signalling mechanisms, clinical implications and targeting in breast cancer.

PubMed

Elster, N; Collins, D M; Toomey, S; Crown, J; Eustace, A J; Hennessy, B T

2015-01-01

Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.
Cdx2 Polymorphism Affects the Activities of Vitamin D Receptor in Human Breast Cancer Cell Lines and Human Breast Carcinomas

PubMed Central

Di Benedetto, Anna; Korita, Etleva; Goeman, Frauke; Sacconi, Andrea; Biagioni, Francesca; Blandino, Giovanni; Strano, Sabrina; Muti, Paola; Mottolese, Marcella; Falvo, Elisabetta

2015-01-01

Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression. PMID:25849303
Coffee consumption modifies risk of estrogen-receptor negative breast cancer

PubMed Central

2011-01-01

Introduction Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes. Methods Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate. Results In the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR≤ 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR≤ 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004). Conclusions A high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women. PMID:21569535
Pembrolizumab and Capecitabine in Treating Patients With Locally Advanced or Metastatic Triple Negative or Hormone-Refractory Breast Cancer That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-03-15

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma
High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance).

PubMed

Chumsri, Saranya; Sperinde, Jeff; Liu, Heshan; Gligorov, Joseph; Spano, Jean-Philippe; Antoine, Martine; Moreno Aspitia, Alvaro; Tan, Winston; Winslow, John; Petropoulos, Christos J; Chenna, Ahmed; Bates, Michael; Weidler, Jodi Marie; Huang, Weidong; Dueck, Amylou; Perez, Edith A

2018-03-12

Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro , but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels ( R 2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-6. ©2018 AACR. ©2018 American Association for Cancer Research.

Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumour of breast.

PubMed

Ikhwan, S M; Kenneth, V K T; Seoparjoo, A; Zin, A A M

2013-06-21

Primary primitive neuroectodermal tumour (PNET) and extraskeletal Ewing's sarcoma belongs to the Ewing's family of tumours. Primary tumours arising from breast are very rare. There are only a few case reports published on primary extraskeletal Ewing's sarcoma and PNET arising from breast. We present an extremely rare case of an inoperable primary Ewing's sarcoma arising from left breast with contralateral breast, lymphatic and lung metastasis.
Acoustic radiation force impulse elastography in evaluation of triple-negative breast cancer: A preliminary experience.

PubMed

Wan, Jing; Wu, Rong; Yao, Minghua; Xu, Guang; Liu, Hui; Pu, Huan; Xiang, Lihua; Zhang, Shupin

2018-05-19

To assess the elastographic features of triple-negative breast cancers and evaluate the diagnostic value of acoustic radiation force impulse imaging (ARFI) for the characterization of triple-negative breast cancers. This study analyzed data from 234 women with breast cancer. Patients were categorized into three groups; 1) triple-negative breast cancers (n = 48); 2) ER-positive tumors (n = 128) and 3) HER2-positive tumors (n = 58). Mean tumor stiffness was evaluated by virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ) and quantified as both qualitative scores (1-5) and shear wave velocity (SWV) (m/s). The relationship between mean SWV and tumor parameters, including tumor size, tumor type, histologic grade and lymph node status, were investigated using multiple linear regression. Triple-negative tumor were more likely to have a large invasive size (p = 0.002), high histological grade (p < 0.001), lymph node involvement (p = 0.022) and strong ki-67 expression (p < 0.001). The highest mean SWV value were recorded in triple-negative tumors (7.36 m/s±1.83), followed by HER2+ tumors (6.65 m/s±2.26) and ER+ tumors (6.60 m/s±2.35) (p = 0.122). Triple-negative tumors were also associated with increased stiffness than ER+ tumors and HER2+ tumors (p = 0.016), as measured by qualitative VTI scores. Tumor size was independently associated with mean SWV value on adjusted regression (p < 0.001). Triple-negative breast cancer is associated with high stiffness scores and SWV in ARFI. The latter may be considered a useful complementary tool in evaluation of triple-negative breast cancer.
Oncogenic HER2Δ16 suppresses miR-15a/16 and deregulates BCL-2 to promote endocrine resistance of breast tumors

PubMed Central

Cittelly, Diana M.; Das, Partha M.; Salvo, Virgilio A.; Fonseca, Juan P.; Burow, Matthew E.; Jones, Frank E.

2010-01-01

Tamoxifen is the most commonly prescribed therapy for patients with estrogen receptor (ER)α-positive breast tumors. Tumor resistance to tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress human epidermal growth factor receptor 2 (HER2). Current preclinical models of HER2 overexpression fail to recapitulate the clinical spectrum of endocrine resistance associated with HER2/ER-positive tumors. Here, we show that ectopic expression of a clinically important oncogenic isoform of HER2, HER2Δ16, which is expressed in >30% of ER-positive breast tumors, promotes tamoxifen resistance and estrogen independence of MCF-7 xenografts. MCF-7/HER2Δ16 cells evade tamoxifen through upregulation of BCL-2, whereas mediated suppression of BCL-2 expression or treatment of MCF-7/HER2Δ16 cells with the BCL-2 family pharmacological inhibitor ABT-737 restores tamoxifen sensitivity. Tamoxifen-resistant MCF-7/HER2Δ16 cells upregulate BCL-2 protein levels in response to suppressed ERα signaling mediated by estrogen withdrawal, tamoxifen treatment or fulvestrant treatment. In addition, HER2Δ16 expression results in suppression of BCL-2-targeting microRNAs miR-15a and miR-16. Reintroduction of miR-15a/16 reduced tamoxifen-induced BCL-2 expression and sensitized MCF-7/HER2Δ16 to tamoxifen. Conversely, inhibition of miR-15a/16 in tamoxifen-sensitive cells activated BCL-2 expression and promoted tamoxifen resistance. Our results suggest that HER2Δ16 expression promotes endocrine-resistant HER2/ERα-positive breast tumors and in contrast to wild-type HER2, preclinical models of HER2Δ16 overexpression recapitulate multiple phenotypes of endocrine-resistant human breast tumors. The mechanism of HER2Δ16 therapeutic evasion, involving tamoxifen-induced upregulation of BCL-2 and suppression of miR-15a/16, provides a template for unique therapeutic interventions combining tamoxifen with modulation of microRNAs and/or ABT-737-mediated BCL-2
Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.

PubMed

Jiang, Qiongchao; Hao, Shaoyun; Xiao, Xiaoyun; Yao, Jiyi; Ou, Bing; Zhao, Zizhuo; Liu, Fengtao; Pan, Xin; Luo, Baoming; Zhi, Hui

2016-05-01

There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors. Phospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model. The average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle. The Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.
Brk/PTK6 cooperates with HER2 and Src in regulating breast cancer cell survival and epithelial-to-mesenchymal transition

PubMed Central

Ai, Midan; Liang, Ke; Lu, Yang; Qiu, Songbo; Fan, Zhen

2013-01-01

Breast tumor kinase (Brk)/protein tyrosine kinase-6 (PTK-6) is a nonreceptor PTK commonly expressed at high levels in breast cancer. Brk interacts closely with members of the human epidermal growth factor receptor (HER) family in breast cancer but the functional role of this interaction remains to be determined. Here, we provide novel mechanistic insights into the role of Brk in regulating cell survival and epithelial-to-mesenchymal transition (EMT) in the context of HER2-positive breast cancer cells. Overexpression of HER2 in MCF7 breast cancer cells (MCF7HER2) led to a higher level of Brk protein and concomitantly reduced Src Y416-phosphorylation, and the cells became mesenchymal in morphology. An in vivo selection of MCF7HER2 cells in nude mice resulted in a subline, termed EMT1, that exhibited not only mesenchymal morphology but also enhanced migration potential. Compared with MCF7HER2 cells, EMT1 cells maintained a similar level of HER2 protein but had much higher level of activated HER2, and the increase in Brk protein and the decrease in Src Y416-phosphorylation were less in EMT1 cells. EMT1 cells exhibited increased sensitivity to both pharmacological inhibition of HER2 and knockdown of Brk than did MCF7HER2 cells. Knockdown of Brk induced apoptosis and partially reversed the EMT phenotype in EMT1 cells. Overexpression of a constitutively active STAT3, a known substrate of Brk, overcame Brk knockdown-induced effects in EMT1 cells. Together, our findings support a new paradigm wherein Brk plays both a complementary and a counterbalancing role in cooperating with HER2 and Src to regulate breast cancer cell survival and EMT. PMID:23291984
A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study.

PubMed

Wiedermann, Ursula; Wiltschke, C; Jasinska, J; Kundi, M; Zurbriggen, R; Garner-Spitzer, E; Bartsch, R; Steger, G; Pehamberger, H; Scheiner, O; Zielinski, C C

2010-02-01

We have previously shown in mice that vaccination with three Her-2-peptides representing B-cell epitopes of the extracellular domain of Her-2/neu induces Her-2/neu-specific IgG antibodies with strong anti-tumor activity in vitro and in vivo. We have now finalized a phase I clinical trial with an anti-Her-2/neu vaccine-construct of immunopotentiating reconstituted influenza virosomes with the three peptides in patients with metastatic breast cancer (MBC). Ten MBC patients with low protein overexpression of Her-2/neu of MBC (+ or ++ upon immunohistochemistry, FISH negative) and positive hormone receptor status were enrolled in a single center phase I study. The virosomal formulated vaccine, consisting of 10 microg/peptide, was intramuscularly applied three times on days 1, 28, and 56. The primary endpoint of the study, which lasted 12 weeks, was safety, the secondary endpoint immunogenicity. Local erythema at the injection site was the only vaccine-related side effect occurring in four patients. In 8 of 10 patients an increase in peptide-specific antibody titer measured by ELISA was found. Importantly, the induced antibodies were also directed against the native Her-2/neu protein. Cellular immune responses, as measured by in vitro production of IL-2, IFN-c, and TNF-a of PBMCs showed a marked increase after vaccination in the majority of vaccinees. Notably, the number of CD4+CD25+Foxp3+T regulatory cells, which were significantly increased compared to healthy controls prior to vaccination, was markedly reduced following vaccination. In all, the immunological responses after vaccination indicated that the patients in stage IV of disease were immunocompetent and susceptible to vaccination. The Her-2/neu multipeptide vaccine was safe, well tolerated and effective in overcoming immunological tolerance to Her-2/neu. The induction of anti-Her-2-specific antibodies could result in clinical benefit comparable to passive anti-Her-2 antibody therapy.
Imaging features of breast cancers on digital breast tomosynthesis according to molecular subtype: association with breast cancer detection.

PubMed

Lee, Su Hyun; Chang, Jung Min; Shin, Sung Ui; Chu, A Jung; Yi, Ann; Cho, Nariya; Moon, Woo Kyung

2017-12-01

To evaluate imaging features of breast cancers on digital breast tomosynthesis (DBT) according to molecular subtype and to determine whether the molecular subtype affects breast cancer detection on DBT. This was an institutional review board--approved study with a waiver of informed consent. DBT findings of 288 invasive breast cancers were reviewed according to Breast Imaging Reporting and Data System lexicon. Detectability of breast cancer was quantified by the number of readers (0-3) who correctly detected the cancer in an independent blinded review. DBT features and the cancer detectability score according to molecular subtype were compared using Fisher's exact test and analysis of variance. Of 288 invasive cancers, 194 were hormone receptor (HR)-positive, 48 were human epidermal growth factor receptor 2 (HER2) positive and 46 were triple negative breast cancers. The most common DBT findings were irregular spiculated masses for HR-positive cancer, fine pleomorphic or linear branching calcifications for HER2 positive cancer and irregular masses with circumscribed margins for triple negative breast cancers (p < 0.001). Cancer detectability on DBT was not significantly different according to molecular subtype (p = 0.213) but rather affected by tumour size, breast density and presence of mass or calcifications. Breast cancers showed different imaging features according to molecular subtype; however, it did not affect the cancer detectability on DBT. Advances in knowledge: DBT showed characteristic imaging features of breast cancers according to molecular subtype. However, cancer detectability on DBT was not affected by molecular subtype of breast cancers.
Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer

ClinicalTrials.gov

2018-03-15

HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Breast Adenocarcinoma; Inflammatory Breast Carcinoma
Tumour bed boost radiotherapy for women after breast-conserving surgery.

PubMed

Kindts, Isabelle; Laenen, Annouschka; Depuydt, Tom; Weltens, Caroline

2017-11-06

analysis and applied GRADE to assess the quality of the evidence. We included 5 randomised controlled trials analysing a total of 8325 women.Local control appeared to be better for women receiving a tumour bed boost compared to no tumour bed boost (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.55 to 0.75; 5 studies, 8315 women, low-quality evidence). Overall survival did not differ with or without a tumour bed boost (HR 1.04, 95% CI 0.94 to 1.14; 2 studies, 6342 women, moderate-quality evidence). Disease-free survival did not differ with or without a tumour bed boost (HR 0.94, 95% CI 0.87 to 1.02; 3 studies, 6549 women, low-quality evidence). Late toxicity scored by means of percentage of breast retraction assessment did not differ with or without a tumour bed boost (mean difference 0.38, 95% CI -0.18 to 0.93; 2 studies, 1526 women, very low-quality evidence). Cosmesis scored by a panel was better (i.e. excellent or good compared to fair or poor) in the no-boost group (odds ratio (OR) 1.41, 95% CI 1.07 to 1.85; 2 studies, 1116 women, low-quality evidence). Cosmesis scored by a physician did not differ with or without a tumour bed boost (OR 1.58, 95% CI 0.93 to 2.69; 2 studies, 592 women, very low-quality evidence).We excluded two studies in a sensitivity analysis of local recurrence (because the biological equivalent dose (BED) to the tumour bed was lower, in situ tumours were included, or there was a high risk of selective reporting bias or blinding of outcome assessment bias), which resulted in a HR of 0.62 (95% CI 0.52 to 0.73; 3 studies, 6963 women, high-quality evidence). Subgroup analysis including women older than 40 years of age yielded a HR of 0.65 (95% CI 0.53 to 0.81; 2 studies, 5058 women, high-quality evidence).We found no data for the outcomes of acute toxicity, quality of life, or costs. It appears that local control rates are increased with the boost to the tumour bed, but we found no evidence of a benefit for other oncological outcomes. Subgroup
Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects.

PubMed

Brandão, Mariana; Pondé, Noam F; Poggio, Francesca; Kotecki, Nuria; Salis, Mauren; Lambertini, Matteo; de Azambuja, Evandro

2018-05-24

HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1, and neratinib, alone or combined in 'dual HER2-blockade' regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity, and cost-effectiveness. Expert commentary: The combination of trastuzumab/pertuzumab is approved in all disease settings, while trastuzumab/neratinib is approved in the adjuvant setting and trastuzumab/lapatinib in metastatic disease. Meanwhile, as breast cancer biology and resistance mechanisms become clearer, combinations with drugs like PI3K/Akt/mTOR inhibitors, CDK4/6 inhibitors, anti-PD(L)1 antibodies, endocrine therapy, and new anti-HER2 agents (panHER and HER2 tyrosine kinase inhibitors, bispecific antibodies, anti-HER3 antibodies, and antibody-drug conjugates) are being extensively tested in clinical trials. More specific strategies for the 'triple-positive' (estrogen receptor-positive/HER2-positive) disease are also being explored. However, there is an urgent need for the development of predictive biomarkers for a better tailoring of anti-HER2 directed therapy. This is the only way to further improve clinical outcomes and quality of life and to decrease costs and toxicities of unnecessary treatments.
Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub-types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial.

PubMed

Ali, Alaa M; Provenzano, Elena; Bartlett, John M S; Abraham, Jean; Driver, Kristy; Munro, Alison F; Twelves, Christopher; Poole, Christopher J; Hiller, Louise; Dunn, Janet A; Earl, Helena M; Caldas, Carlos; Pharoah, Paul D

2013-09-15

Breast cancer can be classified into molecular sub-types that have distinct survival patterns. We evaluated the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with ECMF (epirubicin and CMF). Furthermore, we evaluated whether the sub-types were predictive of the added benefit of epirubicin in these trials. Tumour tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumours into six intrinsic sub-types. We used Cox regression to compare overall survival (OS), breast cancer-specific survival (BCSS) and relapse-free survival (RFS) in the different sub-groups. We also compared the effect of ECMF with CMF by sub-group. Immunohistochemistry data were available for 1,725 cases of whom 805 were luminal 1-basal negative. Median follow-up time was 7 years. The luminal 1-basal negative tumours were associated with the best prognosis in five years after surgery and the HER2-like tumours were associated with the poorest prognosis. There was little evidence for significant heterogeneity of this effect by tumour sub-type (OS p = 0.40, BCSS p = 0.53 RFS p = 0.50) - the largest additional benefit of epirubicin was in women with tumours of the 5-negative phenotype (OS HR = 0.39 95% CI: 0.21-0.73) and the smallest was in Luminal 1-basal negative tumours (OS HR = 0.86 95% CI: 0.64-1.16). We confirmed that breast cancer sub-types show distinct behaviour with differences in short- and long-term survival. The benefit of ECMF over CMF was statistically similar in all disease sub-types. Copyright © 2013 UICC.
An immunohistochemical and fluorescence in situ hybridization-based comparison between the Oracle HER2 Bond Immunohistochemical System, Dako HercepTest, and Vysis PathVysion HER2 FISH using both commercially validated and modified ASCO/CAP and United Kingdom HER2 IHC scoring guidelines.

PubMed

O'Grady, Anthony; Allen, David; Happerfield, Lisa; Johnson, Nicola; Provenzano, Elena; Pinder, Sarah E; Tee, Lilian; Gu, Mai; Kay, Elaine W

2010-12-01

Immunohistochemistry (IHC) is used as the frontline assay to determine HER2 status in invasive breast cancer patients. The aim of the study was to compare the performance of the Leica Oracle HER2 Bond IHC System (Oracle) with the current most readily accepted Dako HercepTest (HercepTest), using both commercially validated and modified ASCO/CAP and UK HER2 IHC scoring guidelines. A total of 445 breast cancer samples from 3 international clinical HER2 referral centers were stained with the 2 test systems and scored in a blinded fashion by experienced pathologists. The overall agreement between the 2 tests in a 3×3 (negative, equivocal and positive) analysis shows a concordance of 86.7% and 86.3%, respectively when analyzed using commercially validated and modified ASCO/CAP and UK HER2 IHC scoring guidelines. There is a good concordance between the Oracle and the HercepTest. The advantages of a complete fully automated test such as the Oracle include standardization of key analytical factors and improved turn around time. The implementation of the modified ASCO/CAP and UK HER2 IHC scoring guidelines has minimal effect on either assay interpretation, showing that Oracle can be used as a methodology for accurately determining HER2 IHC status in formalin fixed, paraffin-embedded breast cancer tissue.
Immunotherapeutic interventions of Triple Negative Breast Cancer.

PubMed

Li, Zehuan; Qiu, Yiran; Lu, Weiqi; Jiang, Ying; Wang, Jin

2018-05-30

Triple Negative Breast Cancer (TNBC) is a highly heterogeneous subtype of breast cancer that lacks the expression of oestrogen receptors, progesterone receptors and human epidermal growth factor receptor 2. Although TNBC is sensitive to chemotherapy, the overall outcomes of TNBC are worse than for other breast cancers, and TNBC is still one of the most fatal diseases for women. With the discovery of antigens specifically expressed in TNBC cells and the developing technology of monoclonal antibodies, chimeric antigen receptors and cancer vaccines, immunotherapy is emerging as a novel promising option for TNBC. This review is mainly focused on the tumour microenvironment and host immunity, Triple Negative Breast Cancer and the clinical treatment of TNBC, novel therapies for cancer and immunotherapy for TNBC, and the future outlook for the treatment for TNBC and the interplay between the therapies, including immune checkpoint inhibitors, combination of immune checkpoint inhibitors with targeted treatments in TNBC, adoptive cell therapy, cancer vaccines. The review also highlights recent reports on the synergistic effects of immunotherapy and chemotherapy, antibody-drug conjugates, and exosomes, as potential multifunctional therapeutic agents in TNBC.
Inflamed Phylloides Tumour in a Girl: A Challenging Diagnosis in Paediatric Breast Lesions.

PubMed

Testa, Ilaria; Salvatori, Cristina; Prestipino, Marco; Laurenti, Maria Elena; Gerli, Paolo; Di Cara, Giuseppe; Principi, Nicola; Esposito, Susanna; Bertozzi, Mirko

2018-05-11

Introduction : Phylloides tumours (PTs) are rare fibroepithelial neoplasms that account for 0.3⁻0.9% of all breast tumours. These tumours typically occur in women aged 30⁻70 years. The occurrence of these tumours in older children and adolescents poses particular diagnostic and therapeutic problems. However, early diagnosis is mandatory because although most of the cases of PTs in children are benign, the borderline and malignant cases with potential negative outcomes cannot be excluded. Case presentation : A 12-year-old girl presented at the Paediatric Emergency Department for hyperaemia and warmth of the left breast that occurred a few days prior without fever. The girl experienced menarche 8 months previously. She experienced no previous trauma and she had no family history of breast cancer. On physical examination, the left breast was painful, enlarged and tender. The overlying skin was erythematous and warm. A breast ultrasonography (US) revealed a large mass with features of an abscess, including a hyperechoic wall, scattered internal echoes and hypoechoic peripheral lacunae of apparent colliquative nature. After 4 days of unsuccessful antibiotic therapy, surgical drainage was performed due to the suspicion of a mammary abscess. At the surgical incision site, the lesion was not-well circumscribed and lacked a capsule. In addition, purulent material was not detected. Histological examination revealed that the tissue alterations were compatible with benign PT. With this diagnosis, the girl underwent definitive surgical removal of the lesion. The postoperative period passed without negative events. An US performed 6 months later revealed that no new mass was present at this time, suggesting no recurrence of the tumour. Conclusion : This case shows that in the presence of a clinical picture suggesting the inflammation of the breast in adolescent females, PT should be considered as a possible diagnosis and US-guided core biopsy should be considered to confirm
Systemic therapy for HER2-positive early-stage breast cancer.

PubMed

Mathew, Aju; Romond, Edward H

The advent of the targeted monoclonal antbody trastuzumab for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer marked a revolution in the understanding and management of mammary carcinoma and, in practice, separated this subtype from other kinds of primary breast malignancy. Long term follow-up from the initial large adjuvant trials continue to show remarkably positive results. Currently, at least four additional agents targeting this receptor, using different and complementary mechanisms of action compared with trastuzumab, have been incorporated into clinical trials. The small molecule tyrosine kinase inhibitors lapatinib and neratinib, in addition to the antibody pertuzumab and the antibody-drug conjugate trastuzumab-ematansine, have shown efficacy in metastatic breast cancer and are being evaluated both in neoadjuvant and adjuvant trials for early stage disease. The cytotoxic chemotherapy regimens used in combination with these agents also are evolving and different therapeutic approaches are emerging for patients depending on their relative level of risk from their cancers, thus moving clinical management toward individualized therapy. Much has been learned about managing the toxicities of treatment and pre-operative approaches have provided a means of assessing the sensitivity of individual patients' cancers to specific treatment regimens. This review traces the development of these studies and focuses on improvements in adjuvant and neoadjuvant therapy for patients with HER2-positive disease whose prognosis has changed in the last decade from dire to favorable. A path forward has been set by which the goal of cure is attainable for almost all patients faced with this aggressive form of breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.
Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer

PubMed Central

Castagnoli, L; Ghedini, G C; Koschorke, A; Triulzi, T; Dugo, M; Gasparini, P; Casalini, P; Palladini, A; Iezzi, M; Lamolinara, A; Lollini, P L; Nanni, P; Chiodoni, C; Tagliabue, E; Pupa, S M

2017-01-01

We have previously shown that the d16HER2 splice variant is linked to HER2-positive breast cancer (BC) tumorigenesis, progression and response to Trastuzumab. However, the mechanisms by which d16HER2 contributes to HER2-driven aggressiveness and targeted therapy susceptibility remain uncertain. Here, we report that the d16HER2-positive mammary tumor cell lines MI6 and MI7, derived from spontaneous lesions of d16HER2 transgenic (tg) mice and resembling the aggressive features of primary lesions, are enriched in the expression of Wnt, Notch and epithelial–mesenchymal transition pathways related genes compared with full-length wild-type (WT) HER2-positive cells (WTHER2_1 and WTHER2_2) derived from spontaneous tumors arising in WTHER2 tg mice. MI6 cells exhibited increased resistance to anoikis and significantly higher mammosphere-forming efficiency (MFE) and self-renewal capability than the WTHER2-positive counterpart. Furthermore, d16HER2-positive tumor cells expressed a higher fraction of CD29High/CD24+/SCA1Low cells and displayed greater in vivo tumor engraftment in serial dilution conditions than WTHER2_1 cells. Accordingly, NOTCH inhibitors impaired mammosphere formation only in MI6 cells. A comparative analysis of stemness-related features driven by d16HER2 and WTHER2 in ad hoc engineered human BC cells (MCF7 and T47D) revealed a higher MFE and aldehyde dehydrogenase-positive staining in d16HER2- vs WTHER2-infected cells, sustaining consistent BC-initiating cell enrichment in the human setting. Moreover, marked CD44 expression was found in MCF7_d16 and T47D_d16 cells vs their WTHER2 and Mock counterparts. Clinically, BC cases from two distinct HER2-positive cohorts characterized by high levels of expression of the activated-d16HER2 metagene were significantly enriched in the Notch family and signal transducer genes vs those with low levels of the metagene. PMID:27641338
Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping

PubMed Central

Wulfkuhle, Julia D.; Berg, Daniela; Wolff, Claudia; Langer, Rupert; Tran, Kai; Illi, Julie; Espina, Virginia; Pierobon, Mariaelena; Deng, Jianghong; DeMichele, Angela; Walch, Axel; Bronger, Holger; Becker, Ingrid; Waldhör, Christine; Höfler, Heinz; Esserman, Laura; Liotta, Lance A.; Becker, Karl-Friedrich; Petricoin, Emanuel F.

