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  1. Quantum dots-based double-color imaging of HER2 positive breast cancer invasion

    SciTech Connect

    Liu, Xiu-Li; Peng, Chun-Wei; Chen, Chuang; Yang, Xue-Qin; Hu, Ming-Bai; Xia, He-Shun; Liu, Shao-Ping; and others

    2011-06-10

    Highlights: {yields} HER2 level is closely related to the biologic behaviors of breast cancer cells. {yields} A new method to simultaneously image HER2 and type IV collagen was established. {yields} HER2 status and type IV collagen degradation predict breast cancer invasion. {yields} The complex interactions between tumor and its environment were revealed. -- Abstract: It has been well recognized that human epidermal growth factor receptor 2 (HER2) level in breast cancer (BC) is closely related to the malignant biologic behaviors of the tumor, including invasion and metastasis. Yet, there has been a lack of directly observable evidence to support such notion. Here we report a quantum dots (QDs)-based double-color imaging technique to simultaneously show the HER2 level on BC cells and the type IV collagen in the tumor matrix. In benign breast tumor, the type IV collagen was intact. With the increasing of HER2 expression level, there has been a progressive decrease in type IV collagen around the cancer nest. At HER2 (3+) expression level, there has virtually been a total destruction of type IV collagen. Moreover, HER2 (3+) BC cells also show direct invasion into the blood vessels. This novel imaging method provides direct observable evidence to support the theory that the HER2 expression level is directly related to BC invasion.

  2. 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

  3. HER2-positive mucinous adenocarcinomas of the ovary have an expansile invasive pattern associated with a favorable prognosis.

    PubMed

    Kim, Sang Kyum; Cho, Nam Hoon

    2014-01-01

    Ovarian primary mucinous adenocarcinomas (MACs) are refractory to conventional therapy. Biomarkers for ovarian MAC could facilitate prognosis and targeted therapy, but are not currently available. The expression of human epidermal growth factor 2 (HER-2) has been linked to enhanced survival of MAC patients and may hold potential as a biomarker, but this potential has not been sufficiently investigated. In this study, we examined the clinicopathological features of 46 cases of MAC and 36 cases of patients with mucinous borderline tumors (MBTs). The expression of estrogen receptors (ER), progesterone receptors (PR), and HER2 were measured by immunohistochemistry and fluorescent in situ hybridization (FISH). Next, we compared the clinicopathological characteristics according to the HER2 expression profile. MBTs of the endocervical type tended to have simultaneous ER and PR expression (P = 0.0028) while MACs rarely showed ER or PR expression. HER2 expression was observed in 14 out of the 46 MACs (37.84%) and in none of the MBTs (P = 0.0002). HER2-positive MACs occurred approximately 10 years earlier than HER2-negative MACs (35.21 ± 4.768 years compared to 46.78 ± 1.977 years; P = 0.0105). All HER2-positive MACs demonstrated an expansile invasive pattern, while all MACs with infiltrative invasion pattern were HER2-negative (P = 0.0406). Kaplan-Meier survival analysis demonstrated a tendency for improved overall survival in HER2-positive MACs compared to HER2-negative MACs (P = 0.0389). In conclusion, HER2 overexpression in ovarian MACs is associated with an expansile, but not an infiltrative, invasion pattern and a favorable prognosis. Therefore, we suggest that HER2 may be a practical marker for histopathological categorization and a prognostic marker in ovarian MACs. PMID:25120802

  4. HER2 intratumoral heterogeneity analyses by concurrent HER2 gene and protein assessment for the prognosis of HER2 negative invasive breast cancer patients.

    PubMed

    Kurozumi, Sasagu; Padilla, Mary; Kurosumi, Masafumi; Matsumoto, Hiroshi; Inoue, Kenichi; Horiguchi, Jun; Takeyoshi, Izumi; Oyama, Tetsunari; Ranger-Moore, Jim; Allred, D Craig; Dennis, Eslie; Nitta, Hiroaki

    2016-07-01

    HER2 gene-protein assay (GPA) is a new method for the simultaneous evaluation of HER2 immunohistochemistry (IHC) and HER2 dual in situ hybridization (DISH) on single tissue sections of breast cancer. We investigated the presence of HER2 gene and protein discrepancy and HER2-heterogeneity using HER2-GPA. HER2 status was analyzed for the correlation between the presence of HER2-heterogeneity and patient prognosis. Consecutive 280 invasive breast cancer were examined. Statuses of HER2 protein and gene were evaluated in whole tumor sections of HER2 GPA slides. HER2 protein and gene combination patterns were classified to six phenotypic and genotypic types for each case, as well as at individual cell levels: (A) IHC and DISH positive; (B) IHC positive and DISH negative; (C) IHC equivocal and DISH positive; (D) IHC equivocal and DISH negative; (E) IHC negative and DISH positive; and (F) IHC and DISH negative. The presence of HER2-heterogeneity was determined by the existence of at least two of six types within one tumor. HER2-IHC positive patients had significantly worse survival than IHC negative patients and HER2-DISH positive patients had significantly worse survival than DISH negative patients. HER2 IHC negative and DISH positive patients had significantly worse recurrence-free survival than IHC and DISH negative patients. In the HER2 IHC and DISH negative group, the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Notably, among triple negative breast cancer (TNBC), the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Our study suggests that the presence of HER2-heterogeneity might be a prognostic factor in HER2 negative breast cancer patients, especially in TNBC. PMID:27318853

  5. The positive is inside the negative: HER2-negative tumors can express the HER2 intracellular domain and present a HER2-positive phenotype.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Corrêa, Stephany; Binato, Renata; Lemos, Gabriela Ferreira; Herrera, Ana Cristina da Silva do Amaral; Seixas, Teresa Fernandes; Cecchini, Rubens; Abdelhay, Eliana

    2015-02-01

    Overexpression of human epithelial growth factor receptor 2 (HER2) is a poor prognostic factor in breast cancer. HER2 is a transmembrane receptor comprising an extracellular domain (ECD), a single transmembrane domain, and an intracellular domain (ICD) with tyrosine-kinase activity. Receptor dimerization triggers pivotal effector pathways in cancer, such as phosphatidylinositol 3-kinase (PI3K) signaling. Currently, screening of HER2 in breast tumors for prognostic and therapeutic purposes involves immunohistochemical (IHC) phenotyping for the ECD, in which tumors with IHC scores below 2+ are reported as HER2-negative. We used a label-free liquid chromatography-mass spectrometry (LC-MS) proteomic approach to compare plasma samples from patients with HER2-positive breast tumors and patients with HER2-negative tumors. Patients with HER2-negative tumors expressed higher circulating levels of calpain-10 than patients with HER2-positive tumors. Calpains cleave HER2, releasing its ECD and transforming phenotypically positive tumors into phenotypically negative tumors. Therefore, we investigated the expression of the ICD in HER2-negative samples that overexpressed calpain-10. We found that 16% of HER2-negative tumors were positive for HER2-ICD, which was associated with circulating HER2-ECD. HER2 gene amplification was also observed in some HER2-negative tumors. Positive staining for the PI3K pathway was observed in the HER2-negative, ICD-positive tumors, similar to the HER2-positive cohort. Microarray analysis revealed that HER2-negative, ICD-positive samples clustered between HER2-positive tumors and triple-negative tumors. Survival analysis revealed that outcome in women with HER2-negative, ICD-positive tumors was better than in women bearing HER2-negative, ICD-negative (triple negative) tumors but was quite similar to HER2-positive tumors and worse than women with luminal A tumors. Moreover, in vitro analyses revealed that MDA-MB 231, a triple negative cell line

  6. Association between Ultrasound Features and the 21-Gene Recurrence Score Assays in Patients with Oestrogen Receptor-Positive, HER2-Negative, Invasive Breast Cancer.

    PubMed

    Chae, Eun Young; Moon, Woo Kyung; Kim, Hak Hee; Kim, Won Hwa; Cha, Joo Hee; Shin, Hee Jung; Choi, Woo Jung; Han, Wonshik; Noh, Dong-Young; Lee, Sae Byul; Ahn, Sei Hyun

    2016-01-01

    A multigene expression assay corresponds to the likelihood of breast cancer recurrence after the initial diagnosis and can be used to guide the decision for additional chemotherapy. However, only few studies have investigated the associations between the imaging features of breast cancer and the results of multigene expression assays. Our study was to identify the relationship between imaging features on ultrasound (US) and the recurrence score (RS) on a 21-gene expression assay in patients with oestrogen receptor (ER)-positive, HER2-negative breast cancer. 267 patients with ER-positive, HER-negative invasive breast cancer who underwent examinations using US and Oncotype DX assay were included. US images were independently reviewed by dedicated breast radiologists who were blind to the RS. Tumour roundness was measured using a laboratory-developed software program. The pathological data were reviewed, including immunohistochemistry results. Univariate analysis was performed to assess the associations between the RS and each variable. Multiple logistic regression analysis was used to identify independent predictors of high RS. Of 267 patients, 147 (55%) had low, 96 (36%) intermediate, and 24 (9%) had high RS. According to the univariate analysis, parallel orientation, presence of calcification in the mass, and tumour roundness were positively associated with high RS. Multiple logistic regression analysis showed that parallel orientation (OR = 5.53) and tumour roundness (OR = 1.70 per 10 increase) were associated with high RS. Parallel orientation and tumour roundness are independent variables that may predict high RS in patients with ER-positive, HER2-negative breast cancer. PMID:27362843

  7. Association between Ultrasound Features and the 21-Gene Recurrence Score Assays in Patients with Oestrogen Receptor-Positive, HER2-Negative, Invasive Breast Cancer

    PubMed Central

    Chae, Eun Young; Kim, Won Hwa; Cha, Joo Hee; Shin, Hee Jung; Choi, Woo Jung; Han, Wonshik; Noh, Dong-Young; Lee, Sae Byul; Ahn, Sei Hyun