2017-01-01

Purpose Targeting of the HER2 protein in human breast cancer represents a major advance in oncology, but relies on measurements of total HER2 protein and not HER2 signaling network activation. We utilized reverse phase protein microarrays (RPMAs) to measure total and phosphorylated HER2 in the context of HER family signaling to understand correlations between phosphorylated and total levels of HER2 and downstream signaling activity. Experimental Design Three independent study sets, comprising a total of 415 individual patient samples from flash frozen core biopsy samples and FFPE surgical and core samples, were analyzed via RPMA. The phosphorylation and total levels of the HER receptor family proteins and downstream signaling molecules were measured in laser capture microdissected (LCM) enriched tumor epithelium from 127 frozen pre-treatment core biopsy samples and whole tissue lysates from 288 FFPE samples and these results were compared to FISH and IHC. Results RPMA measurements of total HER2 were highly concordant (> 90% all sets) with FISH and/or IHC data, as was phosphorylation of HER2 in the FISH/IHC+ population. Phosphorylation analysis of HER family signaling identified HER2 activation in some FISH/IHC- tumors and, identical to that seen with FISH/IHC+ tumors, the HER2 activation was concordant with EGFR and HER3 phosphorylation and downstream signaling endpoint activation. Conclusions Molecular profiling of HER2 signaling of a large cohort of human breast cancer specimens using a quantitative and sensitive functional pathway activation mapping technique reveals IHC-/FISH-/pHER2+ tumors with HER2 pathway activation independent of total HER2 levels and functional signaling through HER3 and EGFR. PMID:23045247
Performance of automated scoring of ER, PR, HER2, CK5/6 and EGFR in breast cancer tissue microarrays in the Breast Cancer Association Consortium

PubMed Central

Howat, William J; Blows, Fiona M; Provenzano, Elena; Brook, Mark N; Morris, Lorna; Gazinska, Patrycja; Johnson, Nicola; McDuffus, Leigh‐Anne; Miller, Jodi; Sawyer, Elinor J; Pinder, Sarah; van Deurzen, Carolien H M; Jones, Louise; Sironen, Reijo; Visscher, Daniel; Caldas, Carlos; Daley, Frances; Coulson, Penny; Broeks, Annegien; Sanders, Joyce; Wesseling, Jelle; Nevanlinna, Heli; Fagerholm, Rainer; Blomqvist, Carl; Heikkilä, Päivi; Ali, H Raza; Dawson, Sarah‐Jane; Figueroa, Jonine; Lissowska, Jolanta; Brinton, Louise; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli‐Matti; Cox, Angela; Brock, Ian W; Cross, Simon S; Reed, Malcolm W; Couch, Fergus J; Olson, Janet E; Devillee, Peter; Mesker, Wilma E; Seyaneve, Caroline M; Hollestelle, Antoinette; Benitez, Javier; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Bolla, Manjeet K; Easton, Douglas F; Schmidt, Marjanka K; Pharoah, Paul D; Sherman, Mark E

2014-01-01

Abstract Breast cancer risk factors and clinical outcomes vary by tumour marker expression. However, individual studies often lack the power required to assess these relationships, and large‐scale analyses are limited by the need for high throughput, standardized scoring methods. To address these limitations, we assessed whether automated image analysis of immunohistochemically stained tissue microarrays can permit rapid, standardized scoring of tumour markers from multiple studies. Tissue microarray sections prepared in nine studies containing 20 263 cores from 8267 breast cancers stained for two nuclear (oestrogen receptor, progesterone receptor), two membranous (human epidermal growth factor receptor 2 and epidermal growth factor receptor) and one cytoplasmic (cytokeratin 5/6) marker were scanned as digital images. Automated algorithms were used to score markers in tumour cells using the Ariol system. We compared automated scores against visual reads, and their associations with breast cancer survival. Approximately 65–70% of tissue microarray cores were satisfactory for scoring. Among satisfactory cores, agreement between dichotomous automated and visual scores was highest for oestrogen receptor (Kappa = 0.76), followed by human epidermal growth factor receptor 2 (Kappa = 0.69) and progesterone receptor (Kappa = 0.67). Automated quantitative scores for these markers were associated with hazard ratios for breast cancer mortality in a dose‐response manner. Considering visual scores of epidermal growth factor receptor or cytokeratin 5/6 as the reference, automated scoring achieved excellent negative predictive value (96–98%), but yielded many false positives (positive predictive value = 30–32%). For all markers, we observed substantial heterogeneity in automated scoring performance across tissue microarrays. Automated analysis is a potentially useful tool for large‐scale, quantitative scoring of immunohistochemically stained tissue
Multi-epitope Folate Receptor Alpha Peptide Vaccine, Sargramostim, and Cyclophosphamide in Treating Patients With Triple Negative Breast Cancer

ClinicalTrials.gov

2018-06-18

Bilateral Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Stage IB Breast Cancer AJCC v7; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma; Unilateral Breast Carcinoma
Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

PubMed

Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

2013-02-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Clinicopathological Features, Patterns of Recurrence, and Survival Among Women With Triple-Negative Breast Cancer in the National Comprehensive Cancer Network

PubMed Central

Lin, Nancy U.; Vanderplas, Ann; Hughes, Melissa E.; Theriault, Richard L.; Edge, Stephen B.; Wong, Yu-Ning; Blayney, Douglas W.; Niland, Joyce C.; Winer, Eric P.; Weeks, Jane C.

2012-01-01

Background We aimed to describe clinicopathological features, patterns of recurrence, and survival according to breast cancer subtype, with a focus on triple-negative tumors. Methods We evaluated 15,204 women presenting to NCCN centers with stage I-III breast cancer between January 2000 and December 2006. Tumors were classified as hormone receptor positive [HR+]/HER2− (ER+ and/or PR+, and HER2−), HER2+ (HER2+, any ER or PR), or triple-negative (ER−, PR−, and HER2−). Results Subtype distribution was: triple-negative 17% (n=2,569), HER2+ 17% (n=2,602), HR+/HER2− 66% (n=10,033). Triple-negative subtype was more frequent in African-Americans, compared with Caucasians (adjusted odds ratio [OR] 1.98; p<0.0001). Premenopausal, but not postmenopausal, women with high body mass index had an increased likelihood of triple negative subtype (p=0.02). Women with triple-negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs. 48%, p<0.0001), more likely to present with higher T stage, but less likely to have nodal involvement. Relative to HR+/HER2− tumors, triple-negative tumors were associated with a higher risk of brain or lung metastases, and had worse breast cancer-specific and overall survival, even after adjusting for age, stage, race, grade, and receipt of adjuvant chemotherapy (adjusted hazard ratio [HR] for overall survival 2.72, 95% CI 2.39–3.10, p<0.0001). The difference in risk of death by subtype was most dramatic within the first two years after diagnosis (HR for OS for 0 to 2 yrs 6.10 [95% CI 4.81, 7.74]). Conclusions Triple-negative tumors are associated with unique risk factors and worse outcomes compared to HR+/HER2− tumors. PMID:22544643
A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways

PubMed Central

Lae, Marick; Moarii, Matahi; Sadacca, Benjamin; Pinheiro, Alice; Galliot, Marion; Abecassis, Judith; Laurent, Cecile; Reyal, Fabien

2016-01-01

Introduction HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions. Methods We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset). Results We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the “Immunity” metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28–11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36–0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs). Conclusion The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation. PMID:28005906
Assessment of HER2 status in breast cancer biopsies is not affected by accelerated tissue processing.

PubMed

Bulte, Joris P; Halilovic, Altuna; Kalkman, Shona; van Cleef, Patricia H J; van Diest, Paul J; Strobbe, Luc J A; de Wilt, Johannes H W; Bult, Peter

2018-03-01

To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to determine accurately the human epidermal growth factor receptor 2 (HER2) status of breast cancer. A consecutive case-series from two high-volume breast clinics was created. We compared routine HER2 immunohistochemistry (IHC) assessment between accelerated processing CNB specimens and routinely processed postoperative excision specimens. Additional amplification-based testing was performed in cases with equivocal results. The formalin fixation time was less than 2 h and between 6 and 72 h, respectively. Fluorescence in-situ hybridisation and multiplex ligation-dependent probe amplification were used for amplification testing. One hundred and forty-four cases were included, 15 of which were HER2-positive on the routinely processed excision specimens. On the CNB specimens, 44 were equivocal on IHC and required an amplification-based test. Correlation between the CNB specimens and the corresponding excision specimens was high for final HER2 status, with an accuracy of 97% and a kappa of 0.85. HER2 status can be determined reliably on CNB specimens with accelerated processing time using standard clinical testing methods. Using this accelerated technology the minimum 6 h of formalin fixation, which current guidelines consider necessary, can be decreased safely. This allows for a complete and expedited histology-based diagnosis of breast lesions in the setting of a one-stop-shop, same-day breast clinic. © 2018 The Authors. Histopathology Published by John Wiley & Sons Ltd.
[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

PubMed

Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

2015-06-01

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.
Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice.

PubMed

Anisimov, V N; Khavinson, V Kh; Alimova, I N; Semchenko, A V; Yashin, A I

2002-08-01

Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.
A Phase I Study of LJM716 in Squamous Cell Carcinoma of Head and Neck, or HER2+ Breast Cancer or Gastric Cancer

ClinicalTrials.gov

2014-04-21

HER2 + Breast Cancer, HER2 + Gastric Cancer, Squamous Cell Carcinoma of Head and Neck, Esophageal Squamous Cell Carcinoma; HER2 + Breast Cancer; HER2 + Gastric Cancer; Squamous Cell Carcinoma of Head and Neck; Esophageal Squamous Cell Carcinoma
Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells

PubMed Central

2009-01-01

Background Nanocarrier-based antibody targeting is a promising modality in therapeutic and diagnostic oncology. Single-walled carbon nanotubes (SWNTs) exhibit two unique optical properties that can be exploited for these applications, strong Raman signal for cancer cell detection and near-infrared (NIR) absorbance for selective photothermal ablation of tumors. In the present study, we constructed a HER2 IgY-SWNT complex and demonstrated its dual functionality for both detection and selective destruction of cancer cells in an in vitro model consisting of HER2-expressing SK-BR-3 cells and HER2-negative MCF-7 cells. Methods The complex was constructed by covalently conjugating carboxylated SWNTs with anti-HER2 chicken IgY antibody, which is more specific and sensitive than mammalian IgGs. Raman signals were recorded on Raman spectrometers with a laser excitation at 785 nm. NIR irradiation was performed using a diode laser system, and cells with or without nanotube treatment were irradiated by 808 nm laser at 5 W/cm2 for 2 min. Cell viability was examined by the calcein AM/ethidium homodimer-1 (EthD-1) staining. Results Using a Raman optical microscope, we found the Raman signal collected at single-cell level from the complex-treated SK-BR-3 cells was significantly greater than that from various control cells. NIR irradiation selectively destroyed the complex-targeted breast cancer cells without harming receptor-free cells. The cell death was effectuated without the need of internalization of SWNTs by the cancer cells, a finding that has not been reported previously. Conclusion We have demonstrated that the HER2 IgY-SWNT complex specifically targeted HER2-expressing SK-BR-3 cells but not receptor-negative MCF-7 cells. The complex can be potentially used for both detection and selective photothermal ablation of receptor-positive breast cancer cells without the need of internalization by the cells. Thus, the unique intrinsic properties of SWNTs combined with high
Anti-HER2 IgY antibody-functionalized single-walled carbon nanotubes for detection and selective destruction of breast cancer cells.

PubMed

Xiao, Yan; Gao, Xiugong; Taratula, Oleh; Treado, Stephen; Urbas, Aaron; Holbrook, R David; Cavicchi, Richard E; Avedisian, C Thomas; Mitra, Somenath; Savla, Ronak; Wagner, Paul D; Srivastava, Sudhir; He, Huixin

2009-10-02

Nanocarrier-based antibody targeting is a promising modality in therapeutic and diagnostic oncology. Single-walled carbon nanotubes (SWNTs) exhibit two unique optical properties that can be exploited for these applications, strong Raman signal for cancer cell detection and near-infrared (NIR) absorbance for selective photothermal ablation of tumors. In the present study, we constructed a HER2 IgY-SWNT complex and demonstrated its dual functionality for both detection and selective destruction of cancer cells in an in vitro model consisting of HER2-expressing SK-BR-3 cells and HER2-negative MCF-7 cells. The complex was constructed by covalently conjugating carboxylated SWNTs with anti-HER2 chicken IgY antibody, which is more specific and sensitive than mammalian IgGs. Raman signals were recorded on Raman spectrometers with a laser excitation at 785 nm. NIR irradiation was performed using a diode laser system, and cells with or without nanotube treatment were irradiated by 808 nm laser at 5 W/cm2 for 2 min. Cell viability was examined by the calcein AM/ethidium homodimer-1 (EthD-1) staining. Using a Raman optical microscope, we found the Raman signal collected at single-cell level from the complex-treated SK-BR-3 cells was significantly greater than that from various control cells. NIR irradiation selectively destroyed the complex-targeted breast cancer cells without harming receptor-free cells. The cell death was effectuated without the need of internalization of SWNTs by the cancer cells, a finding that has not been reported previously. We have demonstrated that the HER2 IgY-SWNT complex specifically targeted HER2-expressing SK-BR-3 cells but not receptor-negative MCF-7 cells. The complex can be potentially used for both detection and selective photothermal ablation of receptor-positive breast cancer cells without the need of internalization by the cells. Thus, the unique intrinsic properties of SWNTs combined with high specificity and sensitivity of IgY antibodies
Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

PubMed

Limon, Dror; Gal, Omer; Gordon, Noa; Katz, Lior; Perl, Gali; Purim, Ofer; Amit, Limor; Stemmer, Salomon M; Kundel, Yulia; Ben-Aharon, Irit; Brenner, Baruch; Siegal, Tali; Yust-Katz, Shlomit

2018-06-01

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.
Blockade of a key region in the extracellular domain inhibits HER2 dimerization and signaling.

PubMed

Menendez, Javier A; Schroeder, Barbara; Peirce, Susan K; Vellon, Luciano; Papadimitropoulou, Adriana; Espinoza, Ingrid; Lupu, Ruth

2015-06-01

Several treatment strategies target the human epidermal growth factor receptor 2 (HER2) in breast carcinomas, including monoclonal antibodies directed against HER2's extracellular domain (ECD) and small molecule inhibitors of its tyrosine kinase activity. Yet, novel therapies are needed that prevent HER2 dimerization with other HER family members, because current treatments are only partially effective. To test the hypothesis that HER2 activation requires a protein sequence in the HER2-ECD that mediates HER2 homo- and heterodimerization, we introduced a series of deletion mutations in the third subdomain of HER2-ECD. These deletion mutants were retrovirally expressed in breast cancer (BC) cells that naturally overexpress HER2 and in noncancerous, HER2-negative breast epithelial cells. One-factor analysis of variance or Student's t test were used to analyze differences. All statistical tests were two-sided. The smallest deletion in the ECD domain of HER2, which removed only 16 amino acids (HER2-ECDΔ451-466), completely disrupted the oncogenic potential of HER2. In contrast to wild-type HER2, the mutant-inhibited anchorage-independent growth (mean number of colonies: mutant, 70, 95% confidence interval [CI] = 55 to 85; wild-type, 400, 95% CI = 320 to 480, P < .001) increased sensitivity to paclitaxel treatment in both transformed and nontransformed cells. Overexpression of HER2Δ451-466 efficiently inhibited activation of HER1, HER2, and HER3 in all cell lines tested. These findings reveal that an essential "activating" sequence exists in the extracellular domain of HER2. Disruption of this sequence disables the HER2 dimerization loop, blocks subsequent activation of HER2-driven oncogenic signaling, and generates a dominant-negative form of HER2. Reagents specifically against this molecular activation switch may represent a novel targeted approach for the management of HER2-overexpressing carcinomas. © The Author 2015. Published by Oxford University Press. All
[Primary safety analysis of trastuzumab after adjuvant chemotherapy in 30 Chinese Her2-positive early breast cancer patients].

PubMed

Zhou, Ning-Ning; Teng, Xiao-Yu; Liu, Dong-Geng; Xu, Ran; Guan, Zhong-Zhen

2008-12-01

It has been proved that trastuzumab has clinical activity in early and advanced breast cancer with Her2-overexpression. This study was to analyze the safety of trastuzumab after adjuvant chemotherapy in 30 Chinese Her2-positive early breast cancer patients. Trastuzumab was administrated after adjuvant chemotherapy every 21 days. The initial dose was 8 mg/kg, and the subsequent dose was 6 mg/kg, for four to 35 cycles (medium 18 cycles). The side effects of these patients, especially cardiotoxicity, were analyzed. Thirty patients with Her2-positive early breast cancer were entered into the study. The average treatment period was one year (range nine weeks to two years). Two patients had shivering and fever during the first infusion with trastuzumab. Left ventricular ejection fraction (LVEF) level dropped in 18 cases after treatment with trastuzumab, half of which decreased more then 10%û however, no cardiac failure was observed. The post-surgical treatment of trastuzumab in Chinese patients with Her2-positive early breast cancer shows a satisfactory safety profile. However, the potential cardiotoxicity of trastuzumab should be carefully monitored during therapy.
Regional Nodal Irradiation After Breast Conserving Surgery for Early HER2-Positive Breast Cancer: Results of a Subanalysis From the ALTTO Trial.

PubMed

Gingras, Isabelle; Holmes, Eileen; De Azambuja, Evandro; Nguyen, David H A; Izquierdo, Miguel; Anne Zujewski, Jo; Inbar, Moshe; Naume, Bjorn; Tomasello, Gianluca; Gralow, Julie R; Wolff, Antonio C; Harris, Lyndsay; Gnant, Michael; Moreno-Aspitia, Alvaro; Piccart, Martine J; Azim, Hatem A

2017-08-01

Two randomized trials recently demonstrated that regional nodal irradiation (RNI) could reduce the risk of recurrence in early breast cancer; however, these trials were conducted in the pretrastuzumab era. Whether these results are applicable to human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with anti-HER2-targeted therapy is unknown. This retrospective analysis was performed on patients with node-positive breast cancer who were enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). A multivariable cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to investigate the relationship between RNI and DFS. One thousand six hundred sixty-four HER2-positive breast cancer patients were included, of whom 878 (52.8%) had received RNI to the axillary, supraclavicular, and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden and more frequently had tumors larger than 2 cm. At a median follow-up of 4.5 years, DFS was 84.3% in the RNI group and 88.3% in the non-RNI group. No differences in regional recurrence (0.9 % vs 0.6 %) or in overall survival (93.6% vs 95.3%) were observed between the two groups. After adjustment in multivariable analysis, there was no statistically significant association between RNI and DFS (hazard ratio = 0.96, 95% confidence interval = 0.71 to 1.29). Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node-positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials. © The Author 2017. Published by Oxford University Press. All
Everolimus plus exemestane as first-line therapy in HR⁺, HER2⁻ advanced breast cancer in BOLERO-2.

PubMed

Beck, J Thaddeus; Hortobagyi, Gabriel N; Campone, Mario; Lebrun, Fabienne; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Masuda, Norikazu; Hart, Lowell; Melichar, Bohuslav; Dakhil, Shaker; Geberth, Matthias; Nunzi, Martina; Heng, Daniel Y C; Brechenmacher, Thomas; El-Hashimy, Mona; Douma, Shyanne; Ringeisen, Francois; Piccart, Martine

2014-02-01

The present exploratory analysis examined the efficacy, safety, and quality-of-life effects of everolimus (EVE) + exemestane (EXE) in the subgroup of patients in BOLERO-2 whose last treatment before study entry was in the (neo)adjuvant setting. In BOLERO-2, patients with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer recurring/progressing after a nonsteroidal aromatase inhibitor (NSAI) were randomly assigned (2:1) to receive EVE (10 mg/day) + EXE (25 mg/day) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local assessment. Overall, 137 patients received first-line EVE + EXE (n = 100) or PBO + EXE (n = 37). Median PFS by local investigator assessment nearly tripled to 11.5 months with EVE + EXE from 4.1 months with PBO + EXE (hazard ratio = 0.39; 95 % CI 0.25-0.62), while maintaining quality of life. This was confirmed by central assessment (15.2 vs 4.2 months; hazard ratio = 0.32; 95 % CI 0.18-0.57). The marked PFS improvement in patients receiving EVE + EXE as first-line therapy for disease recurrence during or after (neo)adjuvant NSAI therapy supports the efficacy of this combination in the first-line setting. Furthermore, the results highlight the potential benefit of early introduction of EVE + EXE in the management of HR(+), HER2(-) advanced breast cancer in postmenopausal patients.
BMP9 Inhibits Proliferation and Metastasis of HER2-Positive SK-BR-3 Breast Cancer Cells through ERK1/2 and PI3K/AKT Pathways

PubMed Central

Ren, Wei; Liu, Yuehong; Wan, Shaoheng; Fei, Chang; Wang, Wei; Chen, Yingying; Zhang, Zhihui; Wang, Ting; Wang, Jinshu; Zhou, Lan; Weng, Yaguang; He, Tongchuan; Zhang, Yan

2014-01-01

Bone morphogenetic protein 9 (BMP9), a member of TGF-β superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over-expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer. PMID:24805814
BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways.

PubMed

Ren, Wei; Liu, Yuehong; Wan, Shaoheng; Fei, Chang; Wang, Wei; Chen, Yingying; Zhang, Zhihui; Wang, Ting; Wang, Jinshu; Zhou, Lan; Weng, Yaguang; He, Tongchuan; Zhang, Yan

2014-01-01

Bone morphogenetic protein 9 (BMP9), a member of TGF-β superfamily, is reported to inhibit the growth and migration of prostate cancer, osteosarcoma and triple-negative MDA-MB-231 breast cancer cells. However, little is known about the effect of on the biological behaviors of HER2-positive SK-BR-3 breast cancer cells and the underlying mechanisms. This study aimed to investigate the effects of BMP9 on the proliferation and metastasis of SK-BR-3 cells with BMP9 over-expression or BMP9 down-regulated expression. Results indicated that exogenously expressed BMP9 inhibited the proliferation and metastasis of SK-BR-3 cells while decreased endogenous BMP9 expression in SK-BR-3 cells promoted the proliferation and migration of breast cancer cells in vitro and in vivo. In SK-BR-3 cells with BMP9 over-expression, the phosphorylation of HER2, ERK1/2 and AKT was markedly suppressed and the HER2 expression decreased at both mRNA and protein levels, while opposite results were observed in SK-BR-3 cells with BMP9 knock down. When the phosphorylation of ERK1/2 and PI3K/AKT was inhibited by PD98059 and LY294002, respectively, the decreased proliferation and invasion induced by BMP9 knock down were eliminated. These findings suggest that BMP9 can inhibit the proliferation and metastasis of SK-BR-3 cells via inactivating ERK1/2 and PI3K/AKT signaling pathways. Thus, BMP9 may serve as a useful agent in the treatment of HER-2 positive breast cancer.
TARGETING THE MUC1-C ONCOPROTEIN DOWNREGULATES HER2 ACTIVATION AND ABROGATES TRASTUZUMAB RESISTANCE IN BREAST CANCER CELLS

PubMed Central

Raina, Deepak; Uchida, Yasumitsu; Kharbanda, Akriti; Rajabi, Hasan; Panchamoorthy, Govind; Jin, Caining; Kharbanda, Surender; Scaltriti, Maurizio; Baselga, Jose; Kufe, Donald

2014-01-01

Patients with HER2 positive breast cancer often exhibit intrinsic or acquired resistance to trastuzumab treatment. The transmembrane MUC1-C oncoprotein is aberrantly overexpressed in breast cancer cells and associates with HER2. The present studies demonstrate that silencing MUC1-C in HER2-overexpressing SKBR3 and BT474 breast cancer cells results in downregulation of constitutive HER2 activation. Moreover, treatment with the MUC1-C inhibitor, GO-203, was associated with disruption of MUC1-C/HER2 complexes and decreases in tyrosine phosphorylated HER2 (p-HER2) levels. In studies of trastuzumab-resistant SKBR3R and BT474R cells, we found that the association between MUC1-C and HER2 is markedly increased (~20-fold) as compared to that in sensitive cells. Additionally, silencing MUC1-C in the trastuzumab-resistant cells or treatment with GO-203 decreased p-HER2 and AKT activation. Moreover, targeting MUC1-C was associated with downregulation of phospho-p27 and cyclin E, which confer trastuzumab resistance. Consistent with these results, targeting MUC1-C inhibited the growth and clonogenic survival of both trastuzumab-resistant cells. Our results further demonstrate that silencing MUC1-C reverses resistance to trastuzumab and that the combination of GO-203 and trastuzumab is highly synergistic. These findings indicate that MUC1-C contributes to constitutive activation of the HER2 pathway and that targeting MUC1-C represents a potential approach to abrogate trastuzumab resistance. PMID:23912457
Automated processing of fluorescence in-situ hybridization slides for HER2 testing in breast and gastro-esophageal carcinomas.

PubMed

Tafe, Laura J; Allen, Samantha F; Steinmetz, Heather B; Dokus, Betty A; Cook, Leanne J; Marotti, Jonathan D; Tsongalis, Gregory J

2014-08-01

HER2 fluorescence in-situ hybridization (FISH) is used in breast and gastro-esophageal carcinoma for determining HER2 gene amplification and patients' eligibility for HER2 targeted therapeutics. Traditional manual processing of the FISH slides is labor intensive because of multiple steps that require hands on manipulation of the slides and specifically timed intervals between steps. This highly manual processing also introduces inter-run and inter-operator variability that may affect the quality of the FISH result. Therefore, we sought to incorporate an automated processing instrument into our FISH workflow. Twenty-six cases including breast (20) and gastro-esophageal (6) cancer comprising 23 biopsies and three excision specimens were tested for HER2 FISH (Pathvysion, Abbott) using the Thermobrite Elite (TBE) system (Leica). Up to 12 slides can be run simultaneously. All cases were previously tested by the Pathvysion HER2 FISH assay with manual preparation. Twenty cells were counted by two observers for each case; five cases were tested on three separate runs by different operators to evaluate the precision and inter-operator variability. There was 100% concordance in the scoring between the manual and TBE methods as well as among the five cases that were tested on three runs. Only one case failed due to poor probe hybridization. In total, seven cases were positive for HER2 amplification (HER2:CEP17 ratio >2.2) and the remaining 19 were negative (HER2:CEP17 ratio <1.8) utilizing the 2007 ASCO/CAP scoring criteria. Due to the automated denaturation and hybridization, for each run, there was a reduction in labor of 3.5h which could then be dedicated to other lab functions. The TBE is a walk away pre- and post-hybridization system that automates FISH slide processing, improves work flow and consistency and saves approximately 3.5h of technologist time. The instrument has a small footprint thus occupying minimal counter space. TBE processed slides performed
HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant.

PubMed

Growdon, Whitfield B; Groeneweg, Jolijn; Byron, Virginia; DiGloria, Celeste; Borger, Darrell R; Tambouret, Rosemary; Foster, Rosemary; Chenna, Ahmed; Sperinde, Jeff; Winslow, John; Rueda, Bo R

2015-04-01

Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000 and 2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8RF/mm2 was observed in 53% (n=54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p<0.001). These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer

PubMed Central

Taskar, Kunal S.; Rudraraju, Vinay; Mittapalli, Rajendar K.; Samala, Ramakrishna; R. Thorsheim, Helen; Lockman, Julie; Gril, Brunilde; Hua, Emily; Palmieri, Diane; Polli, Joseph W.; Castellino, Stephen; Rubin, Stephen D.; Lockman, Paul R.; Steeg, Patricia S.; Smith, Quentin R.

2012-01-01

Purpose Lapatinib, a small molecule EGFR/HER2 inhibitor, has limited effect on outgrowth of HER2+ brain metastases in preclinical and clinical trials. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Methods Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. Results 14C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7–9-fold greater than surrounding brain tissue at 2 and 12 hours after oral administration. However, average lapatinib concentration in brain metastases was still only 10–20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells remaining in brain after lapatinib treatment. Conclusions Results show that lapatinib distribution to brain metastases of breast cancer is restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies within and between tumors. PMID:22011930
Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial.

PubMed

Issa-Nummer, Yasmin; Darb-Esfahani, Silvia; Loibl, Sibylle; Kunz, Georg; Nekljudova, Valentina; Schrader, Iris; Sinn, Bruno Valentin; Ulmer, Hans-Ullrich; Kronenwett, Ralf; Just, Marianne; Kühn, Thorsten; Diebold, Kurt; Untch, Michael; Holms, Frank; Blohmer, Jens-Uwe; Habeck, Jörg-Olaf; Dietel, Manfred; Overkamp, Friedrich; Krabisch, Petra; von Minckwitz, Gunter; Denkert, Carsten

2013-01-01

We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). The aim of this study was to prospectively validate the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT. The immunological infiltrate was prospectively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study, a substudy of the neoadjuvant GeparQuinto study. Intratumoral lymphocytes (iTuLy), stromal lymphocytes (strLy) as well as lymphocyte-predominant breast cancer (LPBC) were evaluated by histopathological assessment. Pathological complete response (pCR) rates were analyzed and compared between the defined subgroups using the exact test of Fisher. Patients with lymphocyte-predominant breast cancer (LPBC) had a significantly increased pCR rate of 36.6%, compared to non-LPBC patients (14.3%, p<0.001). LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis (LPBC: OR 2.7, p = 0.003, strLy: OR 1.2, p = 0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p = 0.01) but not in multivariate logistic regression analysis (OR 1.2, p = 0.11). Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies.

Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

PubMed Central

Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

2013-01-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928
Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

PubMed

Malorni, L; Curigliano, G; Minisini, A M; Cinieri, S; Tondini, C A; D'Hollander, K; Arpino, G; Bernardo, A; Martignetti, A; Criscitiello, C; Puglisi, F; Pestrin, M; Sanna, G; Moretti, E; Risi, E; Biagioni, C; McCartney, A; Boni, L; Buyse, M; Migliaccio, I; Biganzoli, L; Di Leo, A

2018-06-11

The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pre-treated patients. Pre-clinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multi-center study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in post-menopausal women with moderately pre-treated, estrogen receptor-positive, HER2 negative advanced breast cancer. Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1:1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary endpoint was clinical benefit rate (CBR); secondary endpoints included progression-free survival (PFS). Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% (95% CI 41.5 - 63.7) for combination therapy, and 60% (95% CI 47.8 - 72.9) for monotherapy. Median PFS was 10.8 months (95% CI 5.6 - 12.7) for combination therapy, and 6.5 months (95% CI, 5.4 to 8.5) for monotherapy (hazard ratio [HR] 0.69; 95% CI 0.4 - 1.1, exploratory P-value = 0.12). Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI 0.3 - 0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Palbociclib has clinical activity as a single agent in women with moderately pre-treated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. NCT02549430.
Epithalon inhibits tumor growth and expression of HER-2/neu oncogene in breast tumors in transgenic mice characterized by accelerated aging.

PubMed

Anisimov, V N; Khavinsov, V Kh; Alimova, I N; Provintsiali, M; Manchini, R; Francheski, K

2002-02-01

Female transgenic FVB mice carrying breast cancer gene HER-2/neu were monthly injected with Vilon or Epithalon (1 microgram subcutaneously for 5 consecutive days) starting from the 2nd month of life. Epithalon markedly inhibited neoplasm development: the maximum size of breast adenocarcinomas was 33% lower than in the control (p < 0.05). The intensity of HER-2/neu mRNA expression in breast tumors of Epithalon-treated mice was 3.7 times lower than in control animals. These results indicate that Epithalon inhibits breast tumor development in transgenic mice, which is probably related to suppression of HER-2/neu expression.
Doxorubicin Hydrochloride, Cyclophosphamide, and Paclitaxel With or Without Bevacizumab in Treating Patients With Lymph Node-Positive or High-Risk, Lymph Node-Negative Breast Cancer

ClinicalTrials.gov

2017-10-10

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer
Segmentation of HER2 protein overexpression in immunohistochemically stained breast cancer images using Support Vector Machines

NASA Astrophysics Data System (ADS)

Pezoa, Raquel; Salinas, Luis; Torres, Claudio; Härtel, Steffen; Maureira-Fredes, Cristián; Arce, Paola

2016-10-01

Breast cancer is one of the most common cancers in women worldwide. Patient therapy is widely supported by analysis of immunohistochemically (IHC) stained tissue sections. In particular, the analysis of HER2 overexpression by immunohistochemistry helps to determine when patients are suitable to HER2-targeted treatment. Computational HER2 overexpression analysis is still an open problem and a challenging task principally because of the variability of immunohistochemistry tissue samples and the subjectivity of the specialists to assess the samples. In addition, the immunohistochemistry process can produce diverse artifacts that difficult the HER2 overexpression assessment. In this paper we study the segmentation of HER2 overexpression in IHC stained breast cancer tissue images using a support vector machine (SVM) classifier. We asses the SVM performance using diverse color and texture pixel-level features including the RGB, CMYK, HSV, CIE L*a*b* color spaces, color deconvolution filter and Haralick features. We measure classification performance for three datasets containing a total of 153 IHC images that were previously labeled by a pathologist.
Cisplatin With or Without Veliparib in Treating Patients With Recurrent or Metastatic Triple-Negative and/or BRCA Mutation-Associated Breast Cancer With or Without Brain Metastases

ClinicalTrials.gov

2018-06-26

Breast Carcinoma Metastatic in the Brain; Deleterious BRCA1 Gene Mutation; Deleterious BRCA2 Gene Mutation; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma
Two E-selectin ligands, BST-2 and LGALS3BP, predict metastasis and poor survival of ER-negative breast cancer.

PubMed

Woodman, Natalie; Pinder, Sarah E; Tajadura, Virginia; Le Bourhis, Xuefen; Gillett, Cheryl; Delannoy, Philippe; Burchell, Joy M; Julien, Sylvain

2016-07-01

Distant metastases account for the majority of cancer-related deaths in breast cancer. The rate and site of metastasis differ between estrogen receptor (ER)-negative and ER-positive tumours, and metastatic fate can be very diverse even within the ER-negative group. Characterisation of new pro-metastatic markers may help to identify patients with higher risk and improve their care accordingly. Selectin ligands aberrantly expressed by cancer cells promote metastasis by enabling interaction between circulating tumour cells and endothelial cells in distant organs. These ligands consist in carbohydrate molecules, such as sialyl-Lewis x antigen (sLex), borne by glycoproteins or glycolipids on the cancer cell surface. We have previously demonstrated that the molecular scaffold presenting sLex to selectins (e.g. glycolipid vs. glycoproteins) was crucial for these interactions to occur. Moreover, we reported that detection of sLex alone in breast carcinomas was only of limited prognostic value. However, since sLex was found to be carried by several glycoproteins in cancer cells, we hypothesized that the combination of the carbohydrate with its carriers could be more relevant than each marker independently. In this study, we addressed this question by analysing sLex expression together with two glycoproteins (BST-2 and LGALS3BP), shown to interact with E-selectin in a carbohydrate-dependent manner, in a cohort of 249 invasive breast cancers. We found both glycoproteins to be associated with distant metastasis risk and poorer survival. Importantly, concomitant high expression of BST-2 with sLex defined a sub-group of patients with ER-negative tumours displaying higher risks of liver and brain metastasis and a 3-fold decreased survival rate.
Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study.

PubMed

Clarke, Christina A; Canchola, Alison J; Moy, Lisa M; Neuhausen, Susan L; Chung, Nadia T; Lacey, James V; Bernstein, Leslie

2017-05-01

Regular users of aspirin may have reduced risk of breast cancer. Few studies have addressed whether risk reduction pertains to specific breast cancer subtypes defined jointly by hormone receptor (estrogen and progesterone receptor) and human epidermal growth factor receptor 2 (HER2) expression. This study assessed the prospective risk of breast cancer (overall and by subtype) according to use of aspirin and other non-steroidal anti-inflammatory medications (NSAIDs) in a cohort of female public school professionals in California. In 1995 - 1996, participants in the California Teachers Study completed a baseline questionnaire on family history of cancer and other conditions, use of NSAIDs, menstrual and reproductive history, self-reported weight and height, living environment, diet, alcohol use, and physical activity. In 2005-2006, 57,164 participants provided some updated information, including use of NSAIDs and 1457 of these participants developed invasive breast cancer before January 2013. Multivariable Cox proportional hazards regression models provided hazard rate ratios (HRR) for the association between NSAID use and risk of invasive breast cancer as well as hormone receptor- and HER2-defined subtypes. Developing breast cancer was associated inversely with taking three or more tablets of low-dose aspirin per week (23% of participants). Among women reporting this exposure, the HRR was 0.84 (95% confidence interval (CI) 0.72-0.98) compared to those not taking NSAIDs and this was particularly evident in women with the hormone receptor-positive/HER2-negative subtype (HRR = 0.80, 95% CI 0.66-0.96). Use of three or more tablets of "other" NSAIDs was marginally associated with lower risk of breast cancer (HRR = 0.79, 95% CI 0.62-1.00). Other associations with NSAIDs were generally null. Our observation of reduced risk of breast cancer, among participants who took three or more tablets of low-dose aspirin weekly, is consistent with other reports looking at
Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer.

PubMed

Darlix, Amélie; Griguolo, Gaia; Thezenas, Simon; Kantelhardt, Eva; Thomssen, Christoph; Dieci, Maria Vittoria; Miglietta, Federica; Conte, PierFranco; Braccini, Antoine Laurent; Ferrero, Jean Marc; Bailleux, Caroline; Jacot, William; Guarneri, Valentina

2018-06-01

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996-2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan-Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2-/HR+, 24.8% TN, 22.2% HER2+/HR- and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25-85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2-/HR+ 5.3 years (95% CI 4.6-5.9), HER2+/HR+ 4.4 years (95% CI 3.4-5.2), HER2+/HR- 2.6 years (95% CI 2.2-3.1) and TN 2.2 years (95% CI 1.9-2.7) (p < 0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p < 0.001), and between HER2+ and HER2- tumors (3.2 vs. 3.8 years, p = 0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio = 1.36 for ER, p = 0.013, 1.31 for PR, p = 0.021, and 1.01 for HER2+ vs. HER2- tumors, p = 0.880). HR- and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.
Imaging biomarkers to predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer

PubMed Central

Shah, Chirayu; Miller, Todd W.; Wyatt, Shelby K.; McKinley, Eliot T.; Olivares, Maria Graciela; Sanchez, Violeta; Nolting, Donald D.; Buck, Jason R.; Zhao, Ping; Ansari, M. Sib; Baldwin, Ronald M.; Gore, John C.; Schiff, Rachel; Arteaga, Carlos L.; Manning, H. Charles

2010-01-01

Purpose To evaluate non-invasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and non-responding tumor-bearing cohorts. Experimental Design Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin-V accumulation), glucose metabolism ([18F]FDG-PET), and proliferation ([18F]FLT-PET) were evaluated throughout a bi-weekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical (IHC) analysis of cleaved caspase-3, phosphorylated AKT (p-AKT) and Ki67. Results NIR700-Annexin-V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed, but not in non-responding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and IHC analysis. Conclusions Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2(+) tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not appear to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer. PMID:19584166
Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients.

PubMed

Al-Dasooqi, Noor; Bowen, Joanne M; Gibson, Rachel J; Sullivan, Thomas; Lees, Jude; Keefe, Dorothy M

2009-04-01

To characterise the gastrointestinal toxicities associated with Trastuzumab administration in HER2-overexpressing breast cancer patients. All patients (n = 46) who received Trastuzumab as a single agent or in conjunction with conventional anti-cancer treatment within the Royal Adelaide Hospital Cancer Centre from 2002-2007 were included in this study. A retrospective analysis of case-notes was conducted to investigate the toxicities associated with Trastuzumab. Trastuzumab as a single agent induced toxicities following 22% of administrations. Gastrointestinal toxicities were observed following 12% of administrations and included nausea and vomiting, diarrhoea, abdominal pain and bloating. However, other prominent toxicities that were not related to the gastrointestinal tract were also observed including fatigue and lung symptoms (10.4%). Elderly patients (> or =60 years) and those with metastatic disease experienced the highest frequency of toxicity. Trastuzumab induces a range of gastrointestinal toxicities in HER2-overexpressing breast cancer patients. These toxicities are separate to those caused by concurrent chemotherapy and/or radiotherapy.
Breast Cancer: Current Molecular Therapeutic Targets and New Players.

PubMed

Nagini, Siddavaram

2017-01-01

Breast cancer is the most common cancer and the most frequent cause of cancer death among women worldwide. Breast cancer is a complex, heterogeneous disease classified into hormone-receptor-positive, human epidermal growth factor receptor-2 overexpressing (HER2+) and triple-negative breast cancer (TNBC) based on histological features. Endocrine therapy, the mainstay of treatment for hormone-responsive breast cancer involves use of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs) and aromatase inhibitors (AIs). Agents that target estrogen receptor (ER) and HER2 such as tamoxifen and trastuzumab have been the most extensively used therapeutics for breast cancer. Crosstalk between ER and other signalling networks as well as epigenetic mechanisms have been envisaged to contribute to endocrine therapy resistance. TNBC, a complex, heterogeneous, aggressive form of breast cancer in which the cells do not express ER, progesterone receptor or HER2 is refractory to therapy. Several molecular targets are being explored to target TNBC including androgen receptor, epidermal growth factor receptor (EGFR), poly(ADP-ribose) polymerase (PARP), and vascular endothelial growth factor (VEGF). Receptors, protein tyrosine kinases, phosphatases, proteases, PI3K/Akt signalling pathway, microRNAs (miRs) and long noncoding RNAs (lncRNAs) are potential therapeutic targets. miR-based therapeutic approaches include inhibition of oncomiRs by antisense oligonucleotides, restoration of tumour suppressors using miR mimics, and chemical modification of miRs. The lnRNAs HOTAIR, SPRY4-IT1, GAS5, and PANDAR, new players in tumour development and prognosis may have theranostic applications in breast cancer. Several novel classes of mechanism-based drugs have been designed and synthesised for treatment of breast cancer. Integration of nucleic acid sequencing studies with mass spectrometry-based peptide sequencing and posttranslational modifications as
Patterns of initial management of node-negative breast cancer in two Canadian provinces

PubMed Central

Goel, V; Olivotto, I; Hislop, T G; Sawka, C; Coldman, A; Holowaty, E J

1997-01-01

OBJECTIVE: To describe the patterns of initial management of node-negative breast cancer in Ontario and British Columbia and to compare the characteristics of the patients and tumours and of the physicians and hospitals involved in management. DESIGN: Retrospective, population-based, cohort study. PARTICIPANTS: All 942 newly diagnosed cases of node-negative breast cancer in 1991 in British Columbia and a random sample of 938 newly diagnosed cases in Ontario in the same year. OUTCOME MEASURES: Number and proportion of patients with newly diagnosed node-negative breast cancer who received breast-conserving surgery (BCS) or mastectomy and who received radiation therapy after BCS. RESULTS: BCS was used in 413 cases (43.8%) in British Columbia and in 634 cases (67.6%) in Ontario (p < 0.001). After BCS, radiation therapy was received by 378 patients (91.5% of those who had undergone BCS) in British Columbia and 479 patients (75.6% of those who had undergone BCS) in Ontario (p < 0.001). In both provinces, lower patient age, smaller tumour size, a noncentral unifocal tumour, absence of extensive ductal carcinoma in situ and initial surgery by a surgeon with an academic affiliation were associated with greater use of BCS. Lower patient age and larger tumour size were associated with greater use of radiation therapy after BCS in both provinces. CONCLUSION: Patient, tumour and physician factors are associated with the choice of initial management of breast cancer in these two Canadian provinces. However, the differences in management between the two provinces are only partly explained by these factors. Other possible explanations, such as the presence of provincial guidelines, differences in the organization of the health care system or differences in patient preference, require further research. PMID:9006561
Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer

ClinicalTrials.gov

2018-06-08

Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage II Breast Cancer AJCC v6 and v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Triple-Negative Breast Carcinoma
[Prevalence of breast cancer sub-types by immunohistochemistry in patients in the Regional General Hospital 72, Instituto Mexicano del Seguro Social].

PubMed

Pérez-Rodríguez, Gabriel

2015-01-01

Breast cancer mortality has increased in women 25 years and over, and since 2006 it has surpassed cervical cancer. Breast cancer is a heterogeneous disease, with several clinical and histological presentations that require a thorough study of all clinical and pathological parameters, including immunohistochemistry to classify it into subtypes, have a better prognosis, provide individualised treatment, increase survival, and reduce mortality. To evaluate the prevalence of sub-types of breast cancer and the association with the clinical and histopathological features of the tumour. An observational, retrospective, cross-sectional and analytical study conducted on 1380 patients with a diagnosis of breast cancer have been classified by immunohistochemistry into four subtypes: luminal A, triple negative, luminal B and HER2. An analysis was performed on the association with age, risk factors, and the clinical and histopathological features of the tumour. The mean age of the patients was 53.3 ± 11.4. The frequency was luminal A (65%), triple negative (14%), luminal B (12%), and HER2 (9%). The most frequent characteristics were the 50 to 59 age range, late menopause, the right side, upper external quadrant, stage II, metastatic lymph nodes, and mastectomy. The most frequent sub-type was luminal A, and together with the luminal B are those which have better prognosis compared with the triple negative and HER2. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.
ABCG2 transporter inhibitor restores the sensitivity of triple negative breast cancer cells to aminolevulinic acid-mediated photodynamic therapy.

PubMed

Palasuberniam, Pratheeba; Yang, Xue; Kraus, Daniel; Jones, Patrick; Myers, Kenneth A; Chen, Bin

2015-08-18

Photosensitizer protoporphyrin IX (PpIX) fluorescence, intracellular localization and cell response to photodynamic therapy (PDT) were analyzed in MCF10A normal breast epithelial cells and a panel of human breast cancer cells including estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) positive and triple negative breast cancer (TNBC) cells after treatment with PpIX precursor aminolevulinic acid (ALA). Although PpIX fluorescence was heterogeneous in different cells, TNBC cells showed significantly lower PpIX level than MCF10A and ER- or HER2-positive cells. PpIX fluorescence in TNBC cells also had much less mitochondrial localization than other cells. There was an inverse correlation between PpIX fluorescence and cell viability after PDT. Breast cancer cells with the highest PpIX fluorescence were the most sensitive to ALA-PDT and TNBC cells with the lowest PpIX level were resistant to PDT. Treatment of TNBC cells with ABCG2 transporter inhibitor Ko143 significantly increased ALA-PpIX fluorescence, enhanced PpIX mitochondrial accumulation and sensitized cancer cells to ALA-PDT. Ko143 treatment had little effect on PpIX production and ALA-PDT in normal and ER- or HER2-positive cells. These results demonstrate that enhanced ABCG2 activity renders TNBC cell resistance to ALA-PDT and inhibiting ABCG2 transporter is a promising approach for targeting TNBC with ALA-based modality.
Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth.

PubMed

Chen, Jun; Kinoshita, Taisei; Sukbuntherng, Juthamas; Chang, Betty Y; Elias, Laurence

2016-12-01

Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC 50 s were lower than that of lapatinib and dacomitinib. Inhibition of cell growth by ibrutinib coincided with downregulation of phosphorylation on HER2 and EGFR and their downstream targets, AKT and ERK. Irreversible inhibition of HER2 and EGFR in breast cancer cells was established after 30-minute incubation above 100 nmol/L or following 2-hour incubation at lower concentrations. Furthermore, ibrutinib inhibited recombinant HER2 and EGFR activity that was resistant to dialysis and rapid dilution, suggesting an irreversible interaction. The dual activity toward TEC family (BTK and ITK) and ERBB family kinases was unique to ibrutinib, as ERBB inhibitors do not inhibit or covalently bind BTK or ITK. Xenograft studies with HER2 + MDA-MB-453 and BT-474 cells in mice in conjunction with determination of pharmacokinetics demonstrated significant exposure-dependent inhibition of growth and key signaling molecules at levels that are clinically achievable. Ibrutinib's unique dual spectrum of activity against both TEC family and ERBB kinases suggests broader applications of ibrutinib in oncology. Mol Cancer Ther; 15(12); 2835-44. ©2016 AACR. ©2016 American Association for Cancer Research.
FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

PubMed

Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

2015-11-01

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.
Is the skin a sanctuary for breast cancer cells during treatment with anti-HER2 antibodies?