    2016-01-01

    A multigene expression assay corresponds to the likelihood of breast cancer recurrence after the initial diagnosis and can be used to guide the decision for additional chemotherapy. However, only few studies have investigated the associations between the imaging features of breast cancer and the results of multigene expression assays. Our study was to identify the relationship between imaging features on ultrasound (US) and the recurrence score (RS) on a 21-gene expression assay in patients with oestrogen receptor (ER)-positive, HER2-negative breast cancer. 267 patients with ER-positive, HER-negative invasive breast cancer who underwent examinations using US and Oncotype DX assay were included. US images were independently reviewed by dedicated breast radiologists who were blind to the RS. Tumour roundness was measured using a laboratory-developed software program. The pathological data were reviewed, including immunohistochemistry results. Univariate analysis was performed to assess the associations between the RS and each variable. Multiple logistic regression analysis was used to identify independent predictors of high RS. Of 267 patients, 147 (55%) had low, 96 (36%) intermediate, and 24 (9%) had high RS. According to the univariate analysis, parallel orientation, presence of calcification in the mass, and tumour roundness were positively associated with high RS. Multiple logistic regression analysis showed that parallel orientation (OR = 5.53) and tumour roundness (OR = 1.70 per 10 increase) were associated with high RS. Parallel orientation and tumour roundness are independent variables that may predict high RS in patients with ER-positive, HER2-negative breast cancer. PMID:27362843

  8. 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

  9. Predicting discordant HER2 results in ipsilateral synchronous invasive breast carcinomas: experience from a single institution.

    PubMed

    Chou, Shaun; Khan, Tayyaba; Mahajan, Hema; Pathmanathan, Nirmala

    2015-12-01

    With the emergence of multiple lines of highly effective Human Epidermal Growth Factor Receptor 2 (HER2) directed therapy, accurate identification of HER2 positive tumour has become a critical aspect in the histopathological analysis of breast cancers. Multifocal invasive breast carcinomas are relatively common, and given the aggressive inherent biology of HER2 positive disease, identification of even small tumours with HER2 positive status may be of importance for treatment planning. There are currently no clear guidelines as to whether all of these foci should be tested for HER2 status. We reviewed the results of 172 patients in whom HER2 in situ hybridisation (ISH) testing was performed on at least two ipsilateral synchronous invasive carcinomas. Discordant results in different invasive foci were relatively uncommon and occurred in only eight (5%) of the 172 patients. This showed a statistically significant correlation with similarly discordant oestrogen receptor (ER) results. In addition HER2 discordance was more likely amongst different tumour foci if these arose in distinct and separate areas of DCIS. An algorithm based on a combination of College of American Pathologists (CAP) recommendation for HER2 testing, differing ER status and background DCIS profile may be useful in detecting these discordant cases. PMID:26517643

  10. HER2-positive metastatic breast cancer: a changing scenario.

    PubMed

    Mustacchi, G; Biganzoli, L; Pronzato, P; Montemurro, F; Dambrosio, M; Minelli, M; Molteni, L; Scaltriti, L

    2015-07-01

    Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic "de novo" HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active. PMID:25748080

  11. HER-2 Positive Breast Cancer - a Mini-Review.

    PubMed

    Asif, Hafiz Muhammad; Sultana, Sabira; Ahmed, Saeed; Akhtar, Naheed; Tariq, Muhammad

    2016-01-01

    Breast cancer is one of among all cancers with increased incidence, high mortality rate, and high economic and social costs. The the most common type of cancer among females worldwide, breast cancer is actually the uncontrolled proliferation of cells which attain malignancy. Recently it has shown that breast cancer contributes 11% among all types of cancer diagnosed globally on an annual basis and it is one of the leading causes of death among women. The human epidermal growth factor receptor 2 (HER-2) is a receptor tyrosine-protein kinase erbB-2 normally involved in the proliferation and division of breast cells. In some abnormal cases the HER2 gene does not work correctly and makes too many copies of itself. HER2-positive (HER2+) breast cancers constitute an aggressive type of breast cancer and tend to grow faster and are more likely to spread. However, therapies that specifically target HER2, such as Herceptin® (traztuzumab), are very effective. HER2 targeted therapies, has significantly improved the therapeutic outcome for patients with HER2 positive breast cancer. PMID:27221828

  12. Active targeting using HER-2-affibody-conjugated nanoparticles enabled sensitive and specific imaging of orthotopic HER-2 positive ovarian tumors.

    PubMed

    Satpathy, Minati; Wang, Liya; Zielinski, Rafal; Qian, Weiping; Lipowska, Malgorzata; Capala, Jacek; Lee, Gee Young; Xu, Hong; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2014-02-12

    Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER-2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery. PMID:24038985

  13. In a cohort of breast cancer screened patients the proportion of HER2 positive cases is lower than that earlier reported and pathological characteristics differ between HER2 3+ and HER2 2+/Her2 amplified cases.

    PubMed

    Giuliani, Silvia; Ciniselli, Chiara Maura; Leonardi, Elena; Polla, Enzo; Decarli, Nicola; Luchini, Claudio; Cantaloni, Chiara; Gasperetti, Fabio; Cazzolli, Daniela; Berlanda, Gabriella; Bernardi, Daniela; Pellegrini, Marco; Triolo, Renza; Ferro, Antonella; Verderio, Paolo; Barbareschi, Mattia

    2016-07-01

    Human epithelial growth factor receptor 2 (HER2) overexpression and/or amplification is of predictive and prognostic value in infiltrating breast carcinoma (IBC). We evaluated the proportion of HER2-positive cases (score 3 overexpression/score 2 plus fluorescence in situ hybridization (FISH) amplification) in a consecutive series of 2163 patients. According to immunohistochemical analysis of HER2 expression, using Herceptest and FDA criteria, 839 cases had score 0, 476 score 1+, 699 score 2+, and 149 score 3+. Of the 699 scoring 2+ cases, 160 (22.88 %) showed Her2 gene amplification by FISH analysis, making a total of 309 (14.28 %) HER2-positive cases. Grade 1 ductal and special type IBC were never HER2 positive, while only three infiltrating lobular carcinomas but a relevant percentage of small IBC were HER2 positive. Of HER2-positive cases, 52.1 % was pT1 and of these, 38.5 % was pT1b or smaller. Logistic regression analysis revealed that estrogen receptor (ER), progesterone receptor (PgR), grade, and pT were significantly associated with HER2 positivity and that HER2 3+ cases were more frequently of higher grade and pT than HER2 2+/Her2 amplified cases. In addition, HER2 3+ cases were more frequently in ER and PgR negative than HER2 2+/Her2 amplified cases. We conclude that the proportion of HER2 positive cases is lower than that reported in older literature and that pathological characteristics differ between HER2 3+ and HER2 2+/Her2 amplified cases. PMID:27097809

  14. Brain metastases in Asian HER2-positive breast cancer patients: anti-HER2 treatments and their impact on survival

    PubMed Central

    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

    2012-01-01

    Background: 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). Methods: 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. Results: 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). Conclusion: 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. PMID:22918394

  15. Characteristics of HER2-positive breast cancer diagnosed following the introduction of universal HER2 testing.

    PubMed

    Pathmanathan, Nirmala; Provan, Pamela J; Mahajan, Hema; Hall, Geoffrey; Byth, Karen; Bilous, A Michael; Balleine, Rosemary L

    2012-12-01

    The aim of this study was to determine the impact of universal HER2 testing on the clinico-pathologic profile of HER2+ breast cancer. Data were extracted from breast cancer pathology reports spanning two periods: before (2003/4, n = 379), and after (2008/9, n = 560) the introduction of universal testing. In 2003/4, 43.3% of breast cancers were tested for HER2 with 16% of tested cases HER2+. In 2008/9, 98.4% of cases were tested with 14.7% HER2+. In 2008/9, HER2+ status was associated with younger age, higher grade, increased tumour size, lymph node involvement, negative oestrogen and/or progesterone receptor status. HER2+ cases diagnosed in 2003/4 were not significantly different in respect of these features. The rate of HER2+ breast cancer amongst screen detected cases in 2008/9 was 8.3%. The phenotype of HER2+ breast cancer was stable following the introduction of universal testing. The overall rate of HER2+ breast cancer was influenced by screen detection. PMID:23099207

  16. Predictive biomarkers in the treatment of HER2-positive breast cancer: an ongoing challenge.

    PubMed

    Triulzi, Tiziana; Bianchi, Giulia Valeria; Tagliabue, Elda

    2016-06-01

    The transmembrane tyrosine kinase receptor HER2 is overexpressed in 20% of invasive breast cancers and is associated with more aggressive disease. Until the advent of targeted agents, HER2 was associated with worse outcome. Trastuzumab, a recombinant humanized anti-HER2 monoclonal antibody, combined with chemotherapy improves disease-free and overall survival in both primary and metastatic tumors and represents a foundation of care for patients with HER2-positive breast cancers. However, a sizeable number of patients do not respond to this reagent, indicating the need for a biomarker able to recognize resistant tumors. Here, we review various studies on mechanisms of action and resistance to trastuzumab that have proven relevant in understanding how tumor care can be tailored to all HER2-positive patients. PMID:27007660

  17. Salivary expression of soluble HER2 in breast cancer patients with positive and negative HER2 status

    PubMed Central

    Laidi, Fatna; Bouziane, Amal; Lakhdar, Amina; Khabouze, Samira; Rhrab, Brahim; Zaoui, Fatima

    2014-01-01

    Background The aim of this study was to investigate the relationship between salivary concentration of the soluble fragment of the HER2 (human epidermal growth factor receptor) protein and its status in mammary tissues. Methods This case-control study was done in 27 breast cancer patients with no visible metastatic disease treated at the gynecology service, Maternity Souissi Hospital, Rabat, Morocco. Two groups were selected, ie, patients with positive and negative HER2 status in mammary tissue. The salivary HER2 protein concentration was assessed by enzyme-linked immunosorbent assay. The salivary HER2 concentration was compared between the HER2-positive and HER2-negative groups using the Mann-Whitney U test. A P-value <0.05 was considered to be statistically significant. Results No statistically significant difference in salivary HER2 protein expression was found between the case and control groups. There was also no significant difference in clinical characteristics according to positive and negative HER2 status (P>0.05), except for the progesterone hormone receptor which was statistically significant in both the case and control groups (P=0.047). Conclusion According to our data, salivary expression of the HER2 receptor may not be a reliable alternative to tissue assessment. PMID:25053886

  18. The role of MAPK signaling pathway in the Her-2-positive meningiomas.

    PubMed

    Wang, Zhaoyin; Wang, Weijia; Xu, Shan; Wang, Shanshan; Tu, Yi; Xiong, Yifeng; Mei, Jinhong; Wang, Chunliang

    2016-08-01

    Meningiomas are common types of adult nerve system tumors. Although most cases are considered benign, due to its high rate of recurrence and easy malignant progression to anaplastic meningioma they present a puzzle for the current treatment. The HER-2 oncogene has important value for meningioma cells development and progression. So far, little is known about the effect on the exact underlying signal pathway and molecular mechanisms of HER-2-positive meningioma cells. The goal of the present study was to determine the effects of HER-2 gene and possible involvement of MAPK signal pathway in human malignant meningioma. We applied q-PCR analysis, immunofluorescence (IF) staining, western blot analysis, animal model, MAPK inhibition, MTT assay and cell invasion analysis for the investigation. The results demonstrated that the downregulation of the expression of HER-2 significantly inhibited cell motility and proliferation of human meningioma cells in vivo. Accordingly, in the HER-2-overexpression meningioma cells with the inhibition of ERK1/2, ERK5, JNK, in the cells with the ERK1/2, ERK5 inhibition, protein expression was markedly suppressed as well as the cell proliferation resistance. No difference was observed in the HER-2-overexpression meningioma cells with the inhibition of JNK. These findings suggest that HER-2 gene can affect the proliferation ability of human meningioma cells in vivo and MAPK signal pathway may contribute to the carcinogenesis and development of human meningiomas combinating with HER-2. PMID:27279438

  19. The role of MAPK signaling pathway in the Her-2-positive meningiomas

    PubMed Central

    Wang, Zhaoyin; Wang, Weijia; Xu, Shan; Wang, Shanshan; Tu, Yi; Xiong, Yifeng; Mei, Jinhong; Wang, Chunliang

    2016-01-01

    Meningiomas are common types of adult nerve system tumors. Although most cases are considered benign, due to its high rate of recurrence and easy malignant progression to anaplastic meningioma they present a puzzle for the current treatment. The HER-2 oncogene has important value for meningioma cells development and progression. So far, little is known about the effect on the exact underlying signal pathway and molecular mechanisms of HER-2-positive meningioma cells. The goal of the present study was to determine the effects of HER-2 gene and possible involvement of MAPK signal pathway in human malignant meningioma. We applied q-PCR analysis, immunofluorescence (IF) staining, western blot analysis, animal model, MAPK inhibition, MTT assay and cell invasion analysis for the investigation. The results demonstrated that the downregulation of the expression of HER-2 significantly inhibited cell motility and proliferation of human meningioma cells in vivo. Accordingly, in the HER-2-overexpression meningioma cells with the inhibition of ERK1/2, ERK5, JNK, in the cells with the ERK1/2, ERK5 inhibition, protein expression was markedly suppressed as well as the cell proliferation resistance. No difference was observed in the HER-2-overexpression meningioma cells with the inhibition of JNK. These findings suggest that HER-2 gene can affect the proliferation ability of human meningioma cells in vivo and MAPK signal pathway may contribute to the carcinogenesis and development of human meningiomas combinating with HER-2. PMID:27279438

  20. Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer.

    PubMed

    Kim, Ji Young; Cho, Youngkwan; Oh, Eunhye; Lee, Nahyun; An, Hyunsook; Sung, Daeil; Cho, Tae-Min; Seo, Jae Hong

    2016-08-28

    HER2-positive breast tumors are known to harbor cancer stem-like cell populations and are associated with an aggressive tumor phenotype and poor clinical outcomes. Disulfiram (DSF), an anti-alcoholism drug, is known to elicit cytotoxicity in many cancer cell types in the presence of copper (Cu). The objective of the present study was to investigate the mechanism of action responsible for the induction of apoptosis by DSF/Cu and its effect on cancer stem cell properties in HER2-positive breast cancers in vitro and in vivo. DSF/Cu treatment induced apoptosis, associated with a marked decrease in HER2, truncated p95HER2, phospho-HER2, HER3, phospho-HER3 and phospho-Akt levels, and p27 nuclear accumulation. This was accompanied by the eradication of cancer stem-like populations, concomitant with the suppression of aldehyde dehydrogenase 1 (ALDH1) activity and mammosphere formation. DSF administration resulted in a significant reduction in tumor growth and an enhancement of apoptosis, as well as HER2 intracellular domain (ICD) and ALDH1A1 downregulation. Our results demonstrate that DSF/Cu induces apoptosis and eliminates cancer stem-like cells via the suppression of HER2/Akt signaling, suggesting that DSF may be potentially effective for the treatment of HER2-positive cancers. PMID:27238567

  1. 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

  2. HER2 and uPAR cooperativity contribute to metastatic phenotype of HER2-positive breast cancer

    PubMed Central

    Chandran, Vineesh Indira; Eppenberger-Castori, Serenella; Venkatesh, Thejaswini; Vine, Kara Lea; Ranson, Marie

    2015-01-01

    Human epidermal growth factor receptor type 2 (HER2)-positive breast carcinoma is highly aggressive and mostly metastatic in nature though curable/manageable in part by molecular targeted therapy. Recent evidence suggests a subtype of cells within HER2-positive breast tumors that concomitantly expresses the urokinase plasminogen activator receptor (uPAR) with inherent stem cell/mesenchymal-like properties promoting tumor cell motility and a metastatic phenotype. This HER-positive/uPAR-positive subtype may be partially responsible for the failure of HER2-targeted treatment strategies. Herein we discuss and substantiate the cumulative preclinical and clinical evidence on HER2-uPAR cooperativity in terms of gene co-amplification and/or mRNA/protein co-overexpression. We then propose a regulatory signaling model that we hypothesize to maintain upregulation and cooperativity between HER2 and uPAR in aggressive breast cancer. An improved understanding of the HER2/uPAR interaction in breast cancer will provide critical biomolecular information that may help better predict disease course and response to therapy. PMID:25897424

  3. Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer

    ClinicalTrials.gov

    2016-02-12

    Tubular Breast Cancer Stage II; Mucinous Breast Cancer Stage II; Breast Cancer Female NOS; Invasive Ductal Breast Cancer; Tubular Breast Cancer Stage III; HER-2 Positive Breast Cancer; Inflammatory Breast Cancer Stage IV; Inflammatory Breast Cancer

  4. HER2 induces cell proliferation and invasion of non-small-cell lung cancer by upregulating COX-2 expression via MEK/ERK signaling pathway

    PubMed Central

    Chi, Feng; Wu, Rong; Jin, Xueying; Jiang, Min; Zhu, Xike

    2016-01-01

    HER2 positivity has been well studied in various cancers, but its importance in non-small-cell lung cancer (NSCLC) is still being explored. In this study, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect HER2 and COX-2 expression in NSCLC tissues. Then, pcDNA3.1-HER2 was used to overexpress HER2, while HER2 siRNA and COX-2 siRNA were used to silence HER2 and COX-2 expression. MTT assay and invasion assay were used to detect the effects of HER2 on cell proliferation and invasion. Our study revealed that HER2 and COX-2 expression were upregulated in NSCLC tissues and HER2 exhibited a significant positive correlation with the levels of COX-2 expression. Overexpression of HER2 evidently elevated COX-2 expression, while silencing of HER2 evidently decreased COX-2 expression. Furthermore, overexpressed HER2 induced the ERK phosphorylation, and this was abolished by the treatment with U0126, a pharmacological inhibitor of MEK, an upstream kinase of ERK. HER2-induced expression and promoter activity of COX-2 were also suppressed by U0126, suggesting that the MEK/ERK signaling pathway regulates COX-2 expression. In addition, HER2 induced activation of AKT signaling pathway, which was reversed by pretreatment with U0126 and COX-2 siRNA. MTT and invasion assays revealed that HER2 induced cell proliferation and invasion that were reversed by pretreatment with U0126 and COX-2 siRNA. In this study, our results demonstrated for the first time that HER2 elevated COX-2 expression through the activation of MEK/ERK pathway, which subsequently induced cell proliferation and invasion via AKT pathway in NSCLC tissues. PMID:27217781

  5. Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy

    PubMed Central

    Cao, Lu; Cai, Gang; Xu, Fei; Yang, Zhao-Zhi; Yu, Xiao-Li; Ma, Jin-Li; Zhang, Qian; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi

    2016-01-01

    Abstract The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2–positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT. Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed. At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor–positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR−/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07–15.35; P = 0.039). Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID:27512838

  6. STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers

    PubMed Central

    Seong, Min-Ki; Seol, Hyesil; Oh, Jeong Su; Kim, Eun-Kyu; Chang, Jong Wook; Hwang, Sang-Gu; Noh, Woo Chul

    2016-01-01

    Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers. PMID:26755645

  7. Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

    PubMed Central

    Lion, Maëva; Harlé, Alexandre; Salleron, Julia; Ramacci, Carole; Campone, Mario; Merlin, Jean-Louis