PubMed

Graziano, Vincenzo; Scognamiglio, Maria Teresa; Zilli, Marinella; Giampietro, Jamara; Vici, Patrizia; Natoli, Clara; Grassadonia, Antonino

2015-01-01

The occurrence of skin metastases is a common event in patients affected by advanced breast cancer, usually associated with systemic disease progression. Here we describe 2 cases of diffuse cutaneous metastases from HER2-overexpressing breast cancer occurring despite a dramatic response in liver and bone, respectively, during treatment with anti-HER2 antibodies Trastuzumab and Pertuzumab. We discuss the reasons for this discrepancy and suggest a possible implication of impaired immune response in the skin. Future research should provide strategies to overcome the induction of immune privilege in the skin in order to avoid discontinuation of effective treatments.
Targeting GPR110 in HER2-Overexpressing Breast Cancers

DTIC Science & Technology

2015-10-01

lentiviral plasmids containing GPR110 cDNA using the pHAGE system, which includes the HA tag, under the control of inducible Tet-on promoter. The map of... pHAGE lentiviral plasmid is shown in Figure 3A. Using this, the BT474 and SKBR3 parental cells were stably infected with the lentiviral plasmid...in HER2+ breast cancer. Figure𔃽.’GPR110/overexpression’using’pHAGE’len:viral’mediated’infec:on’of’BT474’cells.’ A.#Map#of# pHAGE # len/viral

Modeling invasive breast cancer: growth factors propel progression of HER2-positive premalignant lesions

PubMed Central

Pradeep, C-R; Zeisel, A; Köstler, WJ; Lauriola, M; Jacob-Hirsch, J; Haibe-Kains, B; Amariglio, N; Ben-Chetrit, N; Emde, A; Solomonov, I; Neufeld, G; Piccart, M; Sagi, I; Sotiriou, C; Rechavi, G; Domany, E; Desmedt, C; Yarden, Y

2013-01-01

The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients’ lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment. PMID:22139081
Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells.

PubMed

Kim, Hee-Jun; Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Lee, Kyung Hun; Lau, Alan; Lee, Miso; Kim, Seongyeong; Yang, Yaewon; Kim, Jungeun; Kim, Tae Yong; Oh, Do-Youn; Brown, Jeffrey; O'Connor, Mark J; Bang, Yung-Jue

2017-01-01

Ataxia telangiectasia and Rad3-related (ATR) proteins are sensors of DNA damage, which induces homologous recombination (HR)-dependent repair. ATR is a master regulator of DNA damage repair (DDR), signaling to control DNA replication, DNA repair and apoptosis. Therefore, the ATR pathway might be an attractive target for developing new drugs. This study was designed to investigate the antitumor effects of the ATR inhibitor, AZD6738 and its underlying mechanism in human breast cancer cells. Growth inhibitory effects of AZD6738 against human breast cancer cell lines were studied using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (methyl thiazolyl tetrazolium, MTT) assay. Cell cycle analysis, Western blotting, immunofluorescence and comet assays were also performed to elucidate underlying mechanisms of AZD6738 action. Anti-proliferative and DDR inhibitory effects of AZD6738 were demonstrated in human breast cancer cell lines. Among 13 cell lines, the IC 50 values of nine cell lines were less than 1 μmol/L using MTT assay. Two cell lines, SK-BR-3 and BT-474, were chosen for further evaluation focused on human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. Sensitive SK-BR-3 but not the less sensitive BT-474 breast cancer cells showed increased level of apoptosis and S phase arrest and reduced expression levels of phosphorylated check-point kinase 1 (CHK1) and other repair markers. Decreased functional CHK1 expression induced DNA damage accumulation due to HR inactivation. AZD6738 showed synergistic activity with cisplatin. Understanding the antitumor activity and mechanisms of AZD6738 in HER2-positive breast cancer cells creates the possibility for future clinical trials targeting DDR in HER2-positive breast cancer treatment. © 2016 UICC.
Super resolution imaging of HER2 gene amplification

NASA Astrophysics Data System (ADS)

Okada, Masaya; Kubo, Takuya; Masumoto, Kanako; Iwanaga, Shigeki

2016-02-01

HER2 positive breast cancer is currently examined by counting HER2 genes using fluorescence in situ hybridization (FISH)-stained breast carcinoma samples. In this research, two-dimensional super resolution fluorescence microscopy based on stochastic optical reconstruction microscopy (STORM), with a spatial resolution of approximately 20 nm in the lateral direction, was used to more precisely distinguish and count HER2 genes in a FISH-stained tissue section. Furthermore, by introducing double-helix point spread function (DH-PSF), an optical phase modulation technique, to super resolution microscopy, three-dimensional images were obtained of HER2 in a breast carcinoma sample approximately 4 μm thick.
Baseline blood immunological profiling differentiates between Her2-breast cancer molecular subtypes: implications for immunomediated mechanisms of treatment response.

PubMed

Tudoran, Oana; Virtic, Oana; Balacescu, Loredana; Lisencu, Carmen; Fetica, Bogdan; Gherman, Claudia; Balacescu, Ovidiu; Berindan-Neagoe, Ioana

2015-01-01

Breast cancer patients' response to treatment is highly dependent on the primary tumor molecular features, with triple-negative breast tumors having the worst prognosis of all subtypes. According to the molecular features, tumors stimulate the microenvironment to induce distinct immune responses, baseline immune activation being associated with higher likelihood of pathologic response. In this study, we investigated the deconvolution of the immunological status of triple-negative tumors in comparison with luminal tumors and the association with patients' clinicopathological characteristics. Gene expression of 84 inflammatory molecules and their receptors were analyzed in 40 peripheral blood samples from patients with Her2- primary breast cancer tumors. We studied the association of triple-negative phenotype with age, clinical stage, tumor size, lymph nodes, and menopausal status. We observed that more patients with estrogen (ER)/progesterone (PR)-negative tumors had grade III, while more patients with ER/PR-positive tumors had grade II tumors. Gene expression analysis revealed a panel of 14 genes to have differential expression between the two groups: several interleukins: IL13, IL16, IL17C and IL17F, IL1A, IL3; interleukin receptors: IL10RB, IL5RA; chemokines: CXCL13 and CCL26; and cytokines: CSF2, IFNA2, OSM, TNSF13. The expression levels of these genes have been previously shown to be associated with reduced immunological status; indeed, the triple-negative breast cancer patients presented with lower counts of lymphocytes and eosinophils than the ER/PR-positive ones. These results contribute to a better understanding of the possible role of antitumor immune responses in mediating the clinical outcome.
HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials

PubMed Central

Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

2016-01-01

Abstract HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti‐EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK–AKT pathway activation through HER2 up‐regulation. We assessed HER2‐amplification/overexpression in stage II–III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II–III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2‐amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression‐free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II–III tumours showed HER2 protein overexpression. Of the HER2‐overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II–III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2‐overexpression was associated with KRAS/BRAF wild‐type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II–III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II–III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2‐overexpressing cases experienced recurrence, but the difference was not significant. HER2‐amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II–III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2‐targeted therapy in patients with HER2‐amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John
HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

PubMed

Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

2016-03-01

HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society
Anti-HER2 immunoliposomes for selective delivery of electron paramagnetic resonance imaging probes to HER2-overexpressing breast tumor cells

PubMed Central

Burks, Scott R.; Macedo, Luciana F.; Barth, Eugene D.; Tkaczuk, Katherine H.; Martin, Stuart S.; Rosen, Gerald M.; Halpern, Howard J.; Brodie, Angela M.

2014-01-01

Electron paramagnetic resonance (EPR) imaging is an emerging modality that can detect and localize paramagnetic molecular probes (so-called spin probes) in vivo. We previously demonstrated that nitroxide spin probes can be encapsulated in liposomes at concentrations exceeding 100 mM, at which nitroxides exhibit a concentration-dependent quenching of their EPR signal that is analogous to the self-quenching of fluorescent molecules. Therefore, intact liposomes encapsulating high concentrations of nitroxides exhibit greatly attenuated EPR spectral signals, and endocytosis of such liposomes represents a cell-activated contrast-generating mechanism. After endocytosis, the encapsulated nitroxide is liberated and becomes greatly diluted in the intracellular milieu. This dequenches the nitroxides to generate a robust intracellular EPR signal. It is therefore possible to deliver a high concentration of nitroxides to cells while minimizing background signal from unendocytosed liposomes. We report here that intracellular EPR signal can be selectively generated in a specific cell type by exploiting its expression of Human Epidermal Growth Factor Receptor 2 (HER2). When targeted by anti-HER2 immunoliposomes encapsulating quenched nitroxides, Hc7 cells, which are novel HER2-overexpressing cells derived from the MCF7 breast tumor cell line, endocytose the liposomes copiously, in contrast to the parent MCF7 cells or control CV1 cells, which do not express HER2. HER2-dependent liposomal delivery enables Hc7 cells to accumulate 750 μM nitroxide intracellularly. Through the use of phantom models, we verify that this concentration of nitroxides is more than sufficient for EPR imaging, thus laying the foundation for using EPR imaging to visualize HER2-overexpressing Hc7 tumors in animals. PMID:20066490
Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer

ClinicalTrials.gov

2011-12-07

Ductal Breast Carcinoma in Situ; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Male Breast Cancer; Medullary Ductal Breast Carcinoma With Lymphocytic Infiltrate; Mucinous Ductal Breast Carcinoma; Papillary Ductal Breast Carcinoma; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Tubular Ductal Breast Carcinoma
Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain.

PubMed

Priceman, Saul J; Tilakawardane, Dileshni; Jeang, Brook; Aguilar, Brenda; Murad, John P; Park, Anthony K; Chang, Wen-Chung; Ostberg, Julie R; Neman, Josh; Jandial, Rahul; Portnow, Jana; Forman, Stephen J; Brown, Christine E

2018-01-01

Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95-105. ©2017 AACR . ©2017 American Association for Cancer Research.
Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program

PubMed Central

Francis, Glenn D; Dimech, Margaret; Giles, Leanne; Hopkins, Alison

2007-01-01

Background and Aims Immunohistochemistry (IHC) has replaced radioligand binding assay for the determination of oestrogen receptor (ER) status in breast carcinoma. IHC is also used for assessment of progesterone receptor (PR) and HER2. The Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program (QAP) introduced a breast markers module in 2003 to evaluate the performance of laboratories with IHC for ER, PR and HER2. Methods An audit of laboratories reporting breast carcinomas was performed in 2005 and 2006 to evaluate in‐house results. Laboratories were asked to submit the hormone receptor and HER2 status on each invasive breast carcinoma for the previous 6 month period up to a maximum of 100 cases. The time periods were 1 July 2004 to 31 December 2004, and 1 July 2005 to 31 December 2005. A total of 55 laboratories returned information for 2004 and 67 for 2005. Results Complete data on 8128 patients was returned for both surveys, 3353 cases for 2004 and 4775 for 2005. The results were similar for both surveys. Of the 8128 cases, 59.0% were ER+/PR+, 15.9% ER+/PR−, 2.4% ER−/PR+ and 22.7% ER−/PR−. HER2 data were submitted for a total of 6512 patients (excludes 52 patients with incomplete data sets); 17.1% were reported as 3+ positive on IHC, 12.5% as 2+ and 70.4% as negative. Conclusions A laboratory audit was introduced into the RCPA QAP for breast markers due to concerns raised by participating laboratories about technical differences in supplied tissues for testing. This audit indicates that overall the results for ER, PR and HER2 fall inside established parameters. However, a number of individual laboratories do not meet the target values and variation in results would impact on patient treatment decisions. PMID:17259294
Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program.

PubMed

Francis, Glenn D; Dimech, Margaret; Giles, Leanne; Hopkins, Alison

2007-11-01

Immunohistochemistry (IHC) has replaced radioligand binding assay for the determination of oestrogen receptor (ER) status in breast carcinoma. IHC is also used for assessment of progesterone receptor (PR) and HER2. The Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program (QAP) introduced a breast markers module in 2003 to evaluate the performance of laboratories with IHC for ER, PR and HER2. An audit of laboratories reporting breast carcinomas was performed in 2005 and 2006 to evaluate in-house results. Laboratories were asked to submit the hormone receptor and HER2 status on each invasive breast carcinoma for the previous 6 month period up to a maximum of 100 cases. The time periods were 1 July 2004 to 31 December 2004, and 1 July 2005 to 31 December 2005. A total of 55 laboratories returned information for 2004 and 67 for 2005. Complete data on 8128 patients was returned for both surveys, 3353 cases for 2004 and 4775 for 2005. The results were similar for both surveys. Of the 8128 cases, 59.0% were ER+/PR+, 15.9% ER+/PR-, 2.4% ER-/PR+ and 22.7% ER-/PR-. HER2 data were submitted for a total of 6512 patients (excludes 52 patients with incomplete data sets); 17.1% were reported as 3+ positive on IHC, 12.5% as 2+ and 70.4% as negative. A laboratory audit was introduced into the RCPA QAP for breast markers due to concerns raised by participating laboratories about technical differences in supplied tissues for testing. This audit indicates that overall the results for ER, PR and HER2 fall inside established parameters. However, a number of individual laboratories do not meet the target values and variation in results would impact on patient treatment decisions.
Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy

PubMed Central

Muntasell, Aura; Cabo, Mariona; Servitja, Sonia; Tusquets, Ignasi; Martínez-García, María; Rovira, Ana; Rojo, Federico; Albanell, Joan; López-Botet, Miguel

2017-01-01

Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab) to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα) and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i) the configuration of the patient NK cell repertoire; (ii) tumor molecular features (i.e., estrogen receptor expression); (iii) concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors); and (iv) evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through combinatorial
A single-domain antibody-linked Fab bispecific antibody Her2-S-Fab has potent cytotoxicity against Her2-expressing tumor cells.

PubMed

Li, Aifen; Xing, Jieyu; Li, Li; Zhou, Changhua; Dong, Bin; He, Ping; Li, Qing; Wang, Zhong

2016-12-01

Her2, which is frequently overexpressed in breast cancer, is one of the most studied tumor-associated antigens for cancer therapy. Anti-HER2 monoclonal antibody, trastuzumab, has achieved significant clinical benefits in metastatic breast cancer. In this study, we describe a novel bispecific antibody Her2-S-Fab targeting Her2 by linking a single domain anti-CD16 VHH to the trastuzumab Fab. The Her2-S-Fab antibody can be efficiently expressed and purified from Escherichia coli, and drive potent cancer cell killing in HER2-overexpressing cancer cells. In xenograft model, the Her2-S-Fab suppresses tumor growth in the presence of human immune cells. Our results suggest that the bispecific Her2-S-Fab may provide a valid alternative to Her2 positive cancer therapy.
Mirvetuximab Soravtansine and Gemcitabine Hydrochloride in Treating Patients With FRa-Positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial, or Triple Negative Breast Cancer

ClinicalTrials.gov

2018-02-21

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Triple-Negative Breast Carcinoma; Folate Receptor Alpha Positive
Global metabolite profiling analysis of lipotoxicity in HER2/neu-positive breast cancer cells.

PubMed

Baumann, Jan; Kokabee, Mostafa; Wong, Jason; Balasubramaniyam, Rakshika; Sun, Yan; Conklin, Douglas S

2018-06-05

Recent work has shown that HER2/neu-positive breast cancer cells rely on a unique Warburg-like metabolism for survival and aggressive behavior. These cells are dependent on fatty acid (FA) synthesis, show markedly increased levels of stored fats and disruption of the synthetic process results in apoptosis. In this study, we used global metabolite profiling and a multi-omics network analysis approach to model the metabolic changes in this physiology under palmitate-supplemented growth conditions to gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Computational analyses were used to define pathway enrichment based on the dataset of significantly altered metabolites and to integrate metabolomics and transcriptomics data in a multi-omics network analysis. Network-predicted changes and functional relationships were tested with cell assays in vitro . Palmitate-supplemented growth conditions induce distinct metabolic alterations. Growth of HER2-normal MCF7 cells is unaffected under these conditions whereas HER2/neu-positive cells display unchanged neutral lipid content, AMPK activation, inhibition of fatty acid synthesis and significantly altered glutamine, glucose and serine/glycine metabolism. The predominant upregulated lipid species is the novel bioactive lipid N-palmitoylglycine, which is non-toxic to these cells. Limiting the availability of glutamine significantly ameliorates the lipotoxic effects of palmitate, reduces CHOP and XBP1(s) induction and restores the expression levels of HER2 and HER3. The study shows that HER2/neu-positive breast cancer cells change their metabolic phenotype in the presence of palmitate. Palmitate induces AMPK activation and inhibition of fatty acid synthesis that feeds back into glycolysis as well as anaplerotic glutamine metabolism.
Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells.

PubMed

Ludyga, Natalie; Anastasov, Natasa; Rosemann, Michael; Seiler, Jana; Lohmann, Nadine; Braselmann, Herbert; Mengele, Karin; Schmitt, Manfred; Höfler, Heinz; Aubele, Michaela

2013-04-01

Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer. ©2013 AACR.
Final Results of the Randomized Phase II NorCap-CA223 Trial Comparing First-Line All-Oral Versus Taxane-Based Chemotherapy for HER2-Negative Metastatic Breast Cancer.

PubMed

Cinieri, Saverio; Chan, Arlene; Altundag, Kadri; Vandebroek, An; Tubiana-Mathieu, Nicole; Barnadas, Agusti; Dodyk, Patricia; Lazzarelli, Silvia; Botha, Michiel; Rauch, Daniel; Villanova, Gustavo; Coskun, Ugur

2017-04-01

The purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC). In this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age. The primary end point was disease control rate (DCR; complete or partial response, or stable disease for ≥3 months). The DCR was 73% (95% confidence interval [CI], 59-85) with NORCAP (36 of 49 patients), 78% (95% CI, 64-88) with GEMPAC (39 of 50 patients), and 80% (95% CI, 66-90) with GEMDOC (40 of 50 patients). Objective response rates were 33% (16 of 49 patients), 24% (12 of 50 patients), and 50% (25 of 50 patients), respectively; median progression-free survival was 7.6, 9.0, and 11.4 months, respectively. Median overall survival was 30 to 31 months with all regimens. The most common Grade ≥3 adverse event with each regimen was neutropenia (24 patients [50%], 23 patients [46%], and 43 patients [86%], respectively). The most common nonhematological Grade ≥3 adverse event was fatigue. Grade 2 alopecia occurred in 36 patients (72%) who received GEMPAC and 38 patients (76%) who received GEMDOC, but only 4 patients (8%) who received NORCAP. There was no evidence of a detrimental effect of NORCAP on quality of life. All-oral NORCAP is an active first-line chemotherapy regimen and might be offered as an alternative to first-line taxane-based therapy for HER2-negative mBC, particularly if patients wish to avoid alopecia or frequent intravenous administrations. Copyright © 2016 Elsevier Inc. All rights reserved.
Phyllodes tumours of the breast: retrospective analysis of a University Hospital's experience.

PubMed

Toh, Y F; Cheah, P L; Looi, L M; Teoh, K H; Tan, P H

2016-04-01

Taking cognizance of the purported variation of phyllodes tumours in Asians compared with Western populations, this study looked at phyllodes tumours of the breast diagnosed at the Department of Pathology, University of Malaya Medical Centre over an 8-year period with regards to patient profiles, tumour parameters, treatment offered and outcome. Sixty-four new cases of phyllodes tumour were diagnosed during the period, however only 30 (21 benign, 4 borderline and 5 malignant) finally qualified for entry into the study. These were followed-up for 4-102 months (average = 41.7 months). Thirteen cases (8 benign, 3 borderline, 2 malignant) were Chinese, 9 (all benign) Malay, 7 (4 benign, 1 borderline, 2 malignant) Indian and 1 (malignant) Indonesian. Prevalence of benign versus combined borderline and malignant phyllodes showed a marginally significant difference (p=0.049) between the Malays and Chinese. Patients' ages ranged from 21-70 years with a mean of 44.9 years with no significant difference in age between benign, borderline or malignant phyllodes tumours. Except for benign phyllodes tumours (mean size = 5.8 cm) being significantly smaller at presentation compared with borderline (mean size = 12.5 cm) and malignant (mean size = 15.8 cm) (p<0.05) tumours, history of previous pregnancy, breast feeding, hormonal contraception and tumour laterality did not differ between the three categories. Family history of breast cancer was noted in 2 cases of benign phyllodes. Local excision was performed in 17 benign, 2 borderline and 3 malignant tumours and mastectomy in 4 benign, 2 borderline and 2 malignant tumours. Surgical clearance was not properly recorded in 10 benign phyllodes tumours. Six benign and all 4 borderline and 5 malignant tumours had clearances of <10 mm. Two benign tumours recurred locally at 15 and 49 months after local excision, however information regarding surgical clearance was not available in both cases. One patient with a malignant tumour developed
[Internal quality control on HER2 status determination in breast cancers: Experience of a cancer center].

PubMed

Ngo, Carine; Laé, Marick; Ratour, Julia; Hamel, Frédérique; Taris, Corinne; Caly, Martial; Le Cunff, Annie; Reyal, Fabien; Kirova, Youlia; Pierga, Jean-Yves; Vincent-Salomon, Anne

The implementation of an internal quality control is mandatory to guarantee the accuracy of HER2 status in invasive breast cancers. To evaluate the impact of our quality control assurance on HER2 status results in invasive breast carcinomas from 2008 to 2014. HER2 status was determined by immunohistochemistry as the first-line indication, completed by fluorescence in situ hybridization (FISH) for scores 2+ by immunohistochemistry. Internal quality control of HER2 status relied on the standardization of pre-analytical phases, the use of external controls with a known number of HER2 gene copies determined by FISH and continued monitoring of concordance between immunohistochemistry and FISH. The proportion of HER2-positive cases corresponding to scores 3+ by immunohistochemistry and 2+ amplified by FISH varied from 10.6% to 13.8% (median of 11.3%). The proportion of scores 2+ amplified by FISH varied from 13.3% to 32.7% during period of study. The rate of concordance between FISH and immunohistochemistry for score 0/1+ and 3+ cases were≥97%. Eight among 12 discordant cases were false positive resulting from errors in interpretation of immunohistochemistry (score 2+ instead of 3+). Calibration of immunohistochemistry on FISH for HER2 status contributes to limit variability of immunohistochemistry results due to technical issues or interpretation. The implementation of an external control of score 3+ on each slide enables accurate interpretation of score 2+ and 3+ by immunohistochemistry. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.
HER2 Targeted Breast Cancer Therapy with Switchable "Off/On" Multifunctional "Smart" Magnetic Polymer Core-Shell Nanocomposites.

PubMed

Vivek, Raju; Thangam, Ramar; Kumar, Selvaraj Rajesh; Rejeeth, Chandrababu; Kumar, Gopal Senthil; Sivasubramanian, Srinivasan; Vincent, Savariar; Gopi, Dhanaraj; Kannan, Soundarapandian

2016-01-27

Multifunctional magnetic polymer nanocombinations are gaining importance in cancer nanotheranostics due to their safety and their potential in delivering targeted functions. Herein, we report a novel multifunctional core-shell magnetic polymer therapeutic nanocomposites (NCs) exhibiting pH dependent "Off-On" release of drug against breast cancer cells. The NCs are intact in blood circulation ("Off" state), i.e., at physiological pH, whereas activated ("On" state) at intracellular acidic pH environment of the targeted breast cancer cells. The NCs are prepared by coating the cannonball (iron nanocore) with hydrophobic nanopockets of pH-responsive poly(d,l-lactic-co-glycolic acid) (PLGA) polymer nanoshell that allows efficient loading of therapeutics. Further, the nanocore-polymer shell is stabilized by poly(vinylpyrrolidone) (PVP) and functionalized with a targeting HER2 ligand. The prepared Her-Fe3O4@PLGA-PVP nanocomposites facilitate packing of anticancer drug (Tamoxifen) without premature release in the bloodstream, recognizing the target cells through binding of Herceptin antibody to HER2, a cell surface receptor expressed by breast cancer cells to promote HER2 receptor mediated endocytosis and finally releasing the drug at the intracellular site of tumor cells ("On" state) to induce apoptosis. The therapeutic efficiency of hemo/cytocompatible NCs drug delivery system (DDS) in terms of targeted delivery and sustained release of therapeutic agent against breast cancer cells was substantiated by in vitro and in vivo studies. The multifunctional properties of Her-Tam-Fe3O4@PLGA-PVP NCs may open up new avenues in cancer therapy through overcoming the limitations of conventional cancer therapy.

TIMP3 Promoter Methylation Represents an Epigenetic Marker of BRCA1ness Breast Cancer Tumours.