    2016-01-01

    Human epidermal growth factor 2 (HER2) is overexpressed in 15–20% of breast carcinomas. The overexpression of HER2 was previously associated with a poor prognosis until the development of the first anti-HER2 therapy, trastuzumab, which drastically improves the prognosis of HER2-overexpressing breast cancers. However, its mechanism of action remains not fully understood. Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo. The present study assesses the ability of trastuzumab to inhibit the phosphorylation of the key-proteins of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin and Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways in vitro, in breast cancer cell lines and in tumor biopsies obtained from patients treated with trastuzumab preoperative monotherapy as part of the Unicancer GEP04 RADHER phase II clinical trial. HER2-positive SKBR3 and HER2-negative MCF-7 cell lines were exposed to trastuzumab for 72 h. In total, 41 patients received trastuzumab alone for 6 weeks of preoperative treatment. Biopsies were collected at the baseline and at surgery. A total of 19 pairs of associated baseline and surgery tumor specimens were eligible for protein extraction and comparative phosphoprotein expression analysis, prior to and subsequent to treatment. The expression of phosphoproteins was quantitatively assessed using a multiplex immunoassay. In the SKBR3 cell line, a statistically significant decrease of the expression level of phosphorylated (p-)AKT, p-ribosomal protein S6 kinase B1, p-extracellular signal regulated kinase 1/2 and p-mitogen-activated protein kinase kinase 1 was observed after exposure to trastuzumab. In contrast, no statistically significant variations for levels expression of these phosphoproteins were observed in patients following treatment. The lack of downregulation of PI3K and MAPK pathways could probably

  8. Pertuzumab: a review of its use for first-line combination treatment of HER2-positive metastatic breast cancer.

    PubMed

    McCormack, Paul L

    2013-09-01

    Pertuzumab (Perjeta®) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2-overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer. PMID:23982598

  9. The expanding role of pertuzumab in the treatment of HER2-positive breast cancer

    PubMed Central

    Moya-Horno, I; Cortés, J

    2015-01-01

    Breast cancer tumors that demonstrate gene amplification or overexpression of human epidermal growth factor receptor 2 (HER2) are classified as HER2-positive. They account for approximately 15% of all breast cancers and represent an adverse prognostic factor. Over the past years, many new therapies have become available for the treatment of breast cancer. Particularly, the treatment of patients with HER2-positive breast cancer has developed with the arrival of anti-HER2 targeted therapies that have been proven to increase survival in both the metastatic and early-stage settings of the disease. Trastuzumab, a monoclonal antibody targeting HER2, significantly improves survival in HER2-positive breast cancer. Nevertheless, it is still a challenge to evolve anti-HER2 therapies, as the disease may progress. Pertuzumab inhibits HER2 by binding to a different HER2 epitope than trastuzumab and represents a complementary mechanism of action to trastuzumab. The efficacy and safety of pertuzumab in combination with trastuzumab with or without chemotherapy have been demonstrated in both advanced and early stages of HER2-positive breast cancer. Herein, we review the available data on the use of pertuzumab for the treatment of patients with HER2-positive breast cancer. PMID:26056489

  10. Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule.

    PubMed

    Tolmachev, Vladimir; Orlova, Anna; Pehrson, Rikard; Galli, Joakim; Baastrup, Barbro; Andersson, Karl; Sandström, Mattias; Rosik, Daniel; Carlsson, Jörgen; Lundqvist, Hans; Wennborg, Anders; Nilsson, Fredrik Y

    2007-03-15

    A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression. PMID:17363599

  11. Concomitant Detection of HER2 Protein and Gene Alterations by Immunohistochemistry (IHC) and Silver Enhanced In Situ Hybridization (SISH) Identifies HER2 Positive Breast Cancer with and without Gene Amplification

    PubMed Central

    Varga, Zsuzsanna; Tubbs, Raymond R.; Moch, Holger

    2014-01-01

    Introduction HER2 status assessment became a mandatory test assay in breast cancer, giving prognostic and predictive information including eligibility for adjuvant anti-HER2 therapy. Precise and reliable assessment of HER2 status is therefore of utmost importance. In this study we analyzed breast cancer samples by a novel technology for concomitant detection of the HER2 protein and gene copy number. Methods Tissue microarrays containing 589 invasive breast cancer samples were analyzed with a double immunohistochemistry (IHC) and silver labeled in situ hybridization (SISH) assay simultaneously detecting HER2 protein and gene copy number in the same tumor cells. This bright-field assay was analyzed using scores according to the modified ASCO guidelines and the results were correlated with patient prognosis. Results Overall concordance rate between protein expression and the presence of gene amplification was 98%. Fifty-seven of 60 tumors (95%) with IHC score 3+, 6 of 10 tumors with IHC score 2+ (60%) and only 3 of 519 tumors (0.6%) with IHC score 0/1+ were amplified by SISH. Patients with gene amplification despite IHC score 0/1+ had a tendency for worse overall survival (p = 0.088, reaching nearly statistical significance) compared to IHC score 0/1+ without amplification. In contrast, there was no difference in overall survival in IHC score 3+/2+ tumors with and without gene amplification. Conclusions The novel double IHC and SISH assay for HER2 is efficient in the identification of breast cancer with discordant HER2 protein and HER2 gene status, especially for the prognostically relevant groups of HER2 protein negative tumors with HER2 amplification and HER2 protein positive tumors without HER2 amplification. Breast cancer without HER2 amplification among IHC score 2+/3+ tumors (10% in our cohort) suggests that other mechanisms than gene amplification contribute to protein overexpression in these cells. PMID:25153153

  12. Current and emerging therapies of HER2-positive metastatic breast cancer.

    PubMed

    Hernández-Blanquisett, Abraham; Touya, Diego; Strasser-Weippl, Kathrin; Ruiz, Rossana; St Louis, Jessica; Goss, Paul

    2016-10-01

    The HER2 receptor as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is overexpressed in 15-20% of all breast cancers and traditionally represents adverse biology and a guarded prognosis, particularly in HER2 positive metastatic breast cancer (MBC). Trastuzumab and newer anti-HER2 targeting agents have significantly improved the clinical outcomes of patients with HER2 positive MBC. The development of new techniques has led to discovery of promising biomarkers that can lead to more precise selection of patients for anti-HER2 therapies. This paper summarizes these new biomarkers, useful in selecting patients for treatment with new and emerging therapies for HER2 positive MBC. Emerging next generation sequencing techniques have truly changed the landscape of HER2 positive MBC. Deployment of multiple anti-HER2 therapies in combination is a strategy which has yielded additive or even synergistic effects and has led to markedly improved patient outcomes in HER2+ MBC. In the future, in order to further improve the treatment of these patients and to reduce toxicities, we need to improve our understanding of HER2-dependent pathways and their function, and to develop further treatment combinations while optimizing selection of patients by identifying new biomarkers. The results of prospective studies using CTCs, cDNA and other promising new biomarkers are awaited with great interest. PMID:27526299

  13. Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer

    PubMed Central

    Carey, Lisa A.; Adamo, Barbara; Vidal, Maria; Tabernero, Josep; Cortés, Javier; Parker, Joel S.; Perou, Charles M.; Baselga, José

    2014-01-01

    Background The clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer. Methods We interrogated The Cancer Genome Atlas (n = 495) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets (n = 1730) of primary breast cancers for molecular data derived from DNA, RNA and protein, and determined intrinsic subtype. Clinical HER2 status was defined according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays. Cox models tested the prognostic significance of each variable in patients not treated with trastuzumab (n = 1711). Results Compared with clinically HER2 (cHER2)-negative breast cancer, cHER2+ breast cancer had a higher frequency of the HER2-enriched (HER2E) subtype (47.0% vs 7.1%) and a lower frequency of Luminal A (10.7% vs 39.0%) and Basal-like (14.1% vs 23.4%) subtypes. The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within each subtype, only 0.3% to 3.9% of genes were found differentially expressed between cHER2+ and cHER2-negative tumors. Within cHER2+ tumors, HER2 gene and protein expression was statistically significantly higher in the HER2E and Basal-like subtypes than either luminal subtype. Neither cHER2 status nor the new 10-subtype copy number-based classification system (IntClust) added independent prognostic value to intrinsic subtype. Conclusions When the intrinsic subtypes are taken into account, cHER2-positivity does not translate into large changes in the expression of downstream signaling pathways, nor does it affect patient survival in the absence of HER2 targeting. PMID:25139534

  14. Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth

    PubMed Central

    Emde, A.; Pradeep, C-R.; Ferraro, DA.; Ben-Chetrit, N.; Sela, M.; Ribba, B.; Kam, Z.; Yarden, Y.

    2013-01-01

    Monoclonal antibodies (mAbs) to HER2 are currently used to treat breast cancer, but low clinical efficacy, along with primary and acquired resistance to therapy, commonly limit clinical applications. We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects, probably due to accelerated receptor degradation. Here, we extend these observations to three-dimensional mammary cell models, and compare the effects of single mAbs with the effects of antibody combinations. Collectively, our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth. Importantly, while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype, combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids. In conclusion, our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells. Hence, combining mAbs offers a therapeutic strategy, potentially able to enhance clinical efficacy of existing antireceptor immuno-therapeutics. PMID:21132012

  15. 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

  16. Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer.

    PubMed

    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

  17. New developments in the treatment of HER2-positive breast cancer

    PubMed Central

    Nahta, Rita

    2012-01-01

    Approximately 20%–30% of metastatic breast cancers show increased expression of the human epidermal growth factor receptor-2 (HER2) tyrosine kinase. Two HER2-specific therapies are currently approved for clinical treatment of patients with HER2-overexpressing metastatic breast cancer. Trastuzumab is a monoclonal antibody against HER2 and is approved for first-line treatment of HER2-positive metastatic breast cancer. Lapatinib is a small molecule dual inhibitor of epidermal growth factor receptor and HER2 tyrosine kinases, and is approved for trastuzumab-refractory disease. Although trastuzumab is a highly effective therapy for patients with HER2-overexpressing metastatic breast cancer, a significant number of patients in the initial clinical trials of trastuzumab monotherapy showed resistance to trastuzumab-based therapy. Further, among those who did respond, the initial trials indicated that the median time to progression was less than 1 year. Similarly, lapatinib is effective in a subset of trastuzumab-refractory cases, but the majority of patients display resistance. This review discusses the multiple molecular mechanisms of resistance that have been proposed in the literature. In addition, novel agents that are being tested for efficacy against HER2-positive breast cancer, including the antibodies pertuzumab and trastuzumab-DM1 and the immunotoxin affitoxin, are reviewed. The introduction of trastuzumab has revolutionized the clinical care of patients with HER2-positive metastatic breast cancer and has resulted in dramatic reductions in recurrences of early-stage HER2-positive breast cancer. The development and implementation of gene- and protein-based assays that measure potential molecular predictors of trastuzumab resistance will allow individualization of HER2-targeted therapeutic approaches, and may ultimately improve treatment of HER2-positive breast cancer. PMID:23869176

  18. The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells — A data description

    PubMed Central

    Hongisto, Vesa; Aure, Miriam Ragle; Mäkelä, Rami; Sahlberg, Kristine Kleivi

    2014-01-01

    A large number of breast cancers are characterized by amplification and overexpression of the chromosome segment surrounding the HER2 (ERBB2) oncogene. As the HER2 amplicon at 17q12 contains multiple genes, we have systematically explored the role of the HER2 co-amplified genes in breast cancer cell growth and their relation to trastuzumab resistance. We integrated array comparative genomic hybridization (aCGH) data of the HER2 amplicon from 71 HER2 positive breast tumors and 10 cell lines with systematic functional RNA interference analysis of 23 core amplicon genes with several phenotypic endpoints in a panel of trastuzumab responding and non-responding HER2 positive breast cancer cells. In this Data in Brief we give a detailed description of the experimental procedures and the data analysis methods used in the study (1). PMID:26484103

  19. Duration of trastuzumab in patients with HER2-positive metastatic breast cancer in prolonged remission

    PubMed Central

    Haq, R.; Gulasingam, P.

    2016-01-01

    Background Outcomes in metastatic breast cancer (mbc) positive for her2 (human epidermal growth factor receptor 2) are generally unfavourable. Trastuzumab has revolutionized the prognosis of her2-positive mbc. Some her2-positive mbc patients go into prolonged remission, and a few patients remain in remission even after discontinuation of trastuzumab, suggesting the possibility of a cure. In our practice, 4 her2-positive mbc patients treated with chemotherapy and trastuzumab have remained in remission on maintenance therapy for 5 years or more. Of those 4 patients, 2 have continued in remission after discontinuation of trastuzumab for more than 1 year. The objective of the present paper was therefore to address the duration of trastuzumab therapy in her2-positive mbc patients in prolonged remission. Methods We conducted a literature review of the duration of trastuzumab in her2-positive mbc patients in remission. We also conducted an online survey of oncologists in Ontario to determine their treatment practices in her2-positive mbc patients. Results The literature search found no specific evidence about the optimal duration of trastuzumab maintenance therapy in her2-positive mbc in prolonged remission. However, retrospective studies suggest predictive markers of good prognosis in patients in complete remission taking maintenance trastuzumab. Identifying those markers could lead to more personalized treatment. Our survey of oncologists about their treatment practices in her2-positive mbc patients revealed that 82.93% of respondents (n = 34) follow the currently available guidelines. Conclusions With the emergence of patients in prolonged remission, duration of trastuzumab in her2-positive mbc has become an important and relevant clinical question worldwide. Collaborative efforts are needed for the further study of this topic. PMID:27122973

  20. Assessment of HER2 status in invasive breast cancers with increased centromere 17 copy number.

    PubMed

    Jang, Min Hye; Kim, Eun Joo; Kim, Hyun Jeong; Chung, Yul Ri; Park, So Yeon

    2015-08-01

    This study was designed to evaluate usefulness of additional fluorescence in situ hybridization (FISH) using other reference genes on chromosome 17 for assessment of HER2 status in invasive breast cancers with increased centromere 17 copy number, and to compare this approach with conventional methods based on the 2007 and 2013 ASCO/CAP guidelines. We performed FISH with probes for SMS, RARA, and TP53 on 253 breast cancers with centromeric probe CEP17 copy number ≥ 2.6 using tissue microarrays. If one or more gene had a mean copy number <2.6, the largest number for that gene(s) was chosen as an alternative to CEP17 copy number. Of the 243 cases in which re-grading was possible, only 2 had copy numbers ≥ 2.6 for RARA, SMS, and TP53. Of the 151 breast cancers which were considered HER2 non-amplified by the 2007 ASCO/CAP guidelines using the HER2:CEP17 ratio, 42 (27.8%) were re-graded as amplified and 33 (21.8%) as equivocal after FISH using additional reference genes. Of the 101 HER2-non-amplified cases by the 2013 ASCO/CAP guidelines, 2 (2.0%) were reclassified as amplified and 24 (23.8%) as equivocal. Of 46 equivocal cases, 35 (76.1%) were re-graded as amplified. After re-grading, HER2-amplified cases were significantly increased, and the concordance between HER2 FISH and HER2 immunohistochemistry decreased. And some pathologic features of the cases which were designated to have HER2 amplification after additional FISH were not compatible with those of HER2-amplified breast cancers. The use of additional reference genes has been suggested as an option for accurate assessment of HER2 status in breast cancers with increased CEP17 copy number. However, this has limitations in that it can cause over-grading of HER2 status in tumors that lose the new reference genes. Thus, at present, it seems that additional FISH using other reference gene such as SMS, RARA, and TP53 for the cases with increased CEP17 copy number is not suitable for daily practice. PMID:26223814

  1. Therapeutic siRNA for drug-resistant HER2-positive breast cancer

    PubMed Central

    Ngamcherdtrakul, Worapol; Castro, David J.; Morry, Jingga; Reda, Moataz M.; Gray, Joe W.; Yantasee, Wassana

    2016-01-01

    HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines. We provided evidence that the drug-resistant cancer maintains dependence on HER2 for survival. Importantly, cell lines did not readily develop resistance following extended treatment with HER2 siRNA. Using our recently developed nanoparticle platform, systemic delivery of HER2 siRNA to trastuzumab-resistant tumors resulted in significant growth inhibition. Moreover, the optimal HER2 siRNA could also silence an exon 16 skipped HER2 splice variant reported to be highly oncogenic and linked to trastuzumab resistance. PMID:26894975

  2. Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma.

    PubMed

    Yoon, Harry H; Lewis, Mark A; Foster, Nathan R; Sukov, William R; Khan, Maliha; Sattler, Christopher A; Wiktor, Anne E; Wu, Tsung-Teh; Jenkins, Robert B; Sinicrope, Frank A

    2016-10-01

    Although HER2-positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2-positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2-targeted therapies that penetrate the blood-brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative-intent surgery during a time period (1980-1997) when no patient received HER2-targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow-up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2-positive (vs -negative) primary tumors showed a higher 5-year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases. PMID:27198655

  3. A systematic analysis of the resistance and sensitivity of HER2YVMA receptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer.

    PubMed

    Shen, Xiaokun; Chen, Beibei; Ma, Zhaosheng; Xie, Bojian; Cao, Xinguang; Yang, Tiejun; Zhao, Yuzhou; Qin, Jianjun; Li, Jicheng; Cao, Feilin; Chen, Xiaobing

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be

  4. Human Epidermal Growth Factor Receptor 2 (HER2) –Specific Chimeric Antigen Receptor–Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma

    PubMed Central

    Ahmed, Nabil; Brawley, Vita S.; Hegde, Meenakshi; Robertson, Catherine; Ghazi, Alexia; Gerken, Claudia; Liu, Enli; Dakhova, Olga; Ashoori, Aidin; Corder, Amanda; Gray, Tara; Wu, Meng-Fen; Liu, Hao; Hicks, John; Rainusso, Nino; Dotti, Gianpietro; Mei, Zhuyong; Grilley, Bambi; Gee, Adrian; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Wels, Winfried S.; Wang, Lisa L.; Anderson, Peter; Gottschalk, Stephen

    2015-01-01

    Purpose The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. Patients and Methods We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) –positive sarcoma received escalating doses (1 × 104/m2 to 1 × 108/m2) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells). Results We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 105/m2) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 106/m2 HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). Conclusion This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. PMID:25800760

  5. Improved Aptamers for the Diagnosis and Potential Treatment of HER2-Positive Cancer

    PubMed Central

    Gijs, Marlies; Penner, Gregory; Blackler, Garth B.; Impens, Nathalie R.E.N.; Baatout, Sarah; Luxen, André; Aerts, An M.