PubMed

Maleva Kostovska, Ivana; Jakimovska, Milena; Popovska-Jankovic, Katerina; Kubelka-Sabit, Katerina; Karagjozov, Mitko; Plaseska-Karanfilska, Dijana

2018-03-09

Tumours presenting BRCAness profile behave more aggressively and are more invasive as a consequence of their complex genetic and epigenetic alterations, caused by impaired fidelity of the DNA repair processes. Methylation of promoter CpG islands represents an alternative mechanism to inactivate DNA repair and tumour suppressor genes. In our study, we analyzed the frequency of methylation changes of 24 tumour suppressor genes and explored their association with BRCAness profile. BRCA1ness profile and aberrant methylation were studied in 233 fresh frozen breast tumour tissues by Multiplex Ligation-dependent Probe Amplification (MLPA) and Methylation Specific (MS)-MLPA methods, respectively. Our analyses revealed that 12.4% of the breast cancer (BC) patients had tumours with a BRCA1ness profile. TIMP3 showed significantly higher (p = 5.8х10 -5 ) methylation frequency in tumours with BRCA1ness, while methylation of APC, GSTP1 and RASSF1 promoters was negatively associated with BRCA1ness (р = 0.0017, р = 0.007 and р = 0.046, respectively). TIMP3 methylation was also associated with triple negative (TN) BC. Furthermore, TN tumours showing BRCA1ness showed stronger association with TIMP3 methylation (p = 0.0008) in comparison to TN tumours without BRCA1ness (p = 0.009). In conclusion, we confirmed that TIMP3 methylation is a marker for TN tumours and furthermore we showed for the first time that TIMP3 promoter methylation is an epigenetic marker of BRCA1ness tumours.
Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer.

PubMed

Mercogliano, María F; Inurrigarro, Gloria; De Martino, Mara; Venturutti, Leandro; Rivas, Martín A; Cordo-Russo, Rosalía; Proietti, Cecilia J; Fernández, Elmer A; Frahm, Isabel; Barchuk, Sabrina; Allemand, Daniel H; Figurelli, Silvina; Deza, Ernesto Gil; Ares, Sandra; Gercovich, Felipe G; Cortese, Eduardo; Amasino, Matías; Guzmán, Pablo; Roa, Juan C; Elizalde, Patricia V; Schillaci, Roxana

2017-12-28

Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry. IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1-6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma. In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently
CPT-11/bevacizumab for the treatment of refractory brain metastases in patients with HER2-neu-positive breast cancer.

PubMed

Sengupta, S; Rojas, R; Mahadevan, A; Kasper, E; Jeyapalan, S

2015-04-01

Nervous system relapse of patients with advanced HER2-neu-positive breast cancer is an increasing problem, with one-third of women developing brain metastases. Standard therapies using steroids, surgery and radiotherapy do not provide a lasting response. We evaluated CPT-11 and bevacizumab, which can both cross the blood-brain barrier, as combination therapy to treat HER2-neu-positive breast cancer with brain metastases.
A Targeted RNAi Screen of the Breast Cancer Genome Identifies KIF14 and TLN1 as Genes That Modulate Docetaxel Chemosensitivity in Triple-Negative Breast Cancer

PubMed Central

Singel, Stina Mui; Cornelius, Crystal; Batten, Kimberly; Fasciani, Gail; Wright, Woodring E.; Lum, Lawrence; Shay, Jerry W.

2015-01-01

Purpose To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer. Experimental Design We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor–negative, progesterone receptor–negative, and Her2-negative (ER−, PR−, and Her2−, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model. Results From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor–positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays. Conclusion KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC. PMID:23479679
Safety Evaluation of Trastuzumab Emtansine in Japanese Patients with HER2-Positive Advanced Breast Cancer

PubMed Central

WATANABE, JUNICHIRO; ITO, YOSHINORI; SAEKI, TOSHIAKI; MASUDA, NORIKAZU; TAKANO, TOSHIMI; TAKAO, SHINTARO; NAKAGAMI, KAZUHIKO; TSUGAWA, KOICHIRO; NAKAGAWA, SHINTARO; KANATANI, KAZUMITSU; NAKAYAMA, TAKAHIRO

2017-01-01

Background/Aim: Tolerability and safety of trastuzumab emtansine (T-DM1) was investigated in Japanese patients with HER2-positive advanced breast cancer who were previously treated with chemotherapy and trastuzumab. Patients and Methods: Patients with inoperable or recurrent breast cancer who were previously treated with chemotherapy and trastuzumab in adjuvant and/or metastatic disease were included. T-DM1 3.6 mg/kg was administered intravenously every 21 days. The administration dosage or schedule of T-DM1 was modified based on laboratory tests on the administration day. Results: Among 232 patients analyzed, adverse events were reported in 228 patients (98.3%); five patients (2.2%) discontinued due to adverse events and twenty patients (8.6%) had serious adverse events. The most commonly reported grade ≥3 adverse event of special interest was thrombocytopenia (69 patients; 29.7%), followed by hepatotoxicity (26 patients; 11.2%). Conclusion: T-DM1 was well tolerated in Japanese patients with HER2-positive advanced breast cancer and no new safety signals were observed. PMID:28438884
A Comparative Performance Analysis of Multispectral and RGB Imaging on HER2 Status Evaluation for the Prediction of Breast Cancer Prognosis.

PubMed

Liu, Wenlou; Wang, Linwei; Liu, Jiuyang; Yuan, Jingping; Chen, Jiamei; Wu, Han; Xiang, Qingming; Yang, Guifang; Li, Yan

2016-12-01

Despite the extensive application of multispectral imaging (MSI) in biomedical multidisciplinary researches, there is a paucity of data available regarding the implication of MSI in tumor prognosis prediction. We compared the behaviors of multispectral (MS) and conventional red-green-blue (RGB) images on assessment of human epidermal growth factor receptor 2 (HER2) immunohistochemistry to explore their impact on outcome in patients with invasive breast cancer (BC). Tissue microarrays containing 240 BC patients were introduced to compare the performance of MS and RGB imaging methods on the quantitative assessment of HER2 status and the prognostic value of 5-year disease-free survival (5-DFS). Both the total and average signal optical density values of HER2 MS and RGB images were analyzed, and all patients were divided into two groups based on the different 5-DFS. The quantification of HER2 MS images was negatively correlated with 5-DFS in lymph node-negative and -positive patients (P<.05), but RGB images were not in lymph node-positive patients (P=.101). Multivariate analysis indicated that the hazard ratio (HR) of HER2 MS was higher than that of HER2 RGB (HR=2.454; 95% confidence interval [CI], 1.636-3.681 vs HR=2.060; 95% CI, 1.361-3.119). Additionally, area under curve (AUC) by receiver operating characteristic analysis for HER2 MS was greater than that for HER2 RGB (AUC=0.649; 95% CI, 0.577-0.722 vs AUC=0.596; 95% CI, 0.522-0.670) in predicting the risk for recurrence. More importantly, the quantification of HER2 MS images has higher prediction accuracy than that of HER2 RGB images (69.6% vs 65.0%) on 5-DFS. Our study suggested that better information on BC prognosis could be obtained from the quantification of HER2 MS images and MS images might perform better in predicting BC prognosis than conventional RGB images. Copyright Â© 2016 The Authors. Published by Elsevier Inc. All rights reserved.
A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.

PubMed

Filipits, Martin; Rudas, Margaretha; Jakesz, Raimund; Dubsky, Peter; Fitzal, Florian; Singer, Christian F; Dietze, Otto; Greil, Richard; Jelen, Andrea; Sevelda, Paul; Freibauer, Christa; Müller, Volkmar; Jänicke, Fritz; Schmidt, Marcus; Kölbl, Heinz; Rody, Achim; Kaufmann, Manfred; Schroth, Werner; Brauch, Hiltrud; Schwab, Matthias; Fritz, Peter; Weber, Karsten E; Feder, Inke S; Hennig, Guido; Kronenwett, Ralf; Gehrmann, Mathias; Gnant, Michael

2011-09-15

According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. RNA levels assessed by quantitative reverse transcriptase PCR in formalin-fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324]. In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 vs. 0.750, P = 0.024 (ABCSG-6) and 0.726 vs. 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively. The multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors. ©2011 AACR.
Sanctuary site leptomeningeal metastases in HER-2 positive breast cancer: A review in the era of trastuzumab.

PubMed

Kordbacheh, T; Law, W Y; Smith, I E

2016-04-01

The development of trastuzumab and other targeted systemic therapies has transformed the management of HER-2 positive breast cancers. However, as patients live longer and systemic therapies may not cross the blood brain barrier a rising number of patients are developing leptomeningeal metastases and brain metastases as a sanctuary site of disease. Intrathecal trastuzumab has been reported to treat these. We describe a breast cancer patient with HER-2 positive leptomeningeal disease in the spinal cord successfully treated with intrathecal trastuzumab and methotrexate, alongside systemic anti-HER-2 therapy and radiotherapy. We also review the literature to date on the efficacy and safety of intrathecal trastuzumab, and recent evidence suggesting that intrathecal trastuzumab passes via the blood brain barrier into the serum to achieve intravenous concentrations similar to that seen with systemic therapy alone. Overall, intrathecal trastuzumab appears to be a safe and often effective treatment for leptomeningeal metastases in HER-2 positive breast cancer. Ongoing phase I and II studies are required to determine optimum dosing schedules, validate CSF and CSF-to-serum pharmacokinetics, determine efficacy, and to assess the added benefits or disadvantages of prior radiotherapy and concomitant systemic therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.
A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer.

PubMed

Menyhárt, Otília; Santarpia, Libero; Győrffy, Balázs

2015-01-01

The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response. Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27(kip1), Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures. Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation. The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.
Pre-menopausal triple-negative breast cancer at HAM hospital medan

NASA Astrophysics Data System (ADS)

Betty; Laksmi, L. I.; Siregar, K. B.

2018-03-01

Triple-negative breast cancers (TNBC) are a type of breast cancer that does not have any or lack expression of the three receptors of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2). This cross-sectional study was performed on patients TNBC in HAM hospital Medan from 2013 to 2016 by immunohistochemistry stained. A total 60 invasive breast cancer samples with TNBC. The more frequent in TNBC group were 51-60 years (19 cases, 31.66%) and pre-menopause (34 cases, 57%). Tumor size T3 and T4 with staging IIIA and IIIB, histology sub-type IC-NOS and ILC with grade 2 and grade 3 of histologic was more common in TNBC.
Overexpression of a novel cell cycle regulator ecdysoneless in breast cancer: a marker of poor prognosis in HER2/neu-overexpressing breast cancer patients.

PubMed

Zhao, Xiangshan; Mirza, Sameer; Alshareeda, Alaa; Zhang, Ying; Gurumurthy, Channabasavaiah Basavaraju; Bele, Aditya; Kim, Jun Hyun; Mohibi, Shakur; Goswami, Monica; Lele, Subodh M; West, William; Qiu, Fang; Ellis, Ian O; Rakha, Emad A; Green, Andrew R; Band, Hamid; Band, Vimla

2012-07-01

Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P=0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P=0.013), mitotic index (P=0.032), and Nottingham Prognostic Index score (P=0.014). Ecd expression was positively associated with HER2/neu (P=0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P=0.008) and disease-free survival (DFS) (P=0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients.
Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

PubMed Central

Mortimer, Joanne E.; Bading, James R.; Colcher, David M.; Conti, Peter S.; Frankel, Paul H.; Carroll, Mary I.; Tong, Shan; Poku, Erasmus; Miles, Joshua K.; Shively, John E.; Raubitschek, Andrew A.

2014-01-01

Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion which may not be representative of the larger tumor mass or other sites of disease. Our long-range goal is to develop positron emission tomography (PET) of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET-CT of 64Cu-DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. Methods Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for ≥ 4 mo underwent complete staging, including 18F-fluorodeoxyglucose (FDG)/PET-CT. For 6 of the 8 patients, 64Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg trastuzumab) was preceded by trastuzumab infusion (45 mg). PET-CT (PET scan duration 1 h) was performed 21-25 (“Day 1”) and 47-49 (“Day 2”) h after 64Cu-DOTA-trastuzumab injection. Scan fields of view were chosen based on 18F-FDG/PET-CT. Lesions visualized relative to adjacent tissue on PET were considered PET-positive; analysis was limited to lesions identifiable on CT. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). Results Liver uptake of 64Cu was reduced approximately 75% with the 45 mg trastuzumab pre-dose, without significant effect on tumor uptake. The study included 89 CT-positive lesions; detection sensitivity was 77, 89 and 93% for Day 1, Day 2 and 18F-FDG, respectively. On average, tumor uptake was similar for 64Cu-DOTA-trastuzumab and 18F-FDG [SUVmax (mean, range): Day 1 (8.1, 3.0-22.5, n=48); Day 2 (8.9, 0.9-28.9, n=38); 18F-FDG (9.7, 3.3-25.4, n=56)], but the extent of same-lesion uptake was not
Non-epithelial malignancies and metastatic tumours of the breast

PubMed Central

O'Donnell, Mark E; McCavert, Mark; Carson, Jim; Mullan, Fred J; Whiteside, Michael W; Garstin, W Ian

2009-01-01

Introduction Non-epithelial breast malignancies include primary lymphomas, sarcomas, haematological malignancies, melanomas as well as secondary metastases to the breast. They account for less than 1% of all breast tumours. The demographics and clinical features are similar to epithelial breast cancers but the prognosis and management options are often very different. Most reported series are small with limited follow-up. The main aim of this study was to review our experience for these malignancies and to compare this with the published literature. Methods A 14-year retrospective review of all breast resection specimens was completed in the Antrim Area Hospital Cancer Unit. Clinical records of patients diagnosed with non-epithelial breast malignancies were then reviewed for data regarding patient demographics, clinical presentation, pre-operative investigations, operative findings and outcome. Pathology reports were examined carefully for tumour type, location and for evidence of lymphovascular spread. This data was compared with the available literature. Results Nineteen (F = 16) patients were found to have non-epithelial breast malignancies between April 1994 and August 2007. Mean age was 61.6 years (range 25–86). 17 patients (89.5%) presented with a palpable lump, mastalgia or skin change, while 2 (10.5%) patients' tumours were detected through screening. The histological types of non-epithelial malignancies were as follows: lymphoma (n = 8; M = 1 and F = 7, mean age: 68.5 range 52–86), sarcoma (n = 5; M = 1 and F = 4, mean age 56.4 range 29–69), malignant melanoma (n = 3; M = 1 and F = 2, mean age 54.3 range 25–70), multiple myeloma (n = 1; F, 71), metastatic renal cell carcinoma (n = 1; F, 63) and metastatic carcinoid tumour (n = 1; F, 52). The mean follow-up was 1541 days (32–4589 days). Nine patients were alive at the end of follow-up. Only 1 of 11 deaths was not directly related to the malignancy. The average time from surgery to death was 798
Decoupling of the PI3K pathway via mutation necessitates combinatorial treatment in HER2+ breast cancer

DOE PAGES

Korkola, James E.; Collisson, Eric A.; Heiser, Laura; ...

2015-07-16

We report here on experimental and theoretical efforts to determine how best to combine drugs that inhibit HER2 and AKT in HER2 + breast cancers. We accomplished this by measuring cellular and molecular responses to lapatinib and the AKT inhibitors (AKT i) GSK690693 and GSK2141795 in a panel of 22 HER2 + breast cancer cell lines carrying wild type or mutant PIK3CA. We observed that combinations of lapatinib plus AKT i were synergistic in HER2 /PIK3CA mut cell lines but not in HER2 +/PIK3CA wt cell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment withmore » lapatinib, AKT i or lapatinib + AKT i to shed light on the underlying signaling dynamics. This revealed that p-S6RP levels were less well attenuated by lapatinib in HER2 +/PIK3CA mut cells compared to HER2 +/PIK3CA wt cells and that lapatinib + AKT i reduced p-S6RP levels to those achieved in HER2 +/PIK3CA wt cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CA mut cells following lapatinib + AKT i treatment. Responses of HER2 + SKBR3 cells transfected with lentiviruses carrying control or PIK3CA mut sequences were similar to those observed in HER2 +/PIK3CA mut cell lines but not in HER2 +/PIK3CA wt cell lines. We used a nonlinear ordinary differential equation model to support the idea that PIK3CA mutations act as downstream activators of AKT that blunt lapatinib inhibition of downstream AKT signaling and that the effects of PIK3CA mutations can be countered by combining lapatinib with an AKT i. This combination does not confer substantial benefit beyond lapatinib in HER2 +/PIK3CA wt cells.« less
From bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer?

PubMed

Wu, Victoria Shang; Kanaya, Noriko; Lo, Chiao; Mortimer, Joanne; Chen, Shiuan

2015-09-01

Breast cancer is a heterogeneous disease. Thanks to extensive efforts from research scientists and clinicians, treatment for breast cancer has advanced into the era of targeted medicine. With the use of several well-established biomarkers, such as hormone receptors (HRs) (i.e., estrogen receptor [ER] and progesterone receptor [PgR]) and human epidermal growth factor receptor-2 (HER2), breast cancer patients can be categorized into multiple subgroups with specific targeted treatment strategies. Although therapeutic strategies for HR-positive (HR+) HER2-negative (HER2-) breast cancer and HR-negative (HR-) HER2-positive (HER2+) breast cancer are well-defined, HR+ HER2+ breast cancer is still an overlooked subgroup without tailored therapeutic options. In this review, we have summarized the molecular characteristics, etiology, preclinical tools and therapeutic options for HR+ HER2+ breast cancer. We hope to raise the attention of both the research and the medical community on HR+ HER2+ breast cancer, and to advance patient care for this subtype of disease. Copyright © 2015 Elsevier Ltd. All rights reserved.
Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.

PubMed

Swain, Sandra M; Baselga, José; Kim, Sung-Bae; Ro, Jungsil; Semiglazov, Vladimir; Campone, Mario; Ciruelos, Eva; Ferrero, Jean-Marc; Schneeweiss, Andreas; Heeson, Sarah; Clark, Emma; Ross, Graham; Benyunes, Mark C; Cortés, Javier

2015-02-19

In patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months. We randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis. The median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab
The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells

PubMed Central

Ram, Sripad; Kim, Dongyoung; Ober, Raimund J; Ward, E Sally

2014-01-01

The receptor tyrosine kinase HER2 is known to play a central role in mitogenic signaling, motivating the development of targeted, HER2-specific therapies. However, despite the longstanding use of antibodies to target HER2, controversies remain concerning antibody/HER2 trafficking behavior in cancer cells. Understanding this behavior has direct relevance to the mechanism of action and effective design of such antibodies. In the current study, we analyzed the intracellular dynamics of trastuzumab, a marketed HER2-targeting antibody, in a panel of breast and prostate cancer cell lines that have a wide range of HER2 expression levels. Our results reveal distinct post-endocytic trafficking behavior of antibody-HER2 complexes in cells with different HER2 expression levels. In particular, HER2-overexpressing cells exhibit efficient HER2 recycling and limited reductions in HER2 levels upon antibody treatment, and consequently display a high level of antibody persistence on their plasma membrane. By contrast, in cells with low HER2 expression, trastuzumab treatment results in rapid antibody clearance from the plasma membrane combined with substantial decreases in HER2 levels and undetectable levels of recycling. A cell line with intermediate levels of HER2 expression exhibits both antibody recycling and clearance from the cell surface. Significantly, these analyses demonstrate that HER2 expression levels, rather than cell origin (breast or prostate), is a determinant of subcellular trafficking properties. Such studies have relevance to optimizing the design of antibodies to target HER2. PMID:25517306
RAI1 Alternate Probe Identifies Additional Breast Cancer Cases as Amplified Following Equivocal HER2 Fluorescence In Situ Hybridization Testing: Experience From a National Reference Laboratory.

PubMed

Hui, Ling; Geiersbach, Katherine B; Downs-Kelly, Erinn; Gulbahce, H Evin

2017-02-01

-In 2013 the American Society of Clinical Oncology and College of American Pathologists updated the HER2 guidelines and changed the equivocal category for HER2 in situ hybridization testing to an average HER2 copy number of 4.0 to 5.9 with a HER2:CEP17 ratio of less than 2.0 and proposed retesting, with an option of using another control probe to avoid false-negative results. RAI1, located at band position 17p11.2, is a popular alternate probe locus for retesting equivocal changes. -To review experience with the RAI1 alternate probe in HER2 fluorescence in situ hybridization equivocal breast cancers. -Primary and metastatic breast cancers with equivocal HER2 fluorescence in situ hybridization, retested with an alternate (RAI1) probe, were identified. HER2, RAI1, and CEP17 copy numbers, HER2 to control probe ratios, and genetic heterogeneity were recorded. Hematoxylin-eosin-stained slides were reviewed for type and grade of cancer. -Of 876 cases tested with CEP17 as the reference probe, 97 (11.1%) had equivocal HER2 fluorescence in situ hybridization results. Additional testing with the RAI1 probe classified 39.2% cases (38 of 97) as amplified with a HER2:RAI1 ratio ranging from 2.0 to 3.2 (mean, 2.37); 3.1% (3 of 97) were still unclassifiable because of a deletion of RAI1. -RAI1 identified close to 40% of original HER2 fluorescence in situ hybridization equivocal cases as amplified, making these patients eligible for targeted therapies. It is not known whether guidelines for US Food and Drug Administration-approved probes can be extrapolated to alternate probes when an alternate control probe shows losses or gains. Because of the lack of guidelines for reporting HER2 status with alternate probes, laboratories face challenges in interpreting results.
Use of droplet digital PCR for quantitative and automatic analysis of the HER2 status in breast cancer patients.

PubMed

Otsuji, Kazutaka; Sasaki, Takeshi; Tanaka, Atsushi; Kunita, Akiko; Ikemura, Masako; Matsusaka, Keisuke; Tada, Keiichiro; Fukayama, Masashi; Seto, Yasuyuki

2017-02-01

Digital polymerase chain reaction (dPCR) has been used to yield an absolute measure of nucleic acid concentrations. Recently, a new method referred to as droplet digital PCR (ddPCR) has gained attention as a more precise and less subjective assay to quantify DNA amplification. We demonstrated the usefulness of ddPCR to determine HER2 gene amplification of breast cancer. In this study, we used ddPCR to measure the HER2 gene copy number in clinical formalin-fixed paraffin-embedded samples of 41 primary breast cancer patients. To improve the accuracy of ddPCR analysis, we also estimated the tumor content ratio (TCR) for each sample. Our determination method for HER2 gene amplification using the ddPCR ratio (ERBB2:ch17cent copy number ratio) combined with the TCR showed high consistency with the conventionally defined HER2 gene status according to ASCO-CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines (P<0.0001, Fisher's exact test). The equivocal area was established by adopting 99% confidence intervals obtained by cell line assays, which made it possible to identify all conventionally HER2-positive cases with our method. In addition, we succeeded in automating a major part of the process from DNA extraction to determination of HER2 gene status. The introduction of ddPCR to determine the HER2 gene status in breast cancer is feasible for use in clinical practice and might complement or even replace conventional methods of examination in the future.
Anti-HER2 Therapy Beyond Second-Line for HER2-Positive Metastatic Breast Cancer: A Short Review and Recommendations for Several Clinical Scenarios from a Spanish Expert Panel

PubMed Central

Martínez-Jañez, Noelia; Chacón, Ignacio; de Juan, Ana; Cruz-Merino, Luis; del Barco, Sònia; Fernández, Isaura; García-Teijido, Paula; Gómez-Bernal, Amalia; Plazaola, Arrate; Ponce, José; Servitja, Sonia; Zamora, Pilar

2016-01-01

Summary Background The aim of this project was to provide an expert opinion regarding anti-human epidermal growth factor receptor 2 (HER2) therapy beyond second-line treatment of metastatic breast cancer (mBC). Methods A group of experts discussed specific issues concerning anti-HER2 therapy in late-line settings in mBC. Results Trastuzumab emtansine (T-DM1) or dual HER2 blockade appeared to be good options for HER2-positive mBC after ≥ 2 HER2-targeted therapies. Once an objective response has been achieved with anti-HER2-containing therapy, the anti-HER2 agent can be continued until progression of the disease, unacceptable toxicity or patient decision. mBC treated with ≥ 3 consecutive lines of anti-HER therapy, ≥ 1 being a dual HER2 blockade and with early progression of disease during a fourth or later-line treatment, are clinically resistant to anti-HER therapy. For progression of metastasis in the brain after anti-HER2 therapy, lapatinib and chemotherapy appear to be a good alternative after best local treatment. Conclusions Further clinical trials are needed to provide valuable knowledge about the best treatment options in the later settings of mBC. PMID:27239176

Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients.