    2016-01-01

    Aptamers provide a potential source of alternative targeting molecules for existing antibody diagnostics and therapeutics. In this work, we selected novel DNA aptamers targeting the HER2 receptor by an adherent whole-cell SELEX approach. Individual aptamers were identified by next generation sequencing and bioinformatics analysis. Two aptamers, HeA2_1 and HeA2_3, were shown to bind the HER2 protein with affinities in the nanomolar range. In addition, both aptamers were able to bind with high specificity to HER2-overexpressing cells and HER2-positive tumor tissue samples. Furthermore, we demonstrated that aptamer HeA2_3 is being internalized into cancer cells and has an inhibitory effect on cancer cell growth and viability. In the end, we selected novel DNA aptamers with great potential for the diagnosis and possible treatment of HER2-positive cancer. PMID:27213406

  6. Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2

    PubMed Central

    Wu, Yifen; Li, Rong; Zhang, Junyi; Wang, Gang; Liu, Bin; Huang, Xiaofang; Zhang, Tao; Luo, Rongcheng

    2015-01-01

    Background Trastuzumab resistance in HER-2 positive breast cancer cells is closely related to overexpression of both epidermal growth factor receptor (EGFR) and human epidermal receptor (HER-2). SHP-1 has been demonstrated to downregulate tyrosine kinase activity including EGFR via its phosphatase function, but its effect on HER-2 activity is still unknown. Here, we examined the hypothesis that SHP-1 enhances the anticancer efficacy of trastuzumab in EGFR/HER-2 positive breast cancer cells through combining dual inhibition of EGFR and HER-2. Methods Trastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3cells in the presence of trastuzumab. The SHP-1 was ectopically expressed by stable transfection. The activity and expression of EGFR, HER-2, and downstream signaling pathways were tested by Western blot. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was examined by flow cytometry. The binding between SHP-1 and EGFR/HER-2 was evaluated by immunoprecipitation assay and bimolecular fluorescence complementation. The effects of SHP-1 on tumorigenicity and trastuzumab sensitivity were confirmed via in vivo xenograft model. Results Trastuzumab-resistant SKBr-3 cells showed aberrant co-expression of EGFR and HER-2. Introduction of wild-type SHP-1 inhibited cell proliferation, clone formation, and promoted the apoptosis induced by trastuzumab. Meanwhile, SHP-1 overexpression reduced phosphorylation levels of EGFR and HER-2 both in parental and trastuzumab-resistant SKBr-3 cells. In vivo study showed an increased antitumor effect of trastuzumab in SHP-1 overexpressed xenografts. At last, we discovered that SHP-1 can make complexes with both EGFR and HER-2, and both phospho-EGFR and phosphor-HER-2 levels in wild-type SHP-1 immunoprecipitates were less than those in phosphatase-inactive SHP-1 (C453S) immunoprecipitates, indicating that EGFR and HER-2 are

  7. In vivo assessment of HER2 receptor density in HER2-positive tumors by near-infrared imaging, using repeated injections of the fluorescent probe.

    PubMed

    Ardeshirpour, Yasaman; Hassan, Moinuddin; Zielinski, Rafal; Horton, Jason A; Capala, Jacek; Gandjbakhche, Amir H; Chernomordik, Victor

    2014-10-01

    HER2 overexpression and amplification of the HER2/neu gene have been found in approximately 25% of invasive breast carcinomas. They are associated with a poor prognosis and resistance to therapy in breast cancer patients. Up to now, clinical evaluation of human epidermal growth factor receptor 2 (HER2) expression is based on ex vivo methods (immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) staining of biopsied tissue). Our goal is to realize "image and treat" paradigm using targeted fluorescent probes to evaluate expression levels of cell biomarkers responsible for cancer progression and to monitor the efficacy of corresponding monoclonal antibody treatments. We used fluorescent Affibody-based probes for in vivo analysis of HER2 receptors using near-infrared optical imaging that do not interfere with binding of the therapeutic agents to these receptors. We have analyzed two types of breast carcinoma xenografts with significant differences in HER2 expression (31 and 21 according to classification) in the mouse model. Using our kinetic model to analyze the temporal variations of the fluorescence intensity in the tumor area after two subsequent injections allowed us to assess quantitatively the difference in HER2 expression levels for two tumor types (BT-474 and MD-MBA-361). This result was substantiated by ELISA ex vivo assays of HER2 expression in the same tumors. PMID:24000992

  8. Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors

    PubMed Central

    Geng, Lingling; Wang, Zihua; Yang, Xiaoliang; Li, Dan; Lian, Wenxi; Xiang, Zhichu; Wang, Weizhi; Bu, Xiangli; Lai, Wenjia; Hu, Zhiyuan; Fang, Qiaojun

    2015-01-01

    To identify peptides with high affinity and specificity against human epidermal growth factor receptor 2 (HER2), a series of peptides were designed based on the structure of HER2 and its Z(HER2:342) affibody. By using a combination protocol of molecular dynamics modeling, MM/GBSA binding free energy calculations, and binding free energy decomposition analysis, two novel peptides with 27 residues, pep27 and pep27-24M, were successfully obtained. Immunocytochemistry and flow cytometry analysis verified that both peptides can specifically bind to the extracellular domain of HER2 protein at cellular level. The Surface Plasmon Resonance imaging (SPRi) analysis showed that dissociation constants (KD) of these two peptides were around 300 nmol/L. Furthermore, fluorescence imaging of peptides against nude mice xenografted with SKBR3 cells indicated that both peptides have strong affinity and high specificity to HER2 positive tumors. PMID:26284145

  9. Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors.

    PubMed

    Geng, Lingling; Wang, Zihua; Yang, Xiaoliang; Li, Dan; Lian, Wenxi; Xiang, Zhichu; Wang, Weizhi; Bu, Xiangli; Lai, Wenjia; Hu, Zhiyuan; Fang, Qiaojun

    2015-01-01

    To identify peptides with high affinity and specificity against human epidermal growth factor receptor 2 (HER2), a series of peptides were designed based on the structure of HER2 and its Z(HER2:342) affibody. By using a combination protocol of molecular dynamics modeling, MM/GBSA binding free energy calculations, and binding free energy decomposition analysis, two novel peptides with 27 residues, pep27 and pep27-24M, were successfully obtained. Immunocytochemistry and flow cytometry analysis verified that both peptides can specifically bind to the extracellular domain of HER2 protein at cellular level. The Surface Plasmon Resonance imaging (SPRi) analysis showed that dissociation constants (K D) of these two peptides were around 300 nmol/L. Furthermore, fluorescence imaging of peptides against nude mice xenografted with SKBR3 cells indicated that both peptides have strong affinity and high specificity to HER2 positive tumors. PMID:26284145

  10. Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab.

    PubMed

    Goldblatt, Erin M; Erickson, Priscilla A; Gentry, Erin R; Gryaznov, Sergei M; Herbert, Brittney-Shea

    2009-11-01

    HER2 amplification in breast cancer is associated with a more aggressive disease, greater likelihood of recurrence, and decreased survival compared to women with HER2-negative breast cancer. Trastuzumab is a monoclonal antibody that inhibits HER2 activity, making this compound an important therapeutic option for patients with HER2-positive breast cancer. However, resistance to trastuzumab develops rapidly in a large number of breast cancer patients. The objective of this study was to determine whether GRN163L, a telomerase template antagonist currently in clinical trials for cancer treatment, can augment the effects of trastuzumab in breast cancer cells with HER2 amplification. GRN163L was effective in inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. We show that GRN163L acts synergistically with trastuzumab in inhibiting HER2-positive breast cancer cell growth. More importantly, we show that GRN163L can restore the sensitivity of therapeutic-resistant breast cancer cells to trastuzumab. These findings implicate that telomerase template antagonists have potential use in the treatment of cancers that have developed resistance to traditional cancer therapy. PMID:18853252

  11. Targeted Therapies in HER2-Positive Breast Cancer – a Systematic Review

    PubMed Central

    Schramm, Amelie; De Gregorio, Nikolaus; Widschwendter, Peter; Fink, Visnja; Huober, Jens

    2015-01-01

    Summary About 20% of all breast cancer patients have a human epidermal growth factor receptor 2 (HER2)-positive breast tumor. This entity underwent an impressive change in prognosis, with notable improvement of progression-free survival and overall survival. Due to more aggressive tumors and no specific therapy, HER2 overexpression was historically seen as a negative prognostic marker, with worse prognosis and increased risk of recurrent disease. Trastuzumab, the first anti-HER2 antibody, revolutionized the systemic therapy options in HER2-positive breast cancer and initiated several targeted therapies and more personalized treatment strategies. Over the years, multiple HER2-targeting drugs stepped into clinical practice, for the curative as well as the metastatic situation. This review summarizes the targeted treatment options in HER2-positive breast cancer and their current impact in the clinical routine. Results of the most outstanding trials in HER2-targeted therapies and important ongoing trials are subsequently described for an up-to-date overview. PMID:26557822

  12. Immunohistochemical determination of HER-2/neu expression in invasive breast carcinoma.

    PubMed

    Vang, R; Cooley, L D; Harrison, W R; Reese, T; Abrams, J

    2000-05-01

    Numerous methods exist for HER-2/neu assessment; however, technical and interpretive standardization is virtually absent. We evaluated 2 commercially available antibodies on routinely fixed paraffin-embedded tissue sections to establish our own guidelines. Thirty-three cases of infiltrating breast carcinoma were evaluated simultaneously with monoclonal and polyclonal antibodies. Only membranous staining, no matter how focal, was considered positive. An additional 32 tumors were studied subsequently using only the polyclonal antibody. Of all carcinomas, 13.0% showed immunohistochemical evidence of HER-2/neu overexpression. High-grade tumors were more often positive. There was no HER-2/neu gene expression in the benign epithelium that generally was present in the tissue section or in any of the well-differentiated tumors tested. The polyclonal antibody proved more sensitive than the monoclonal antibody. While true cytoplasmic staining was present occasionally, it did not create substantial difficulty in interpretation. The polyclonal antibody cost substantially less than the monoclonal antibody. Fluorescence in situ hybridization assay for HER-2/neu gene amplification performed on 32 of 65 cases showed concordant results in 31 cases. The immunohistochemical assay for HER-2/neu gene overexpression, using our methods, is accurate, economic, and easily integrated into the laboratory. PMID:10800399

  13. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure

    SciTech Connect

    Azuma, Koichi; Tsurutani, Junji; Sakai, Kazuko; Kaneda, Hiroyasu; Fujisaka, Yasuhito; Takeda, Masayuki; Watatani, Masahiro; Arao, Tokuzo; Satoh, Taroh; Okamoto, Isamu; Kurata, Takayasu; Nishio, Kazuto; Nakagawa, Kazuhiko

    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 cells (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.

  14. Identification of new miRNA biomarkers associated with HER2-positive breast cancers

    PubMed Central

    Tashkandi, Hossam; Shah, Nirav; Patel, Yogin; Chen, Hexin

    2015-01-01

    Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in ∼30% breast cancers which are associated with poor prognosis. microRNAs are small non-coding RNA which play an important role in many physiological conditions including cancer. Here we screened and identified many miRNAs which are dysregulated by HER2 overexpression. In line with our quantitative PCR analysis data, in silico analysis of microRNA expression profiles of 1302 breast tumors revealed that miR-146a-5p is up-regulated and miR-181d and miR-195-5p are down-regulated in HER2-positive tumors. Furthermore, the expression levels of these microRNAs can significantly predict patient survival and thus potentially serve as new prognostic markers for HER2-positive breast cancer. PMID:26697527

  15. Redox Potential Ultrasensitive Nanoparticle for the Targeted Delivery of Camptothecin to HER2-Positive Cancer Cells

    PubMed Central

    2015-01-01

    Ideal “smart” nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer–drug conjugate of poly[2-(pyridin-2-yldisulfanyl)]-graft-poly(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An in vitro drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2-positive cancer cells while not affecting HER2-negative cells. PMID:24779647

  16. Large palpable ductal carcinoma in situ is Her-2 positive with high nuclear grade

    PubMed Central

    Monabati, Ahmad; Sokouti, Ali-Reza; Noori, Sadat Noori; Safaei, Akbar; Talei, Abd-Rasul; Omidvari, Shapoor; Azarpira, Negar

    2015-01-01

    Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group with variable clinical presentation. The exact molecular mechanism is not known why some ductal carcinomas may reach to such a large size but still remains in situ. Although, molecular classification of DCIS lesions and nuclear grading are important for identification of more aggressive lesions but it is not sufficient. Our aim was to examine the expression pattern of immunohistochemical (IHC) markers of ER, PR, HER-2 in palpable DCIS lesions and compare with clinicopathological findings. Our center is referral hospital from South of Iran. Samples were obtained from fifty four patients with a diagnosis of palpable DCIS. Equivocal (2+) case in HER-2 IHC testing was more characterized by chromogenic in situ hybridization. The positive frequency of HER2, ER, and PR was 92%, 48%, and 37% respectively. Palpable DCIS lesions were significantly more HER-2 positive (92%). The DCIS cases were more likely to be of high nuclear grade (grade III) and Her-2 positive cases were more likely to be of high nuclear grade than intermediate grade. All ER negative tumors had high nuclear grade. The Her-2 positivity is suggested as the most important factor responsible for marked in situ proliferation and production of palpable mass. PMID:26097582

  17. Interactions between αv-Integrin and HER2 and Their Role in the Invasive Phenotype of Breast Cancer Cells In Vitro and in Rat Brain

    PubMed Central

    Lal, Sangeet; Kersch, Cymon; Beeson, Kathleen A.; Wu, Y. Jeffrey; Muldoon, Leslie L.; Neuwelt, Edward A.

    2015-01-01

    Background We tested the hypothesis that αv-integrin and the human epidermal growth factor receptor type 2 (HER2) interact with each other in brain trophic metastatic breast cancer cells and influence their invasive phenotype. Methods Clones of MDA-MB231BR human breast cancer cells with stable knock down of αv-integrin in combination with high or low levels of HER2 were created. The interactions of these two proteins and their combined effect on cell migration and invasion were investigated in vitro and in vivo. Results Knockdown of αv-integrin in MDA-MB231BR clones altered the actin cytoskeleton and cell morphology. HER2 co-precipitated with αv-integrin in three breast cancer cell lines in vitro, suggesting they complex in cells. Knockdown of αv-integrin altered HER2 localization from its normal membrane position to a predominantly lysosomal localization. When αv-integrin expression was decreased by 69–93% in HER2-expressing cells, cellular motility was significantly reduced. Deficiency of both αv-integrin and HER2 decreased cellular migration and invasion by almost 90% compared to cells expressing both proteins (P<0.01). After intracerebral inoculation, cells expressing high levels of both αv-integrin and HER2 showed a diffusely infiltrative tumor phenotype, while cells deficient in αv-integrin and/or HER2 showed a compact tumor growth phenotype. In the αv-integrin positive/HER2 positive tumors, infiltrative growth was 57.2 ± 19% of tumor volume, compared to only 5.8 ± 6.1% infiltration in the double deficient tumor cells. Conclusions αv-integrin interacts with HER2 in breast cancer cells and may regulate HER2 localization. The combined impacts of αv-integrin and HER2 influence the invasive phenotype of breast cancer cells. Targeting αv-integrin in HER2-positive breast cancer may slow growth and decrease infiltration in the normal brain. PMID:26222911

  18. [A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy].

    PubMed

    Sugie, Tomoharu; Nagai, Toshihiro; Ohgaki, Kazuhisa

    2008-04-01

    A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer. PMID:18408445

  19. Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Kawajiri, Hidemi; Takashima, Tsutomu; Kashiwagi, Shinichiro; Noda, Satoru; Onoda, Naoyoshi; Hirakawa, Kosei

    2015-01-01

    Overexpression of HER2 - found in approximately 15-20% of all breast cancers - is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer. PMID:25494663

  20. Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

    PubMed Central

    Phelps-Polirer, Kendall; Abt, Melissa A.; Smith, Danzell; Yeh, Elizabeth S.

    2016-01-01

    Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors in vivo. PMID:27045589

  1. Profiling and targeting HER2-positive breast cancer using trastuzumab emtansine

    PubMed Central

    Sadeghi, Saeed; Olevsky, Olga; Hurvitz, Sara A

    2014-01-01

    Purpose This article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent. Background The development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab. Results Preclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac

  2. An Integrated Model of the Transcriptome of HER2-Positive Breast Cancer

    PubMed Central

    Kalari, Krishna R.; Necela, Brian M.; Tang, Xiaojia; Thompson, Kevin J.; Lau, Melissa; Eckel-Passow, Jeanette E.; Kachergus, Jennifer M.; Anderson, S. Keith; Sun, Zhifu; Baheti, Saurabh; Carr, Jennifer M.; Baker, Tiffany R.; Barman, Poulami; Radisky, Derek C.; Joseph, Richard W.; McLaughlin, Sarah A.; Chai, High-seng; Camille, Stephan; Rossell, David; Asmann, Yan W.; Thompson, E. Aubrey; Perez, Edith A.

    2013-01-01

    Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2-positive breast cancer. We interrogated RNA-Seq data from benign breast lesions, ER+, triple negative, and HER2-positive tumors to identify 685 differentially expressed genes, 102 alternatively spliced genes, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were associated with the HER2-positive tumors in our survey panel. These features were integrated into a transcriptome landscape model that identified 12 highly interconnected genomic modules, each of which represents a cellular processes pathway that appears to define the genomic architecture of the HER2-positive tumors in our test set. The generality of the model was confirmed by the observation that several key pathways were enriched in HER2-positive TCGA breast tumors. The ability of this model to make relevant predictions about the biology of breast cancer cells was established by the observation that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. Additional modules from the HER2 transcriptome model, including ubiquitin-mediated proteolysis, TGF-beta signaling, RHO-family GTPase signaling, and M-phase progression, were linked to response to lapatinib and paclitaxel in vitro and/or risk of relapse in the N9831 dataset. These data indicate that an integrated transcriptome landscape model derived from a test set of HER2-positive breast tumors has potential for predicting outcome and for identifying novel potential therapeutic strategies for this breast cancer subtype. PMID:24223926

  3. Salad vegetables dietary pattern protects against HER-2-positive breast cancer: a prospective Italian study.

    PubMed

    Sant, Milena; Allemani, Claudia; Sieri, Sabina; Krogh, Vittorio; Menard, Sylvie; Tagliabue, Elda; Nardini, Elena; Micheli, Andrea; Crosignani, Paolo; Muti, Paola; Berrino, Franco

    2007-08-15

    Studies investigating the relation of diet to breast cancer have produced conflicting results. We hypothesized that dietary factors associated with breast cancer risk might differentially influence the HER-2 status of the cancers that develop, and investigated this hypothesis by analyzing the data of the ORDET prospective study. We analyzed 8,861 volunteer women residents of the Varese Province, Italy, for whom we had full data. By December 31, 2001, 238 cases had occurred in which HER-2 status was known. Four dietary patterns had been identified previously by factor analysis: salad vegetables (high consumption of raw vegetables and olive oil), prudent (cooked vegetables, poultry, fish), western (potatoes, meat, eggs, butter), and canteen (pasta, tomato sauce, wine). In our study, relative risks (RRs) of developing HER-2-positive and HER-2-negative breast cancers by tertiles of dietary pattern factor scores were assessed by multinomial logistic regression. The salad vegetables dietary pattern had a protective effect against HER-2-positive cancers (RR = 0.25, 95% CI 0.10-0.64, for the highest tertile; p(trend) = 0.001), much stronger than for HER-2-negative cancers (p(heterogeneity) = 0.039). This important finding that a salad vegetables dietary pattern protects mainly against a specific breast cancer subtype indicates that future studies on environmental/dietary risk factors should explicitly take account of the heterogeneity of breast cancer phenotypes. PMID:17455245

  4. Targeting HER2-positive cancer cells with receptor-redirected anthrax protective antigen

    PubMed Central

    McCluskey, Andrew J.; Olive, Andrew J.; Starnbach, Michael N.; Collier, R. John

    2012-01-01

    Targeted therapeutics have emerged in recent years as an attractive approach to treating various types of cancer. One approach is to modify a cytocidal protein toxin to direct its action to a specific population of cancer cells. We created a targeted toxin in which the receptor-binding and pore-forming moiety of anthrax toxin, termed Protective Antigen (PA), was modified to redirect its receptor specificity to HER2, a marker expressed at the surface of a significant fraction of breast and ovarian tumors. The resulting fusion protein (mPA-ZHER2) delivered cytocidal effectors specifically into HER2-positive tumor cells, including a trastuzumab-resistant line, causing death of the cells. No off-target killing of HER2-negative cells was observed, either with homogeneous populations or with mixtures of HER2-positive and HER2-negative cells. A mixture of mPA variants targeting different receptors mediated killing of cells bearing either receptor, without affecting cells devoid of these receptors. Anthrax toxin may serve as an effective platform for developing therapeutics to ablate cells bearing HER2 or other tumor-specific cell-surface markers. PMID:23290417

  5. HER2-positive patients receiving trastuzumab treatment have a comparable prognosis with HER2-negative advanced gastric cancer patients: a prospective cohort observation.