PubMed

Onsum, Matthew D; Geretti, Elena; Paragas, Violette; Kudla, Arthur J; Moulis, Sharon P; Luus, Lia; Wickham, Thomas J; McDonagh, Charlotte F; MacBeath, Gavin; Hendriks, Bart S

2013-11-01

Human epidermal growth factor receptor 2 (HER2) is an important biomarker for breast and gastric cancer prognosis and patient treatment decisions. HER2 positivity, as defined by IHC or fluorescent in situ hybridization testing, remains an imprecise predictor of patient response to HER2-targeted therapies. Challenges to correct HER2 assessment and patient stratification include intratumoral heterogeneity, lack of quantitative and/or objective assays, and differences between measuring HER2 amplification at the protein versus gene level. We developed a novel immunofluorescence method for quantitation of HER2 protein expression at the single-cell level on FFPE patient samples. Our assay uses automated image analysis to identify and classify tumor versus non-tumor cells, as well as quantitate the HER2 staining for each tumor cell. The HER2 staining level is converted to HER2 protein expression using a standard cell pellet array stained in parallel with the tissue sample. This approach allows assessment of HER2 expression and heterogeneity within a tissue section at the single-cell level. By using this assay, we identified distinct subgroups of HER2 heterogeneity within traditional definitions of HER2 positivity in both breast and gastric cancers. Quantitative assessment of intratumoral HER2 heterogeneity may offer an opportunity to improve the identification of patients likely to respond to HER2-targeted therapies. The broad applicability of the assay was demonstrated by measuring HER2 expression profiles on multiple tumor types, and on normal and diseased heart tissues. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
HER2-positive double primary tumor of gastric and breast cancer occur synchronously in a patient: A case report

PubMed Central

OUYANG, QUCHANG; TIAN, CAN; GAO, JIANXIANG; HUANG, JIN; FU, HUA; HE, JINSONG; YANG, JIANBO

2016-01-01

The simultaneous occurrence of primary gastric cancer and breast cancer is rare, and the positive expression of human epidermal growth factor receptor (HER)2 in double primary carcinoma of gastric and breast cancer remains to be reported. The present study presented a 46-year-old woman complaining of irregular acid reflux and stomach discomfort. The stomach cancer was diagnosed by esophagogastroduodenoscopy examination of the pathological biopsies in 2010. The patient underwent a radical gastrectomy for gastric cancer, and postoperative pathological examination revealed moderately-poorly differentiated adenocarcinoma with HER2 positive expression. The tumor invaded into the entire thickness of the gastric wall and lymph nodes. The patient received five treatments of postoperative chemotherapy. In August 2011, the patient felt a lump in the right breast. Simple excision of the right breast mass was performed on September 2011, and postoperative pathological examination revealed the invasive ductal carcinoma of the right breast with HER2 amplification by fluorescent in situ hybridization assay. The patient was treated with postoperative chemotherapy and radiotherapy, and also Trastuzumab target therapy. The patient succumbed to aggressive disease progression in March 2012. PMID:27123269
Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

PubMed Central

Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

2015-01-01

The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737
Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers.

PubMed

Renault, Anne-Laure; Mebirouk, Noura; Fuhrmann, Laetitia; Bataillon, Guillaume; Cavaciuti, Eve; Le Gal, Dorothée; Girard, Elodie; Popova, Tatiana; La Rosa, Philippe; Beauvallet, Juana; Eon-Marchais, Séverine; Dondon, Marie-Gabrielle; d'Enghien, Catherine Dubois; Laugé, Anthony; Chemlali, Walid; Raynal, Virginie; Labbé, Martine; Bièche, Ivan; Baulande, Sylvain; Bay, Jacques-Olivier; Berthet, Pascaline; Caron, Olivier; Buecher, Bruno; Faivre, Laurence; Fresnay, Marc; Gauthier-Villars, Marion; Gesta, Paul; Janin, Nicolas; Lejeune, Sophie; Maugard, Christine; Moutton, Sébastien; Venat-Bouvet, Laurence; Zattara, Hélène; Fricker, Jean-Pierre; Gladieff, Laurence; Coupier, Isabelle; Chenevix-Trench, Georgia; Hall, Janet; Vincent-Salomon, Anne; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Lesueur, Fabienne

2018-04-17

The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological
Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer

PubMed Central

Jadaliha, Mahdieh; Zong, Xinying; Malakar, Pushkar; Ray, Tania; Singh, Deepak K.; Freier, Susan M.; Jensen, Tor; Prasanth, Supriya G.; Karni, Rotem; Ray, Partha S.; Prasanth, Kannanganattu V.

2016-01-01

MALAT1 (metastasis associated lung adenocarcinoma transcript1) is a conserved long non-coding RNA, known to regulate gene expression by modulating transcription and post-transcriptional pre-mRNA processing of a large number of genes. MALAT1 expression is deregulated in various tumors, including breast cancer. However, the significance of such abnormal expression is yet to be fully understood. In this study, we demonstrate that regulation of aggressive breast cancer cell traits by MALAT1 is not predicted solely based on an elevated expression level but is context specific. By performing loss- and gain-of-function studies, both under in vitro and in vivo conditions, we demonstrate that MALAT1 facilitates cell proliferation, tumor progression and metastasis of triple-negative breast cancer (TNBC) cells despite having a comparatively lower expression level than ER or HER2-positive breast cancer cells. Furthermore, MALAT1 regulates the expression of several cancer metastasis-related genes, but displays molecular subtype specific correlations with such genes. Assessment of the prognostic significance of MALAT1 in human breast cancer (n=1992) revealed elevated MALAT1 expression was associated with decreased disease-specific survival in ER negative, lymph node negative patients of the HER2 and TNBC molecular subtypes. Multivariable analysis confirmed MALAT1 to have independent prognostic significance in the TNBC lymph node negative patient subset (HR=2.64, 95%CI 1.35 − 5.16, p=0.005). We propose that the functional significance of MALAT1 as a metastasis driver and its potential use as a prognostic marker is most promising for those patients diagnosed with ER negative, lymph node negative breast cancer who might otherwise mistakenly be stratified to have low recurrence risk. PMID:27250026
Functional and prognostic significance of long non-coding RNA MALAT1 as a metastasis driver in ER negative lymph node negative breast cancer.

PubMed

Jadaliha, Mahdieh; Zong, Xinying; Malakar, Pushkar; Ray, Tania; Singh, Deepak K; Freier, Susan M; Jensen, Tor; Prasanth, Supriya G; Karni, Rotem; Ray, Partha S; Prasanth, Kannanganattu V

2016-06-28

MALAT1 (metastasis associated lung adenocarcinoma transcript1) is a conserved long non-coding RNA, known to regulate gene expression by modulating transcription and post-transcriptional pre-mRNA processing of a large number of genes. MALAT1 expression is deregulated in various tumors, including breast cancer. However, the significance of such abnormal expression is yet to be fully understood. In this study, we demonstrate that regulation of aggressive breast cancer cell traits by MALAT1 is not predicted solely based on an elevated expression level but is context specific. By performing loss- and gain-of-function studies, both under in vitro and in vivo conditions, we demonstrate that MALAT1 facilitates cell proliferation, tumor progression and metastasis of triple-negative breast cancer (TNBC) cells despite having a comparatively lower expression level than ER or HER2-positive breast cancer cells. Furthermore, MALAT1 regulates the expression of several cancer metastasis-related genes, but displays molecular subtype specific correlations with such genes. Assessment of the prognostic significance of MALAT1 in human breast cancer (n=1992) revealed elevated MALAT1 expression was associated with decreased disease-specific survival in ER negative, lymph node negative patients of the HER2 and TNBC molecular subtypes. Multivariable analysis confirmed MALAT1 to have independent prognostic significance in the TNBC lymph node negative patient subset (HR=2.64, 95%CI 1.35- 5.16, p=0.005). We propose that the functional significance of MALAT1 as a metastasis driver and its potential use as a prognostic marker is most promising for those patients diagnosed with ER negative, lymph node negative breast cancer who might otherwise mistakenly be stratified to have low recurrence risk.
Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype.

PubMed

Wiese, David A; Thaiwong, Tuddow; Yuzbasiyan-Gurkan, Vilma; Kiupel, Matti

2013-09-03

Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC. Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs. IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11 of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis. FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA
HER2 Ile655Val polymorphism contributes to breast cancer risk: evidence from 27 case-control studies.

PubMed

Lu, Su; Wang, Zhanwei; Liu, Hong; Hao, Xishan

2010-12-01

Proto-oncogene HER2 (also known as erbB-2 or neu) plays an important role in the carcinogenesis and the prognosis of breast cancer. Many epidemiological studies have been conducted to explore the association between the HER2 Ile655Val polymorphism and breast cancer risk. However, inconsistency existed in the results. Therefore, we performed a meta-analysis of 27 published case-control studies including 11,504 cases and 12,538 controls. We assessed the strength of the association by crude odds ratios (ORs) with 95% confidence intervals (CIs) and reached a result that HER2 Ile655Val polymorphism was associated with an increased breast cancer risk in overall populations (for Ile/Val vs. Ile/Ile: OR = 1.05, 95% CI = 1.00-1.12, P = 0.07 for heterogeneity; for the dominant model Ile/Val + Val/Val vs. Ile/Ile: OR = 1.10, 95% CI = 1.01-1.20, P = 0.01 for heterogeneity). In subgroup analysis by ethnicity, we found a significant association among Africans (for Val/Val vs. Ile/Ile: OR = .78, 95% CI = 1.94-39.72, P = 0.35 for heterogeneity; for the recessive model Val/Val vs. Ile/Val +Ile/Ile: OR = 8.60, 95% CI = 1.92-38.48, P = 0.31 for heterogeneity) and Asians (for Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.39, P = 0.41 for heterogeneity; for the dominant model Val/Val + Ile/Val vs. Ile/Ile: OR = 1.18, 95% CI = 1.01-1.38, P = 0.27 for heterogeneity). In conclusion, our meta-analysis suggests that HER2 Ile 655Val polymorphism may contribute to breast cancer risk.
Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells

PubMed Central

Liu, Tongrui; Yacoub, Rami; Taliaferro-Smith, LaTonia D.; Sun, Shi-Yong; Graham, Tisheeka R.; Dolan, Ryan; Lobo, Christine; Tighiouart, Mourad; Yang, Lily; Adams, Amy; O'Regan, Ruth M.

2016-01-01

Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effects were synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. PMID:21690228
Identification and prognostic value of anterior gradient protein 2 expression in breast cancer based on tissue microarray.

PubMed

Guo, Jilong; Gong, Guohua; Zhang, Bin

2017-07-01

Breast cancer has attracted substantial attention as one of the major cancers causing death in women. It is crucial to find potential biomarkers of prognostic value in breast cancer. In this study, the expression pattern of anterior gradient protein 2 in breast cancer was identified based on the main molecular subgroups. Through analysis of 69 samples from the Gene Expression Omnibus database, we found that anterior gradient protein 2 expression was significantly higher in non-triple-negative breast cancer tissues compared with normal tissues and triple-negative breast cancer tissues (p < 0.05). The data from a total of 622 patients from The Cancer Genome Atlas were analysed. The data from The Cancer Genome Atlas and results from quantitative reverse transcription polymerase chain reaction also verified the anterior gradient protein 2 expression pattern. Furthermore, we performed immunohistochemical analysis. The quantification results revealed that anterior gradient protein 2 is highly expressed in non-triple-negative breast cancer (grade 3 excluded) and grade 1 + 2 (triple-negative breast cancer excluded) tumours compared with normal tissues. Anterior gradient protein 2 was significantly highly expressed in non-triple-negative breast cancer (grade 3 excluded) and non-triple-negative breast cancer tissues compared with triple-negative breast cancer tissues (p < 0.01). In addition, anterior gradient protein 2 was significantly highly expressed in grade 1 + 2 (triple-negative breast cancer excluded) and grade 1 + 2 tissues compared with grade 3 tissues (p < 0.05). Analysis by Fisher's exact test revealed that anterior gradient protein 2 expression was significantly associated with histologic type, histological grade, oestrogen status and progesterone status. Univariate analysis of clinicopathological variables showed that anterior gradient protein 2 expression, tumour size and lymph node status were significantly correlated with overall
64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

PubMed

Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

2013-11-01

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.
Glyceollins as novel targeted therapeutic for the treatment of metastatic triple-negative breast cancer

USDA-ARS?s Scientific Manuscript database

The purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA MB 231 cells. Triple negative (ER , PgR, and Her2/neu ...
The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer

PubMed Central

Mohammed, Z MA; Going, J J; Edwards, J; Elsberger, B; Doughty, J C; McMillan, D C

2012-01-01

Background: The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer. Methods: Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients. Results: The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival. Conclusion: The results of this study show that, using routine
Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor.

PubMed

Tiwari, Shruti Rakesh; Mishra, Prasun; Abraham, Jame

2016-10-01

HER2 gene amplification and receptor overexpression is identified in 20% to 25% of human breast cancers. Use of targeted therapy for HER2-amplified breast cancer has led to improvements in disease-free and overall survival in this subset of patients. Neratinib is an oral pan HER inhibitor, that irreversibly inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR or HER1), HER2, and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib is currently being tested in a number of clinical trials for its safety and efficacy in lung cancer, and colorectal, bladder, and breast cancers. In this review we discuss the available phase I, II, and III data for use of neratinib in the metastatic, adjuvant, neoadjuvant, and extended adjuvant settings along with the ongoing clinical trials of neratinib in breast cancer. We also elaborate on the side effect profile of this relatively new drug and provide guidelines for its use in clinical practice. Copyright © 2016 Elsevier Inc. All rights reserved.
Antiproliferative effects of γ-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells.

PubMed

Alawin, Osama A; Ahmed, Rayan A; Ibrahim, Baher A; Briski, Karen P; Sylvester, Paul W

2016-01-01

A large percentage of human breast cancers are characterized by excessive or aberrant HER2 activity. Lipid rafts are specialized microdomains within the plasma membrane that are required for HER2 activation and signal transduction. Since the anticancer activity of γ-tocotrienol is associated with suppression in HER2 signaling, studies were conducted to examine the effects of γ-tocotrienol on HER2 activation within the lipid raft microdomain in HER2-positive SKBR3 and BT474 human breast cancer cells. Treatment with 0-5μM γ-tocotrienol induced a significant dose-dependent inhibition in cancer cell growth after a 5-day culture period, and these growth inhibitory effects were associated with a reduction in HER2 dimerization and phosphorylation (activation). Phosphorylated HER2 was found to be primarily located in the lipid raft microdomain of the plasma membrane in vehicle-treated control groups, whereas γ-tocotrienol treatment significantly inhibited this effect. Assay of plasma membrane subcellular fractions showed that γ-tocotrienol also accumulates exclusively within the lipid raft microdomain. Hydroxypropyl-β-cyclodextrin (HPβCD) is an agent that disrupts lipid raft integrity. Acute exposure to 3mM HPβCD alone had no effect, whereas an acute 24-h exposure to 20μM γ-tocotrienol alone significantly decreased SKBR3 and BT474 cell viability. However, combined treatment with these agents greatly reduced γ-tocotrienol accumulation in the lipid raft microdomain and cytotoxicity. In summary, these findings demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain and subsequent interference with HER2 dimerization and activation in SKBR3 and BT474 human breast cancer cells. Copyright © 2015 Elsevier Inc. All rights reserved.
Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness.

PubMed

Chan, Arlene

2016-09-01

The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management.
Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness

PubMed Central

Chan, Arlene

2016-01-01

The management of HER-2-positive breast cancer has improved significantly with the use of targeted agents to the HER-2 signaling pathway. Despite the improved survival achieved with the use of trastuzumab and chemotherapy in both the adjuvant and metastatic setting, patients may still recur or progress; whilst preclinical data demonstrate that these cancer cells remain addicted to the HER-2 oncogene. Neratinib, an oral small molecule tyrosine-kinase inhibitor has efficacy in the metastatic and adjuvant setting of patients who have previously received trastuzumab-based treatment. Diarrhea, being a class effect of tyrosine-kinase inhibitor, is the most common side effect seen following neratinib administration, but recent data suggests that a prophylactic loperamide regimen can reduce the incidence of grade 3 diarrhea. Phase I through to III clinical trials of neratinib will be reviewed, with discussion of the postulated mechanism underlying diarrheal events and its management. PMID:27583026
CPT-11/bevacizumab for the treatment of refractory brain metastases in patients with HER2–neu-positive breast cancer

PubMed Central

Sengupta, S.; Rojas, R.; Mahadevan, A.; Kasper, E.; Jeyapalan, S.

2015-01-01

Nervous system relapse of patients with advanced HER2–neu-positive breast cancer is an increasing problem, with one-third of women developing brain metastases. Standard therapies using steroids, surgery and radiotherapy do not provide a lasting response. We evaluated CPT-11 and bevacizumab, which can both cross the blood–brain barrier, as combination therapy to treat HER2–neu-positive breast cancer with brain metastases. PMID:26634139
Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).

PubMed

Beitsch, Peter; Whitworth, Pat; Baron, Paul; Rotkis, Michael C; Mislowsky, Angela M; Richards, Paul D; Murray, Mary K; Pellicane, James V; Dul, Carrie L; Nash, Charles H; Stork-Sloots, Lisette; de Snoo, Femke; Untch, Sarah; Lee, Laura A

2017-09-01

Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping. Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment. In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%). The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.
CA27.29 as a tumour marker for risk evaluation and therapy monitoring in primary breast cancer patients.

PubMed

Rack, Brigitte; Jückstock, Julia; Trapp, Elisabeth; Weissenbacher, Tobias; Alunni-Fabbroni, Marianna; Schramm, Amelie; Widschwendter, Peter; Lato, Krisztian; Zwingers, Thomas; Lorenz, Ralf; Tesch, Hans; Schneeweiss, Andreas; Fasching, Peter; Mahner, Sven; Beckmann, Matthias W; Lichtenegger, Werner; Janni, Wolfgang

2016-10-01

Several trials showed that tumour markers are associated with an impaired prognosis for breast cancer. Whether earlier treatment can improve the course of the disease remains controversial. The SUCCESS Trial compares FEC (500/100/500)-docetaxel (100) vs. FEC (500/100/500)-docetaxel/gemcitabine (75/2000) as well as 2 vs. 5 years of zoledronate in high-risk primary breast cancer patients. In 2669 patients, CA27.29 was measured before and after chemotherapy with the ST AIA-PACK CA27.29 reagent for the AIA-600II automated enzyme immunoassay (Tosoh Bioscience, Belgium). Values above 31 U/ml were considered positive. Of the patients, 7.6 % (n = 202, mean 19, range 3-410) and 19.1 % (n = 511, mean 21, range 3-331) had elevated marker levels before and after chemotherapy, respectively. Of the patients, 4.9 and 78 % showed elevated and low CA27.29, respectively, at both time points. After treatment, 35 % of the pre-therapy positive patients were negative, and 15 % of the initially negative patients became positive. The correlation between both time points was significant (p < 0.0001). No correlations among nodal status, grading, hormonal status, HER2 status and CA27.29 levels were found. However, tumour size (p = 0.02), older age (p < 0.001) and post-menopausal status (p = 0.006) were significantly associated with higher CA27.29 levels. Before treatment, the prevalence of elevated CA27.29 was equally distributed between both treatment arms, whereas after chemotherapy, 13.7 % of the patients in the FEC-doc arm showed an increased level vs. 25.4 % of the patients in the FEC-doc/gemcitabine arm (p < 0.0001). However, we could not show a significant association between the G-CSF application (yes vs. no) and CA27.29 status before/after chemotherapy (p = 0.75). These results indicate a close relationship between CA27.29 levels and tumour mass. Increased values after the completion of chemotherapy might be attributed to treatment effects and should be

Efficacy of punarnavine in restraining organ-specific tumour progression in 4T1-induced murine breast tumour model.

PubMed

George Kallivalappil, Gilcy; Kuttan, Girija

2018-05-17

Most of the breast cancer deaths occur when cancer cells depart from their tumour of origin and spread systemically and colonise distant organs. The present study was to find out whether punarnavine, the quinolizidine alkaloid, with already proven antimetastatic effect on spontaneous B16F10 pulmonary metastasis has got any effect on a drastic organ-specific breast cancer spread. For the study, we selected a syngenic mouse 4T1 breast tumour model that mimics stage four of human breast cancer. The metastatic progression of 4T1 to lymph nodes, lungs, and liver was reduced by punarnavine (40 mg/kg body weight) administration in BALB/c mice. This was evident from the histopathology of these organs as well as from the reduction in the metastatic cell density of cultured 6-thioguanine-resistant 4T1 cells in the punarnavine-treated group compared to the control group. There was also a significant (p < 0.0001) inhibition of the primary breast tumour growth in the orthotopic site of induction with a simultaneous increase (p < 0.0001) in the life span of treated animals. The assessment of biochemical parameters such as hydroxyproline, hexosamine, uronic acid, sialic acid and γ-glutamyl transferase and the analysis of various cytokines VEGF, IL-1β, TNF-α and GM-CSF showed a similar pattern of reduction in punarnavine (p < 0.0001) treated group compared to the control group. The gene expression study revealed the inhibitory effect of punarnavine on the major genes MMP-2, MMP-9, TIMP-1, TIMP-2 and VEGF involved in the metastatic process. These findings undeniably proved the potential of this quinolizidine alkaloid in combating breast tumour development and its progression in the studied murine model.
Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.

PubMed

Lee, Miyoung; Oprea-Ilies, Gabriela; Saavedra, Harold I

2015-11-10

The E2F transcriptional activators E2F1, E2F2 and E2F3a regulate many important cellular processes, including DNA replication, apoptosis and centrosome duplication. Previously, we demonstrated that silencing E2F1 or E2F3 suppresses centrosome amplification (CA) and chromosome instability (CIN) in Her2+ breast cancer cells without markedly altering proliferation. However, it is unknown whether and how silencing a single E2F activator, E2F3, affects malignancy of human breast cancer cells. Thus, we injected HCC1954 Her2+ breast cancer cells silenced for E2F3 into mammary fat pads of immunodeficient mice and demonstrated that loss of E2F3 retards tumor growth. Surprisingly, silencing of E2F3 led to significant reductions in mitotic indices relative to vector controls, while the percentage of cells undergoing S phase were not affected. Nek2 is a mitotic kinase commonly upregulated in breast cancers and a critical regulator of Cdk4- or E2F-mediated CA. In this report, we found that Nek2 overexpression rescued back the CA caused by silencing of shE2F3. However, the effects of Nek2 overexpression in affecting tumor growth rates of shE2F3 and shE2F3; GFP cells were inconclusive. Taken together, our results indicate that E2F3 silencing decreases mammary tumor growth by reducing percentage of cells undergoing mitosis.
[Breast carcinoma metastasis to the gastrointestinal tract and tumour-to-tumour metastasis to renal cell carcinoma].

PubMed

Mosholt, Karina Sif Søndergaard; Pilt, Anette Pedersen; Wittendorff, Hans-Erik

2015-04-06

Breast carcinoma metastasis to the gastrointestinal tract and tumour-to-tumour metastasis is rare. We describe a case of a 71-year-old woman with previous breast cancer presenting with dyspepsia, nausea and weight-loss. Biopsies from the pylorus revealed what appeared to be a gastric carcinoma. A CT scan showed large kidney mass and biopsies revealed clear cell renal cell carcinoma with areas of poorly differentiated adenocarcinoma. Subsequent immunohistochemical analysis revealed the presence of breast carcinoma in both locations.
Vaccine Therapy With Sargramostim (GM-CSF) in Treating Patients With Her-2 Positive Stage III-IV Breast Cancer or Ovarian Cancer

ClinicalTrials.gov

2018-05-01

HER2-positive Breast Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor
MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6.

PubMed

Lu, Xiangdong; Ma, Jingjing; Chu, Jiahui; Shao, Qing; Zhang, Yao; Lu, Guangping; Li, Jun; Huang, Xiang; Li, Wei; Li, Yongfei; Ling, Yang; Zhao, Tao

2017-01-01

Trastuzumab is an important treatment used for patients with Her-2-positive breast cancer, but an increasing incidence of trastuzumab resistance has been observed clinically during the past decade. Aberrant microRNA (miR) expression levels are correlated with prognosis and response to trastuzumab in breast cancer. MiR-129-5p is downregulated in trastuzumab-resistant human breast cancer cells (JIMT-1), but its potential function and underlying mechanism remain unclear. Quantitative RT-PCR (qRT-PCR) was used to determine the expression levels of miR-129-5p and its potential target genes. The effects of miR-129-5p on cell responses to trastuzumab were analyzed by CCK-8 and flow cytometry assays in Her-2-positive breast cancer cells (SKBR-3 and JIMT-1). Bio-informatics analyses were performed to predict target genes of miR-129-5p, and luciferase assays were carried out to confirm the binding of miR-129-5p and rpS6. MiR-129-5p, which was downregulated and predicted to target rpS6 in trastuzumab-resistant breast cancer cells, enhanced the sensitivity of breast cancer cells to trastuzumab by reducing the expression of rpS6. Moreover, the overexpression of rpS6 reversed the sensitivity of cells to trastuzumab induced by miR-129-5p. MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. These findings provide novel insights into the common role of rpS6 and its related molecular mechanisms in mediating trastuzumab-resistance in Her-2-positive breast cancers. © 2017 The Author(s). Published by S. Karger AG, Basel.
Correlation between HER2 gene amplification and protein overexpression through fluorescence in situ hybridization and immunohistochemistry in breast carcinoma patients.

PubMed

Makroo, R N; Chowdhry, Mohit; Kumar, Manoj; Srivastava, Priyanka; Tyagi, Richa; Bhadauria, Preeti; Kaul, Sumaid; Sarin, Ramesh; Das, P K; Dua, Harsh

2012-01-01

In India, the incidence of breast cancer has increased in the urban population, with 1 in every 22 women diagnosed with breast cancer. It is important to know the HER2/neu gene status for a better prognostication of these patients. The aim of this study was to compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for determining HER2/neu alteration in breast carcinoma. A total of 188 histologically proven breast carcinoma cases between the years 2007 and 2011 were retrospectively analyzed on the paraffin tissue sections by both IHC and FISH techniques. FISH for HER2/neu gene amplification was performed on cases where the IHC status was already known and the results were compared. A total of 64 (30%) patients were found to be amplified and the remaining 124 (65.9%) cases were found to be unamplified through FISH. Patients observed with 3+ reading on IHC were later confirmed as unamplified in 29.5% cases through FISH. It has been confirmed with the present study that IHC is a prudent first-step technique to screen tissue samples for HER2/neu gene status, but should be supplemented with the FISH technique especially in equivocal cases.
Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

PubMed

Coussy, F; Lallemand, F; Vacher, S; Schnitzler, A; Chemlali, W; Caly, M; Nicolas, A; Richon, S; Meseure, D; El Botty, R; De-Plater, L; Fuhrmann, L; Dubois, T; Roman-Roman, S; Dangles-Marie, V; Marangoni, E; Bièche, I

2017-06-06

RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/β-catenin pathway, was examined on the growth of an RSPO2-positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC. We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO, and amplification or hypomethylation of RSPO genes. Patients with RSPO2-overexpressing tumours have a poorer metastasis-free survival (P=3.6 × 10 -4 ). RSPO2 and RSPO4 stimulate Wnt/β-catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2-overexpressing PDX. RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.
Age-Specific Incidence of Breast Cancer Subtypes: Understanding the Black–White Crossover

PubMed Central

2012-01-01

Background Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black–white crossover). We used newly available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity. Methods We classified 91908 invasive breast cancers diagnosed in California between January 1, 2006, and December 31, 2009, by subtype based on tumor expression of estrogen receptor (ER) and progesterone receptor (PR)—together referred to as hormone receptor (HR)—and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes were classified as ER or PR positive and HER2 negative (HR+/HER2−), ER or PR positive and HER2 positive (HR+/HER2+), ER and PR negative and HER2 positive (HR−/HER2+), and ER, PR, and HER2 negative (triple-negative). We calculated and compared age-specific incidence rates, incidence rate ratios, and 95% confidence intervals by subtype and race (black, white, Hispanic, and Asian). All P values are two-sided. Results We did not observe an age-related black–white crossover in incidence for any molecular subtype of breast cancer. Compared with white women, black women had statistically significantly higher rates of triple-negative breast cancer at all ages but statistically significantly lower rates of HR+/HER2− breast cancers after age 35 years (all P < .05). The age-specific incidence of HR+/HER2+ and HR−/HER2+ subtypes did not vary markedly between white and black women. Conclusions The black–white crossover in breast cancer incidence occurs only when all breast cancer subtypes are combined and relates largely to higher rates of triple-negative breast cancers and lower rates of HR+/HER2− breast cancers in black vs white women. PMID:22773826
Utility of cytopathological specimens and an automated image analysis for the evaluation of HER2 status and intratumor heterogeneity in breast carcinoma.

PubMed

Arihiro, Koji; Oda, Miyo; Ogawa, Katsunari; Kaneko, Yoshie; Shimizu, Tomomi; Tanaka, Yuna; Marubashi, Yukari; Ishida, Katsunari; Takai, Chikako; Taoka, Chie; Kimura, Shuji; Shiroma, Noriyuki

2016-12-01

Although updated HER2 testing guidelines have been improved by a collaboration between the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) in 2013, HER2 evaluation is still problematic because of issues involving CEP17 polysomy, heterogeneity, and HER2 score 2+ cases. The aim of this retrospective study was to evaluate the relationship between HER2 gene heterogeneity, or so called CEP17 polysomy, using breast carcinoma cells sampled by scraping and the IHC score graded by automated image analysis using whole slide image. We randomly selected 23 breast carcinoma cases with a HER2 score 0, 24 cases with a HER2 score 1+, 24 cases with HER2 score 2+, and 23 cases with HER2 score 3+ from the records of patients with breast cancer at Hiroshima University Hospital. We compared the results of fluorescent in situ hybridization (FISH) using formalin-fixed, paraffin-embedded (FFPE) tissues and cytological samples and compared the HER2 score calculated using an automated image analysis using wholly scanned slide images and visual counting. We successfully performed the FISH assay in 78 of 94 cases (83%) using FFPE tissues and in all 94 (100%) cases using cytological samples. Frequency of both HER2 amplification and CEP17 polysomy was higher when cytological samples were used than when FFPE tissue was used. Frequency of HER2 heterogeneity using cytological samples was higher that than using FFPE tissue, except for the IHC score 3+ cases. When assessment of HER2 status based on FISH using FFPE tissue cannot be accomplished, FISH using cytological samples should be considered. When intensity of HER2 is heterogeneous in the tumor tissue, particularly in cases regarded as score 2+, they should be evaluated by automated image analysis using the whole slide image. Copyright Â© 2016 Elsevier GmbH. All rights reserved.
Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis.

PubMed

Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J; Steinberg, Seth M; Steeg, Patricia S

2011-01-01

Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved antiangiogenic drug that targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, PDGFRα, and c-kit, for prevention of experimental brain metastases and mechanism of action. In vitro assays included B-Raf enzymatic assays, Western blots, and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 postinjection. Brain metastases were counted histologically, imaged, and immunostained. Treatment with 100 mg/kg of pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (P < 0.0001) and a 39% decline in micrometastases (P = 0.004). In vitro, pazopanib was directly antiproliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib-treated brain metastases whereas blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon magnetic resonance imaging (MRI) by 55% (P = 0.067), without affecting brain metastasis vascular density. The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor and suggest its potential for prevention of brain metastatic colonization of HER2(+) breast cancer. ©2010 AACR.
Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).

PubMed

Verma, Sunil; Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C; Rugo, Hope S

2016-10-01

Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed
Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3)

PubMed Central

Bartlett, Cynthia Huang; Schnell, Patrick; DeMichele, Angela M.; Loi, Sherene; Ro, Jungsil; Colleoni, Marco; Iwata, Hiroji; Harbeck, Nadia; Cristofanilli, Massimo; Zhang, Ke; Thiele, Alexandra; Turner, Nicholas C.; Rugo, Hope S.

2016-01-01

Background. Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib’s safety profile to effectively manage toxicity and optimize clinical benefit. Materials and Methods. Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data. Results. A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3–4 neutropenia with palbociclib. Dose modifications for grade 3–4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1–2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients. Conclusion. Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135. Implications for Practice: Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with
Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer.

PubMed

Baselga, José; Lewis Phillips, Gail D; Verma, Sunil; Ro, Jungsil; Huober, Jens; Guardino, Alice E; Samant, Meghna K; Olsen, Steve; de Haas, Sanne L; Pegram, Mark D

2016-08-01

HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR. ©2016 American Association for Cancer Research.
Luminal-like HER2-negative stage IA breast cancer: a multicenter retrospective study on long-term outcome with propensity score analysis

PubMed Central

De Angelis, Carmine; Di Maio, Massimo; Crispo, Anna; Giuliano, Mario; Schettini, Francesco; Bonotto, Marta; Gerratana, Lorenzo; Iacono, Donatella; Cinausero, Marika; Riccardi, Ferdinando; Ciancia, Giuseppe; De Laurentiis, Michelino; Puglisi, Fabio; De Placido, Sabino; Arpino, Grazia

2017-01-01

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome. PMID:29348868
Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis

PubMed Central

Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

2010-01-01

Purpose Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved anti-angiogenic drug that targets VEGFR1-3, PDGFRβ, PDGFRα and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design In vitro assays included B-Raf enzymatic assays, western blots and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 post-injection. Brain metastases were counted histologically, imaged and immunostained. Results Treatment with 100 mg/kg pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (p<0.0001) and 39% decline in micrometastases (p=0.004). In vitro, pazopanib was directly anti-proliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib treated brain metastases while blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon MRI imaging by 55% (p=0.067), without affecting brain metastasis vascular density. Conclusions The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor, and suggest its potential for prevention of brain metastatic colonization of HER2+ breast cancer. PMID:21081656
Early dissemination seeds metastasis in breast cancer

PubMed Central

Hosseini, Hedayatollah; Obradović, Milan M.S.; Hoffmann, Martin; Harper, Kathryn; Sosa, Maria Soledad; Werner-Klein, Melanie; Nanduri, Lahiri Kanth; Werno, Christian; Ehrl, Carolin; Maneck, Matthias; Patwary, Nina; Haunschild, Gundula; Gužvić, Miodrag; Reimelt, Christian; Grauvogl, Michael; Eichner, Norbert; Weber, Florian; Hartkopf, Andreas; Taran, Florin-Andrei; Brucker, Sara Y.; Fehm, Tanja; Rack, Brigitte; Buchholz, Stefan; Spang, Rainer; Meister, Gunter; Aguirre-Ghiso, Julio A.; Klein, Christoph A.

2016-01-01

Accumulating data suggest that metastatic dissemination often occurs early during tumour formation but the mechanisms of early metastatic spread have not yet been addressed. Here, we studied metastasis in a HER2-driven mouse breast cancer model and found that progesterone-induced signalling triggered migration of cancer cells from early lesions shortly after HER2 activation, but promoted proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by elevated HER2 expression and increased tumour cell density involving miRNA-mediated progesterone receptor (PGR) down-regulation and was reversible. Cells from early, low-density lesions displayed more stemness features than cells from dense, advanced tumours, migrated more and founded more metastases. Strikingly, we found that at least 80% of metastases were derived from early disseminated cancer cells (DCC). Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination. PMID:27974799
Automated Image Analysis of HER2 Fluorescence In Situ Hybridization to Refine Definitions of Genetic Heterogeneity in Breast Cancer Tissue

PubMed Central

Radziuviene, Gedmante; Rasmusson, Allan; Augulis, Renaldas; Lesciute-Krilaviciene, Daiva; Laurinaviciene, Aida; Clim, Eduard

2017-01-01

Human epidermal growth factor receptor 2 gene- (HER2-) targeted therapy for breast cancer relies primarily on HER2 overexpression established by immunohistochemistry (IHC) with borderline cases being further tested for amplification by fluorescence in situ hybridization (FISH). Manual interpretation of HER2 FISH is based on a limited number of cells and rather complex definitions of equivocal, polysomic, and genetically heterogeneous (GH) cases. Image analysis (IA) can extract high-capacity data and potentially improve HER2 testing in borderline cases. We investigated statistically derived indicators of HER2 heterogeneity in HER2 FISH data obtained by automated IA of 50 IHC borderline (2+) cases of invasive ductal breast carcinoma. Overall, IA significantly underestimated the conventional HER2, CEP17 counts, and HER2/CEP17 ratio; however, it collected more amplified cells in some cases below the lower limit of GH definition by manual procedure. Indicators for amplification, polysomy, and bimodality were extracted by factor analysis and allowed clustering of the tumors into amplified, nonamplified, and equivocal/polysomy categories. The bimodality indicator provided independent cell diversity characteristics for all clusters. Tumors classified as bimodal only partially coincided with the conventional GH heterogeneity category. We conclude that automated high-capacity nonselective tumor cell assay can generate evidence-based HER2 intratumor heterogeneity indicators to refine GH definitions. PMID:28752092
Automated Image Analysis of HER2 Fluorescence In Situ Hybridization to Refine Definitions of Genetic Heterogeneity in Breast Cancer Tissue.

PubMed

Radziuviene, Gedmante; Rasmusson, Allan; Augulis, Renaldas; Lesciute-Krilaviciene, Daiva; Laurinaviciene, Aida; Clim, Eduard; Laurinavicius, Arvydas

2017-01-01

Human epidermal growth factor receptor 2 gene- (HER2-) targeted therapy for breast cancer relies primarily on HER2 overexpression established by immunohistochemistry (IHC) with borderline cases being further tested for amplification by fluorescence in situ hybridization (FISH). Manual interpretation of HER2 FISH is based on a limited number of cells and rather complex definitions of equivocal, polysomic, and genetically heterogeneous (GH) cases. Image analysis (IA) can extract high-capacity data and potentially improve HER2 testing in borderline cases. We investigated statistically derived indicators of HER2 heterogeneity in HER2 FISH data obtained by automated IA of 50 IHC borderline (2+) cases of invasive ductal breast carcinoma. Overall, IA significantly underestimated the conventional HER2, CEP17 counts, and HER2/CEP17 ratio; however, it collected more amplified cells in some cases below the lower limit of GH definition by manual procedure. Indicators for amplification, polysomy, and bimodality were extracted by factor analysis and allowed clustering of the tumors into amplified, nonamplified, and equivocal/polysomy categories. The bimodality indicator provided independent cell diversity characteristics for all clusters. Tumors classified as bimodal only partially coincided with the conventional GH heterogeneity category. We conclude that automated high-capacity nonselective tumor cell assay can generate evidence-based HER2 intratumor heterogeneity indicators to refine GH definitions.
Novel agents that downregulate EGFR, HER2, and HER3 in parallel

PubMed Central

Ferreira, Renan Barroso; Law, Mary Elizabeth; Jahn, Stephan Christopher; Davis, Bradley John; Heldermon, Coy Don; Reinhard, Mary; Castellano, Ronald Keith; Law, Brian Keith

2015-01-01

EGFR, HER2, and HER3 contribute to the initiation and progression of human cancers, and are therapeutic targets for monoclonal antibodies and tyrosine kinase inhibitors. An important source of resistance to these agents arises from functional redundancy among EGFR, HER2, and HER3. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR, HER2, and HER3 in unison. Here we describe the identification of compounds that kill breast cancer cells that overexpress EGFR or HER2. Cell death parallels downregulation of EGFR, HER2, and HER3. These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs). DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity. DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance. PMID:25865227
The clonal and mutational evolution spectrum of primary triple-negative breast cancers.

PubMed

Shah, Sohrab P; Roth, Andrew; Goya, Rodrigo; Oloumi, Arusha; Ha, Gavin; Zhao, Yongjun; Turashvili, Gulisa; Ding, Jiarui; Tse, Kane; Haffari, Gholamreza; Bashashati, Ali; Prentice, Leah M; Khattra, Jaswinder; Burleigh, Angela; Yap, Damian; Bernard, Virginie; McPherson, Andrew; Shumansky, Karey; Crisan, Anamaria; Giuliany, Ryan; Heravi-Moussavi, Alireza; Rosner, Jamie; Lai, Daniel; Birol, Inanc; Varhol, Richard; Tam, Angela; Dhalla, Noreen; Zeng, Thomas; Ma, Kevin; Chan, Simon K; Griffith, Malachi; Moradian, Annie; Cheng, S-W Grace; Morin, Gregg B; Watson, Peter; Gelmon, Karen; Chia, Stephen; Chin, Suet-Feung; Curtis, Christina; Rueda, Oscar M; Pharoah, Paul D; Damaraju, Sambasivarao; Mackey, John; Hoon, Kelly; Harkins, Timothy; Tadigotla, Vasisht; Sigaroudinia, Mahvash; Gascard, Philippe; Tlsty, Thea; Costello, Joseph F; Meyer, Irmtraud M; Eaves, Connie J; Wasserman, Wyeth W; Jones, Steven; Huntsman, David; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel

2012-04-04

Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.

Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer.

PubMed

Bose, Prithviraj; Ozer, Howard

2009-11-01

The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. A Medline search using Pubmed was conducted using the keywords neratinib, HKI-272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development.
Stage III and oestrogen receptor negativity are associated with poor prognosis after adjuvant high-dose therapy in high-risk breast cancer

PubMed Central

Hohaus, S; Funk, L; Martin, S; Schlenk, R F; Abdallah, A; Hahn, U; Egerer, G; Goldschmidt, H; Schneeweiß, A; Fersis, N; Kaul, S; Wallwiener, D; Bastert, G; Haas, R

1999-01-01

and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone receptor-negative tumours. © 1999 Cancer Research Campaign PMID:10188897
Circulating Bone-related Markers and YKL-40 Versus HER2 and TOPO2a in Bone Metastatic and Nonmetastatic Breast Cancer: Diagnostic Implications.

PubMed

Shaker, Olfat Gamil; Helmy, Hebatullah Samy

2018-06-01

The bone represents one of the most common sites of metastases in breast cancer. The aim of the current study was to evaluate the diagnostic potential of several circulating markers to detect metastasis to bones in patients with breast cancer. Receptor activator of Nuclear Factor-kappa β (NF-Kβ) ligand (RANKL), osteoprotegrin (OPG), vitamin D (VIT D), Chitinase-3-like protein 1; also known as YKL-40, topoisomerase IIα (TOPO2a), and human epidermal growth factor receptor 2 (HER2) were measured in blood samples obtained from 122 patients with breast cancer and 25 healthy controls. All biomarkers were significantly elevated in patients with breast cancer with bone metastasis compared with nonmetastatic patients except YKL-40. RANKL had the highest diagnostic performance for bone metastasis detection with an area under the curve of 97.3, a sensitivity of 85%, and a specificity of 98.6%. Furthermore, logistic regression analysis resulted in a model of RANKL combined with HER2 that had even higher discriminatory power of metastasis to bones than that of RANKL alone. Overall correct classification of the model was 98.9%. We recommend that measuring RANKL together with HER2 can be routinely applied to allow early detection of bone metastases in patients with breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.
PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis.

PubMed

Paul, A; Gunewardena, S; Stecklein, S R; Saha, B; Parelkar, N; Danley, M; Rajendran, G; Home, P; Ray, S; Jokar, I; Vielhauer, G A; Jensen, R A; Tawfik, O; Paul, S

2014-09-01

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a
PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

PubMed Central

Paul, A; Gunewardena, S; Stecklein, S R; Saha, B; Parelkar, N; Danley, M; Rajendran, G; Home, P; Ray, S; Jokar, I; Vielhauer, G A; Jensen, R A; Tawfik, O; Paul, S

2014-01-01

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a
Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis.

PubMed

Lewis Phillips, Gail D; Nishimura, Merry C; Lacap, Jennifer Arca; Kharbanda, Samir; Mai, Elaine; Tien, Janet; Malesky, Kimberly; Williams, Simon P; Marik, Jan; Phillips, Heidi S

2017-08-01

The extent to which efficacy of the HER2 antibody Trastuzumab in brain metastases is limited by access of antibody to brain lesions remains a question of significant clinical importance. We investigated the uptake and distribution of trastuzumab in brain and mammary fat pad grafts of HER2-positive breast cancer to evaluate the relationship of these parameters to the anti-tumor activity of trastuzumab and trastuzumab emtansine (T-DM1). Mouse transgenic breast tumor cells expressing human HER2 (Fo2-1282 or Fo5) were used to establish intracranial and orthotopic tumors. Tumor uptake and tissue distribution of systemically administered 89 Zr-trastuzumab or muMAb 4D5 (murine parent of trastuzumab) were measured by PET and ELISA. Efficacy of muMAb 4D5, the PI3K/mTOR inhibitor GNE-317, and T-DM1 was also assessed. 89 Zr-trastuzumab and muMAb 4D5 exhibited robust uptake into Fo2-1282 brain tumors, but not normal brains. Uptake into brain grafts was similar to mammary grafts. Despite this, muMAb 4D5 was less efficacious in brain grafts. Co-administration of muMAb 4D5 and GNE-317, a brain-penetrant PI3K/mTOR inhibitor, provided longer survival in mice with brain lesions than either agent alone. Moreover, T-DM1 increased survival in the Fo5 brain metastasis model. In models of HER2-positive breast cancer brain metastasis, trastuzumab efficacy does not appear to be limited by access to intracranial tumors. Anti-tumor activity improved with the addition of a brain-penetrant PI3K/mTOR inhibitor, suggesting that combining targeted therapies is a more effective strategy for treating HER2-positive breast cancer brain metastases. Survival was also extended in mice with Fo5 brain lesions treated with T-DM1.
An improved radiolabelled RNA aptamer molecule for HER2 imaging in cancers.

PubMed

Varmira, Kambiz; Hosseinimehr, Seyed Jalal; Noaparast, Zohreh; Abedi, Seyed Mohammad

2014-02-01

Human epidermal growth factor receptor 2 (HER2) expression has been shown to be increased in several types of human tumours. In this study, for the imaging of HER2-related tumours, a modified RNA aptamer with HER2-specific targeting was labelled with (99m)Tc, by using hydrazino nicotinamide (HYNIC) as the chelator in the presence of tricine or ethylenediamine-N,N'-diacetic acid (EDDA) as the co-ligand. Stability testing of the radiolabelled aptamers in the serum was performed through SDS-PAGE. The aptamer-radionuclide conjugate was evaluated for its cellular HER2-specific binding in ovarian cancer cells (SKOV-3), and its biodistribution properties were assessed in normal and SKOV-3 tumour-bearing mice. In the presence of either tricine or EDDA, the HYNIC-RNA aptamers were labelled with (99m)Tc at a high yield and radiochemical purity. Cellular experiments confirmed the specific binding of the RNA aptamer to the HER2 receptor. In the animal biodistribution study, uptake of the EDDA-co-liganded (99m)Tc-HYNIC-RNA aptamer by the liver and spleen was remarkably lower than that of the aptamer with tricine. Tumours also showed a higher accumulation of radioactivity with the EDDA-co-liganded aptamer complex. This study demonstrated EDDA to be better than tricine for use as a co-ligand with the RNA aptamer, which can be a potential tool for the molecular imaging of HER2-overexpressing cancers.
Breast cancer tumour growth modelling for studying the association of body size with tumour growth rate and symptomatic detection using case-control data.

PubMed

Abrahamsson, Linda; Czene, Kamila; Hall, Per; Humphreys, Keith

2015-08-21

A large body size is associated with larger breast cancer tumours at diagnosis. Standard regression models for tumour size at diagnosis are not sufficient for unravelling the mechanisms behind the association. Using Swedish case-control data, we identified 1352 postmenopausal women with incident invasive breast cancer diagnosed between 1993 and 1995. We used a novel continuous tumour growth model, which models tumour sizes at diagnosis through three submodels: for tumour growth, time to symptomatic detection, and screening sensitivity. Tumour size at other time points is thought of as a latent variable. We quantified the relationship between body size with tumour growth and time to symptomatic detection. High body mass index and large breast size are, respectively, significantly associated with fast tumour growth rate and delayed time to symptomatic detection (combined P value = 5.0 × 10(-5) and individual P values = 0.089 and 0.022). We also quantified the role of mammographic density in screening sensitivity. The times at which tumours will be symptomatically detected may vary substantially between women with different breast sizes. The proposed tumour growth model represents a novel and useful approach for quantifying the effects of breast cancer risk factors on tumour growth and detection.
Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post-menopausal breast cancer risk.

PubMed

Shi, Joy; Kobayashi, Lindsay C; Grundy, Anne; Richardson, Harriet; SenGupta, Sandip K; Lohrisch, Caroline A; Spinelli, John J; Aronson, Kristan J

2017-08-01

To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and ≥50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR-/HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status.
Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study.

PubMed

Jones, Stephen E; Collea, Rufus; Paul, Devchand; Sedlacek, Scot; Favret, Anne M; Gore, Ira; Lindquist, Deborah L; Holmes, Frankie Ann; Allison, Mary Ann K; Brooks, Barry D; Portillo, Raul M; Vukelja, Svetislava J; Steinberg, Michael S; Stokoe, Christopher; Crockett, Maria W; Wang, Yunfei; Asmar, Lina; Robert, Nicholas J; O'Shaughnessy, Joyce

2013-10-01

Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2-amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A-amplified and TOP2A-non-amplified disease. This was an open-label, single-group, phase 2 study. Eligible patients were aged 18-75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2-amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m(2), plus intravenous cyclophosphamide 600 mg/m(2), plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A-amplified and TOP2A-non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5-36·7), 2-year DFS was 97·8% (95% CI 94·2-99·2) and 2-year overall survival was 99·5% (95% CI 96·2-99·9) for the 190 patients with TOP2A-amplified disease; 2-year DFS was 97·9% (95% CI 94·9-99·1) and 2-year overall survival was 98·8% (95% CI 96·2-99·6) for the 248 patients with TOP2A-non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most
Prime-boost vaccination with plasmid and adenovirus gene vaccines control HER2/neu+ metastatic breast cancer in mice.

PubMed

Wang, Xiaoyan; Wang, Jian-Ping; Rao, Xiao-Mei; Price, Janet E; Zhou, Heshan S; Lachman, Lawrence B

2005-01-01

Once metastasis has occurred, the possibility of completely curing breast cancer is unlikely, particularly for the 30 to 40% of cancers overexpressing the gene for HER2/neu. A vaccine targeting p185, the protein product of the HER2/neu gene, could have therapeutic application by controlling the growth and metastasis of highly aggressive HER2/neu+ cells. The purpose of this study was to determine the effectiveness of two gene vaccines targeting HER2/neu in preventive and therapeutic tumor models. The mouse breast cancer cell line A2L2, which expresses the gene for rat HER2/neu and hence p185, was injected into the mammary fat pad of mice as a model of solid tumor growth or was injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis virus genes and the gene for rat HER2/neu, and Adeno-neu, an E1,E2a-deleted adenovirus also containing the gene for rat HER2/neu, were tested as preventive and therapeutic vaccines. Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells significantly inhibited the growth of the cells injected into the mammary fat or intravenously. Vaccination 2 days after tumor challenge with either vaccine was ineffective in both tumor models. However, therapeutic vaccination in a prime-boost protocol with SINCP-neu followed by Adeno-neu significantly prolonged the overall survival rate of mice injected intravenously with the tumor cells. Naive mice vaccinated using the same prime-boost protocol demonstrated a strong serum immunoglobulin G response and p185-specific cellular immunity, as shown by the results of ELISPOT (enzyme-linked immunospot) analysis for IFNgamma. We report herein that vaccination of mice with a plasmid gene vaccine and an adenovirus gene vaccine, each containing the gene for HER2/neu, prevented growth of a HER2/neu-expressing breast cancer cell line injected into the mammary fat pad or intravenously. Sequential administration of the vaccines in a prime-boost protocol was
Dysregulation of metabolic-associated pathways in muscle of breast cancer patients: preclinical evaluation of interleukin-15 targeting fatigue.

PubMed

Bohlen, Joseph; McLaughlin, Sarah L; Hazard-Jenkins, Hannah; Infante, Aniello M; Montgomery, Cortney; Davis, Mary; Pistilli, Emidio E

2018-03-26

Breast cancer patients report a perception of increased muscle fatigue, which can persist following surgery and standardized therapies. In a clinical experiment, we tested the hypothesis that pathways regulating skeletal muscle fatigue are down-regulated in skeletal muscle of breast cancer patients and that different muscle gene expression patterns exist between breast tumour subtypes. In a preclinical study, we tested the hypothesis that mammary tumour growth in mice induces skeletal muscle fatigue and that overexpression of the cytokine interleukin-15 (IL-15) can attenuate mammary tumour-induced muscle fatigue. Early stage non-metastatic female breast cancer patients (n = 14) and female non-cancer patients (n = 6) provided a muscle biopsy of the pectoralis major muscle during mastectomy, lumpectomy, or breast reconstruction surgeries. The breast cancer patients were diagnosed with either luminal (ER + /PR + , n = 6), triple positive (ER + /PR + /Her2/neu + , n = 5), or triple negative (ER - /PR - /Her2/neu - , n = 3) breast tumours and were being treated with curative intent either with neoadjuvant chemotherapy followed by surgery or surgery followed by standard post-operative therapy. Biopsies were used for RNA-sequencing to compare the skeletal muscle gene expression patterns between breast cancer patients and non-cancer patients. The C57BL/6 mouse syngeneic mammary tumour cell line, E0771, was used to induce mammary tumours in immunocompetent mice, and isometric muscle contractile properties and fatigue properties were analysed following 4 weeks of tumour growth. RNA-sequencing and subsequent bioinformatics analyses revealed a dysregulation of canonical pathways involved in oxidative phosphorylation, mitochondrial dysfunction, peroxisome proliferator-activated receptor signalling and activation, and IL-15 signalling and production. In a preclinical mouse model of breast cancer, the rate of muscle fatigue was greater in mice exposed to mammary tumour
Concordance Between FISH Analysis of Her-2/Neu Gene in Breast Duct Carcinoma and Corresponding Axillary Nodal Metastases: Egyptian National Cancer Institute Experience.

PubMed

Badawy, Omnia M; Hassan, Hannan; ELBakey, Heba A; Mosaad, Maha

2018-05-10

Breast cancer is a major health problem in Egypt. Her-2/Neu gene is routinely assessed for all breast cancer patients primarily by immunohistochemistry. At National Cancer Institute (NCI), Cairo University, Flourescence In Situ hybridization (FISH) analysis of Her-2/Neu gene is carried out for Her-2/Neu score 2 and for some cases of score 3 (particularly those assessed outside NCI). The test is performed essentially on the primary tumor. However, some situations require testing on corresponding lymph node metastases. There is a debate about the concordance between Her-2/Neu status in the primary tumor and synchronous lymph node metastases in various studies. The aim of this study was to test for the concordance between Her-2/Neu status in the primary breast tumor and corresponding axillary nodal metastases. This is a retrospective study in which FISH analysis of Her-2/Neu was carried out simultaneously on archived material of 50 cases previously diagnosed as invasive duct carcinoma and the corresponding nodal metastases from the Pathology Department, NCI. There was complete concordance between Her-2 status in the primary tumor and the corresponding axillary lymph node metastatic deposits in which Her-2 was amplified in 44% of the studied cohort of Egyptian patients. Her-2/Neu gene assessed by FISH analysis on synchronous lymph node metastases is strongly correlated with the primary tumor. Hence, it is justified to carry out the Her-2/Neu test on synchronous lymph nodes to decide on whether to carry out anti-Her-2/Neu target therapy. Further studies on other metastatic sites is recommended.
Silica-gold nanoshells as potential intraoperative molecular probes for HER2-overexpression in ex vivo breast tissue using near-infrared reflectance confocal microscopy.

PubMed

Bickford, Lissett R; Agollah, Germaine; Drezek, Rebekah; Yu, Tse-Kuan

2010-04-01

Obtaining negative margins is critical for breast cancer patients undergoing conservation therapy in order to reduce the reemergence of the original cancer. Currently, breast cancer tumor margins are examined in a pathology lab either while the patient is anesthetized or after the surgical procedure has been terminated. These current methods often result in cancer cells present at the surgical resection margin due to inadequate margin assessment at the point of care. Due to such limitations evident in current diagnoses, tools for increasing the accuracy and speed of tumor margin detection directly in the operating room are still needed. We are exploring the potential of using a nano-biophotonics system to facilitate intraoperative tumor margin assessment ex vivo at the cellular level. By combining bioconjugated silica-based gold nanoshells, which scatter light in the near-infrared, with a portable FDA-approved reflectance confocal microscope, we first validate the use of gold nanoshells as effective reflectance-based imaging probes by evaluating the contrast enhancement of three different HER2-overexpressing cell lines. Additionally, we demonstrate the ability to detect HER2-overexpressing cells in human tissue sections within 5 min of incubation time. This work supports the use of targeted silica-based gold nanoshells as potential real-time molecular probes for HER2-overexpression in human tissue.
Boron Neutron Capture Therapy for HER2+ breast cancers: A feasibility study evaluating BNCT for potential role in breast conservation therapies

NASA Astrophysics Data System (ADS)

Jenkins, Peter Anthony

A novel Boron Neutron Capture Therapy (BNCT) regimen for the treatment of HER2+ breast cancers has been proposed as an alternative to whole breast irradiation for breast conservation therapy patients. The proposed therapy regimen is based on the assumed production of boron delivery agents that would be synthesized from compounds of Trastuzumab (Herceptin ®) and oligomeric phosphate diesters (OPDs). The combination of the anti-HER2 monoclonal antibody and the high boron loading capability of OPDs has led to the assumption that boron could be delivered to the HER2+ cancer cells at Tumor to Healthy Tissue ratios (T:H) of up to 35:1 and boron concentrations above 50 μg/g. This significantly increased boron delivery efficiency has opened new BNCT possibilities. This proof of concept study examined treatment parameters derived as the results in previous efforts in the context of patient-specific geometry and compared calculated dose results to those observed during actual patient therapy. These results were based on dose calculations performed with a set of calculated Kerma coefficients derived from tissues specific to the regions of interest for breast cancer. A comparison was made of the dose to the tumor region, the patient's skin, and the peripheral organs. The results of this study demonstrated that, given the performance of the proposed boron delivery agent, the BNCT treatment regimen is feasible. The feasibility is based on the findings that the equivalent dose could be delivered to the treatment volume with less dose to the skin and peripheral organs. This is anticipated to improve the treatment outcomes by maintaining local control of tumor cells while reducing dose to healthy tissues.
Mouse mammary tumour virus (MMTV) and human breast cancer with neuroendocrine differentiation.

PubMed

Js, Lawson; Cc, Ngan; Wk, Glenn; Dd, Tran

2017-01-01

Mouse mammary tumour viruses (MMTVs) may have a role in a subset of human breast cancers. MMTV positive human breast cancers have similar histological characteristics to neuroendocrine breast cancers and to MMTV positive mouse mammary tumours. The purpose of this study was to investigate the expression of neuroendocrine biomarkers - synaptophysin and chromogranin, to determine if these histological characteristics and biomarker expression were due to the influences of MMTV. Immunohistochemistry analyses to identify synaptophysin and chromogranin were conducted on a series of human breast cancers in which (i) MMTV had been previously identified and had similar histological characteristics to MMTV positive mouse mammary tumours and (ii) MMTV positive mouse mammary tumours. The expression of synaptophysin and chromogranin in MMTV positive mouse mammary tumors were all positive (7 of 7 specimens - 100% positive). The expression of synaptophysin and chromogranin in MMTV positive human breast cancers was much less prevalent (3 of 22 - 14%). There was no expression of synaptophysin and chromogranin in the normal breast tissue control specimens. It is not possible to draw any firm conclusions from these observations. However, despite the small numbers of MMTV positive mouse mammary tumours in this study, the universal expression in these specimens of synaptophysin and chromogranin proteins is striking. This pattern of synaptophysin and chromogranin expression is very different from their expression in MMTV positive human breast cancers. The reason for these differences is not known. The high prevalence of positive expression of synaptophysin and chromogranin in MMTV positive mouse mammary tumours and low expression of synaptophysin and chromogranin in MMTV positive human breast cancers indicates that MMTV is not usually associated with neuroendocrine human breast cancers.
Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)†.

PubMed

von Minckwitz, G; Loibl, S; Untch, M; Eidtmann, H; Rezai, M; Fasching, P A; Tesch, H; Eggemann, H; Schrader, I; Kittel, K; Hanusch, C; Huober, J; Solbach, C; Jackisch, C; Kunz, G; Blohmer, J U; Hauschild, M; Fehm, T; Nekljudova, V; Gerber, B

2014-12-01

The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms. With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. NCT 00567554, www.clinicaltrials.gov. © The Author 2014. Published by Oxford
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

PubMed

Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

2016-04-01

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were
Fully Automated Fluorescent in situ Hybridization (FISH) Staining and Digital Analysis of HER2 in Breast Cancer: A Validation Study

PubMed Central

van der Logt, Elise M. J.; Kuperus, Deborah A. J.; van Setten, Jan W.; van den Heuvel, Marius C.; Boers, James. E.; Schuuring, Ed; Kibbelaar, Robby E.

2015-01-01

HER2 assessment is routinely used to select patients with invasive breast cancer that might benefit from HER2-targeted therapy. The aim of this study was to validate a fully automated in situ hybridization (ISH) procedure that combines the automated Leica HER2 fluorescent ISH system for Bond with supervised automated analysis with the Visia imaging D-Sight digital imaging platform. HER2 assessment was performed on 328 formalin-fixed/paraffin-embedded invasive breast cancer tumors on tissue microarrays (TMA) and 100 (50 selected IHC 2+ and 50 random IHC scores) full-sized slides of resections/biopsies obtained for diagnostic purposes previously. For digital analysis slides were pre-screened at 20x and 100x magnification for all fluorescent signals and supervised-automated scoring was performed on at least two pictures (in total at least 20 nuclei were counted) with the D-Sight HER2 FISH analysis module by two observers independently. Results were compared to data obtained previously with the manual Abbott FISH test. The overall agreement with Abbott FISH data among TMA samples and 50 selected IHC 2+ cases was 98.8% (κ = 0.94) and 93.8% (κ = 0.88), respectively. The results of 50 additionally tested unselected IHC cases were concordant with previously obtained IHC and/or FISH data. The combination of the Leica FISH system with the D-Sight digital imaging platform is a feasible method for HER2 assessment in routine clinical practice for patients with invasive breast cancer. PMID:25844540
Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial)

ClinicalTrials.gov

2018-06-19

Breast Adenocarcinoma; Estrogen Receptor and/or Progesterone Receptor Positive; HER2/Neu Negative; Stage IA Breast Cancer AJCC v7; Stage IB Breast Cancer AJCC v7; Stage IIA Breast Cancer AJCC v6 and v7; Stage IIB Breast Cancer AJCC v6 and v7; Stage IIIB Breast Cancer AJCC v7

p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial.

PubMed

Sperinde, Jeff; Huang, Weidong; Vehtari, Aki; Chenna, Ahmed; Kellokumpu-Lehtinen, Pirkko-Liisa; Winslow, John; Bono, Petri; Lie, Yolanda S; Petropoulos, Christos J; Weidler, Jodi; Joensuu, Heikki

2018-03-13

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log 10 (p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab ( N = 95), increasing log 10 (p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-7. ©2018 AACR. ©2018 American Association for Cancer Research.
CTLs directed against HER2 specifically cross-react with HER3 and HER4.

PubMed

Conrad, Heinke; Gebhard, Kerstin; Krönig, Holger; Neudorfer, Julia; Busch, Dirk H; Peschel, Christian; Bernhard, Helga

2008-06-15

The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2(369-377) epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN-gamma treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2(369-377)-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3(356-364) and HER4(361-369) were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of "double" or "triple targeting" the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.
A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

PubMed

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Marchand, Loïc Le; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2011-10-30

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

PubMed Central

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Le Marchand, Loïc; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2012-01-01

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. PMID:22037553
Biopsy variability of lymphocytic infiltration in breast cancer subtypes and the ImmunoSkew score

NASA Astrophysics Data System (ADS)

Khan, Adnan Mujahid; Yuan, Yinyin

2016-11-01

The number of tumour biopsies required for a good representation of tumours has been controversial. An important factor to consider is intra-tumour heterogeneity, which can vary among cancer types and subtypes. Immune cells in particular often display complex infiltrative patterns, however, there is a lack of quantitative understanding of the spatial heterogeneity of immune cells and how this fundamental biological nature of human tumours influences biopsy variability and treatment resistance. We systematically investigate biopsy variability for the lymphocytic infiltrate in 998 breast tumours using a novel virtual biopsy method. Across all breast cancers, we observe a nonlinear increase in concordance between the biopsy and whole-tumour score of lymphocytic infiltrate with increasing number of biopsies, yet little improvement is gained with more than four biopsies. Interestingly, biopsy variability of lymphocytic infiltrate differs considerably among breast cancer subtypes, with the human epidermal growth factor receptor 2-positive (HER2+) subtype having the highest variability. We subsequently identify a quantitative measure of spatial variability that predicts disease-specific survival in HER2+ subtype independent of standard clinical variables (node status, tumour size and grade). Our study demonstrates how systematic methods provide new insights that can influence future study design based on a quantitative knowledge of tumour heterogeneity.
Follistatin is a metastasis suppressor in a mouse model of HER2-positive breast cancer.

PubMed

Seachrist, Darcie D; Sizemore, Steven T; Johnson, Emhonta; Abdul-Karim, Fadi W; Weber Bonk, Kristen L; Keri, Ruth A

2017-06-05

Follistatin (FST) is an intrinsic inhibitor of activin, a member of the transforming growth factor-β superfamily of ligands. The prognostic value of FST and its family members, the follistatin-like (FSTL) proteins, have been studied in various cancers. However, these studies, as well as limited functional analyses of the FSTL proteins, have yielded conflicting results on the role of these proteins in disease progression. Furthermore, very few have been focused on FST itself. We assessed whether FST may be a suppressor of tumorigenesis and/or metastatic progression in breast cancer. Using publicly available gene expression data, we examined the expression patterns of FST and INHBA, a subunit of activin, in normal and cancerous breast tissue and the prognostic value of FST in breast cancer metastases, recurrence-free survival, and overall survival. The functional effects of activin and FST on in vitro proliferation, migration, and invasion of breast cancer cells were also examined. FST overexpression in an autochthonous mouse model of breast cancer was then used to assess the in vivo impact of FST on metastatic progression. Examination of multiple breast cancer datasets revealed that FST expression is reduced in breast cancers compared with normal tissue and that low FST expression predicts increased metastasis and reduced overall survival. FST expression was also reduced in a mouse model of HER2/Neu-induced metastatic breast cancer. We found that FST blocks activin-induced breast epithelial cell migration in vitro, suggesting that its loss may promote breast cancer aggressiveness. To directly determine if FST restoration could inhibit metastatic progression, we transgenically expressed FST in the HER2/Neu model. Although FST had no impact on tumor initiation or growth, it completely blocked the formation of lung metastases. These data indicate that FST is a bona fide metastasis suppressor in this mouse model and support future efforts to develop an FST mimetic to
Mucinous cystadenocarcinoma of the breast with amplification of the HER2-gene confirmed by FISH: The first case reported.

PubMed

Petersson, Fredrik; Pang, Brendan; Thamboo, Thomas P; Putti, Thomas Choudary

2010-06-01

We present the first case of a primary mucinous cystadenocarcinoma of the breast that, in addition to the characteristic immunophenotype (CK7(+), CK20(-), ER(-), PR(-), and cdx2(-)), showed a strong membranous HER2-protein expression and HER2-gene amplification documented by fluorescence in situ hybridization. Copyright 2010 Elsevier Inc. All rights reserved.
Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment.

PubMed

Panagopoulos, Vasilios; Leach, Damien A; Zinonos, Irene; Ponomarev, Vladimir; Licari, Giovanni; Liapis, Vasilios; Ingman, Wendy V; Anderson, Peter; DeNichilo, Mark O; Evdokiou, Andreas

2017-04-01

Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.
Budget impact analysis of everolimus for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer in the United States.

PubMed

Xie, Jipan; Diener, Melissa; De, Gourab; Yang, Hongbo; Wu, Eric Q; Namjoshi, Madhav

2013-01-01

To estimate the budget impact of everolimus as the first and second treatment option after letrozole or anastrozole (L/A) failure for post-menopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC). Pharmacy and medical budget impacts (2011 USD) were estimated over the first year of everolimus use in HR+, HER2- ABC from a US payer perspective. Epidemiology data were used to estimate target population size. Pre-everolimus entry treatment options included exemestane, fulvestrant, and tamoxifen. Pre- and post-everolimus entry market shares were estimated based on market research and assumptions. Drug costs were based on wholesale acquisition cost. Patients were assumed to be on treatment until progression or death. Annual medical costs were calculated as the average of pre- and post-progression medical costs weighted by the time in each period, adjusted for survival. One-way and two-way sensitivity analyses were conducted to assess the model robustness. In a hypothetical 1,000,000 member plan, 72 and 159 patients were expected to be candidates for everolimus treatment as first and second treatment option, respectively, after L/A failure. The total budget impact for the first year post-everolimus entry was $0.044 per member per month [PMPM] (pharmacy budget: $0.058 PMPM; medical budget: -$0.014 PMPM), assuming 10% of the target population would receive everolimus. The total budget impacts for the first and second treatment options after L/A failure were $0.014 PMPM (pharmacy budget: $0.018; medical budget: -$0.004) and $0.030 PMPM (pharmacy budget: $0.040; medical budget: -$0.010), respectively. Results remained robust in sensitivity analyses. Assumptions about some model input parameters were necessary and may impact results. Increased pharmacy costs for HR+, HER2- ABC following everolimus entry are expected to be partially offset by reduced medical service costs. Pharmacy and total
MK2206 in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

ClinicalTrials.gov

2017-08-01

Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Progesterone Receptor Positive; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer.

PubMed

Youngblood, Victoria M; Kim, Laura C; Edwards, Deanna N; Hwang, Yoonha; Santapuram, Pranav R; Stirdivant, Steven M; Lu, Pengcheng; Ye, Fei; Brantley-Sieders, Dana M; Chen, Jin

2016-04-01

Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2(+) subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand-independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1-null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1-depleted and EPHA2-overexpressing tumor allografts in vivo Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825-36. ©2016 AACR. ©2016 American Association for Cancer Research.
Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-05

Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer
A gene expression profile indicative of early stage HER2 targeted therapy response.

PubMed

O'Neill, Fiona; Madden, Stephen F; Clynes, Martin; Crown, John; Doolan, Padraig; Aherne, Sinéad T; O'Connor, Robert

2013-07-01

Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
Validation of a new classifier for the automated analysis of the human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer specimens

PubMed Central

2013-01-01

Amplification of the human epidermal growth factor receptor 2 (HER2) is a prognostic marker for poor clinical outcome and a predictive marker for therapeutic response to targeted therapies in breast cancer patients. With the introduction of anti-HER2 therapies, accurate assessment of HER2 status has become essential. Fluorescence in situ hybridization (FISH) is a widely used technique for the determination of HER2 status in breast cancer. However, the manual signal enumeration is time-consuming. Therefore, several companies like MetaSystem have developed automated image analysis software. Some of these signal enumeration software employ the so called “tile-sampling classifier”, a programming algorithm through which the software quantifies fluorescent signals in images on the basis of square tiles of fixed dimensions. Considering that the size of tile does not always correspond to the size of a single tumor cell nucleus, some users argue that this analysis method might not completely reflect the biology of cells. For that reason, MetaSystems has developed a new classifier which is able to recognize nuclei within tissue sections in order to determine the HER2 amplification status on nuclei basis. We call this new programming algorithm “nuclei-sampling classifier”. In this study, we evaluated the accuracy of the “nuclei-sampling classifier” in determining HER2 gene amplification by FISH in nuclei of breast cancer cells. To this aim, we randomly selected from our cohort 64 breast cancer specimens (32 nonamplified and 32 amplified) and we compared results obtained through manual scoring and through this new classifier. The new classifier automatically recognized individual nuclei. The automated analysis was followed by an optional human correction, during which the user interacted with the software in order to improve the selection of cell nuclei automatically selected. Overall concordance between manual scoring and automated nuclei-sampling analysis was 98
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

PubMed

Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

2015-01-01

A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to
Talazoparib and HSP90 Inhibitor AT13387 in Treating Patients With Metastatic Advanced Solid Tumor or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple Negative Breast Cancer

ClinicalTrials.gov

2016-07-22

Adult Solid Neoplasm; Estrogen Receptor Negative; Fallopian Tube Serous Neoplasm; HER2/Neu Negative; Ovarian Serous Adenocarcinoma; Ovarian Serous Tumor; Primary Peritoneal Serous Adenocarcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Triple-Negative Breast Carcinoma
Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial.

PubMed

Rugo, Hope S; Seneviratne, Lasika; Beck, J Thaddeus; Glaspy, John A; Peguero, Julio A; Pluard, Timothy J; Dhillon, Navneet; Hwang, Leon Christopher; Nangia, Chaitali; Mayer, Ingrid A; Meiller, Timothy F; Chambers, Mark S; Sweetman, Robert W; Sabo, J Randy; Litton, Jennifer K

2017-05-01

Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer. This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093. Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently
Aspiration cytology of extramammary tumours metastatic to the breast.

PubMed

Handa, Uma; Chhabra, Seema; Mohan, Harsh

2007-10-01

This study was undertaken to highlight the use of fine needle aspiration cytology (FNAC) to distinguish tumours metastatic to the breast from primary breast malignancies. A total of 1866 fine needle aspirates of the breast were performed during a period of 7 years. Three hundred and fourteen cases of breast malignancies were diagnosed and 5 (1.5%) out of these cases were metastatic in origin. The metastatic tumors included, 2 cases of malignant melanoma (chest wall and left arm), 1 case each of haematolymphoid malignancy, adenocarcinoma of the ovary, and squamous cell carcinoma (left leg). FNA diagnosis of metastasis to the breast is essential in order to avoid unnecessary mastectomy and to ensure appropriate chemotherapy and/or irradiation treatment.
Outcomes by Tumor Subtype and Treatment Pattern in Women With Small, Node-Negative Breast Cancer: A Multi-Institutional Study

PubMed Central

Vaz-Luis, Ines; Ottesen, Rebecca A.; Hughes, Melissa E.; Mamet, Rizvan; Burstein, Harold J.; Edge, Stephen B.; Gonzalez-Angulo, Ana M.; Moy, Beverly; Rugo, Hope S.; Theriault, Richard L.; Weeks, Jane C.; Winer, Eric P.; Lin, Nancy U.

2014-01-01

Purpose Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients. Patients and Methods This was a prospective cohort study within the National Comprehensive Cancer Network Database that included 4,113 women with T1a,bN0M0 breast cancer treated between 2000 and 2009. Tumors were grouped by size (T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. Results Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241). Conclusion Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks. PMID:24888816
Cardiotoxicity of novel HER2-targeted therapies.

PubMed

Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

2013-08-01

Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

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