    PubMed

    Qiu, Miao-Zhen; Li, Qian; Wang, Zhi-Qiang; Liu, Tian-Shu; Liu, Qing; Wei, Xiao-Li; Jin, Ying; Wang, De-Shen; Ren, Chao; Bai, Long; Zhang, Dong-Sheng; Wang, Feng-Hua; Li, Yu-Hong; Xu, Rui-Hua

    2014-05-15

    The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013). PMID:24155030

  6. Cancer Signature Investigation: ERBB2 (HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary.

    PubMed

    Shih, Jennifer; Bashir, Babar; Gustafson, Karen S; Andrake, Mark; Dunbrack, Roland L; Goldstein, Lori J; Boumber, Yanis

    2015-08-01

    Next-generation sequencing of primary and metachronous metastatic cancer lesions may impact patient care. We present a case of relapsed metastatic breast cancer with a dominant pulmonary lesion originally identified as lung adenocarcinoma. A 72-year-old, never-smoker woman with a protracted cough was found to have a large lung mass and regional lymphadenopathy on a chest CT. Lung mass biopsy showed adenocarcinoma with focal TTF-1 (thyroid transcription factor 1) positivity, favoring a lung primary. In addition to stereotactic brain radiation for cerebral metastases, she was started on carboplatin/pemetrexed. As part of the workup, the tumor was analyzed by a 50-gene targeted mutation panel, which detected 3 somatic mutations: ERBB2 (HER2) D769H activating missense mutation, TP53 Y126 inactivating truncating mutation, and SMARCB1 R374Q missense mutation. Of note, the patient had a history of stage IIA triple-negative grade 3 invasive ductal carcinoma of the left breast 1.5 years ago and received neoadjuvant chemotherapy and adjuvant radiation, and underwent a lumpectomy. Further analysis of her primary breast tumor showed a mutational profile identical to that of the lung tumor. Fluorescence in situ hybridization revealed HER2 amplification in the lung tumor, with a HER2/CEP17 ratio of 3.9. The patient was diagnosed with recurrent HER2-positive metastatic breast carcinoma with a coexisting ERBB2 (HER2) activating mutation. Chemotherapy was adjusted to include dual HER2-targeted therapy containing trastuzumab and pertuzumab, resulting in an ongoing partial response. This case demonstrates that a unique genetic mutational profile can clarify whether a tumor represents a metastatic lesion or new malignancy when conventional morphological and immunohistochemical methods are indeterminate, and can directly impact treatment decisions. PMID:26285240

  7. Long-term outcomes of neoadjuvant treatment of HER2-positive breast cancer.

    PubMed

    Zhang, Bingnan; Hurvitz, Sara

    2016-07-01

    Long-term outcomes for women with a diagnosis of human epidermal growth factor receptor 2 (HER2)-driven early-stage breast cancer have significantly improved since the advent of HER2-targeted therapy. Although the first studies in the early-stage setting focused on the adjuvant use of trastuzumab plus chemotherapy, clinical trials increasingly are using a neoadjuvant design to evaluate novel HER2-targeted therapies. Neoadjuvant therapy downstages locally advanced breast cancer, improves rates of breast conservation, and provides information regarding the responsiveness of a cancer to systemic therapy; in addition, studies have shown that the pathologic response to neoadjuvant therapy is correlated with event-free and overall survival. Given these advantages, multiple studies of neoadjuvant therapy, several of which have reported longer-term outcomes, have been conducted to evaluate HER2-targeted therapies. This review summarizes available data from prior and ongoing neoadjuvant trials in HER2-positive breast cancer, focusing on those studies that have reported not only pathologic response rates but also event-free, disease-free, and/or overall survival. The long-term outcomes associated with the achievement of a pathologic complete response are explored, and the comparisons of pathologic complete response rates, event-free survival, and overall survival reported for different HER2-targeted regimens are reviewed. PMID:27379947

  8. Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine

    PubMed Central

    Recondo, Gonzalo; de la Vega, Maximo; Galanternik, Fernando; Díaz-Cantón, Enrique; Leone, Bernardo Amadeo; Leone, José Pablo

    2016-01-01

    The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer. PMID:27274311

  9. Coexistence of malignant phyllodes tumor and her2-positive locally advanced breast cancer in distinct breasts: A case report

    PubMed Central

    Sato, Tomoi; Muto, Ichiro; Sakai, Takeshi

    2016-01-01

    Introduction Phyllodes tumor of the breast is a rare biphasic neoplasm, accounting for less than 1% of all breast tumors. Coexistence of phyllodes tumor and breast cancer in distinct breasts is extremely rare. Case presentation A 47-year-old Japanese woman presented with bilateral breast lumps. A HER2-positive, unresectable invasive carcinoma in the right breast and fibroadenoma in the left were diagnosed via core needle biopsy. During chemotherapy with anti-HER2 therapy, the breast cancer shrank quickly, while the left breast lump suddenly enlarged. Under a diagnosis of malignant neoplasm of the breast, left mastectomy was performed. Malignant phyllodes tumor was diagnosed by postoperative histological examination and recurred in multiple areas as early as 2 months after surgery. Discussion Only 10 cases of coexisting phyllodes tumor and breast cancer in distinct breasts have been reported in the English literature. Phyllodes tumor associated with breast cancer in distinct breasts tends to be malignant. This is the first case of phyllodes tumor rapidly enlarging during anti-HER2 chemotherapy for locally advanced HER2-positive breast cancer. Conclusion Even during effective treatment of advanced or recurrent breast cancer, attention should also be paid to the contralateral breast for the possible association of a second malignancy such as phyllodes tumor. PMID:26773878

  10. Radiation binary targeted therapy for HER-2 positive breast cancers: assumptions, theoretical assessment and future directions

    NASA Astrophysics Data System (ADS)

    Mundy, Daniel W.; Harb, Wael; Jevremovic, Tatjana

    2006-03-01

    A novel radiation targeted therapy is investigated for HER-2 positive breast cancers. The proposed concept combines two known approaches, but never used together for the treatment of advanced, relapsed or metastasized HER-2 positive breast cancers. The proposed radiation binary targeted concept is based on the anti HER-2 monoclonal antibodies (MABs) that would be used as vehicles to transport the nontoxic agent to cancer cells. The anti HER-2 MABs have been successful in targeting HER-2 positive breast cancers with high affinity. The proposed concept would utilize a neutral nontoxic boron-10 predicting that anti HER-2 MABs would assure its selective delivery to cancer cells. MABs against HER-2 have been a widely researched strategy in the clinical setting. The most promising antibody is Trastuzumab (Herceptin®). Targeting HER-2 with the MAB Trastuzumab has been proven to be a successful strategy in inducing tumour regression and improving patient survival. Unfortunately, these tumours become resistant and afflicted women succumb to breast cancer. In the proposed concept, when the tumour region is loaded with boron-10 it is irradiated with neutrons (treatment used for head and neck cancers, melanoma and glioblastoma for over 40 years in Japan and Europe). The irradiation process takes less than an hour producing minimal side effects. This paper summarizes our recent theoretical assessments of radiation binary targeted therapy for HER-2 positive breast cancers on: the effective drug delivery mechanism, the numerical model to evaluate the targeted radiation delivery and the survey study to find the neutron facility in the world that might be capable of producing the radiation effect as needed. A novel method of drug delivery utilizing Trastuzumab is described, followed by the description of a computational Monte Carlo based breast model used to determine radiation dose distributions. The total flux and neutron energy spectra of five currently available neutron

  11. Palbociclib in Treating Patients With Metastatic HER-2 Positive or Triple-Negative Breast Cancer With Brain Metastasis

    ClinicalTrials.gov

    2016-05-13

    Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  12. Trastuzumab-based chemotherapy modulates systemic redox homeostasis in women with HER2-positive breast cancer.

    PubMed

    Lemos, L G T; Victorino, V J; Herrera, A C S A; Aranome, A M F; Cecchini, A L; Simão, A N C; Panis, C; Cecchini, R

    2015-07-01

    Trastuzumab is an immunotargeting therapeutic against breast tumors with amplification of the human epithelial growth factor receptor 2 (HER2). HER2 patients naturally exhibit disruption in the pro-oxidant inflammatory profiling; however, the impact of trastuzumab-based chemotherapy in modulating this process is still unknown. Here we determined the systemic pro-inflammatory profile of women diagnosed with HER2-amplified tumors, undergoing trastuzumab-based chemotherapy (TZ), and compared the results with that of healthy controls (CTR) and untreated patients with HER2-amplified breast cancer (CA). The plasmatic inflammatory profile was assessed by evaluating pro-oxidant parameters such as lipid peroxidation, total antioxidant capacity (TRAP), levels of advanced oxidation protein products (AOPPs), nitric oxide (NO), C-reactive protein (CRP), and total thiol content. Markers of cardiac damage were also assessed. Our findings showed increased NO levels in TZ than that in either CA or CTR groups. Furthermore, TZ augmented TRAP and reduced total thiol than that of the CA group. Our data also revealed that AOPP levels were significantly higher in the TZ than the CA group. AOPP and the MB fraction of creatine-kinase (CKMB) levels were positively correlated in TZ patients. These findings suggest that trastuzumab-associated chemotherapy can modulate the pro-inflammatory markers of HER2-positive breast cancer patients to the levels found in healthy controls. PMID:25937481

  13. Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors.

    PubMed

    Goel, Shom; Wang, Qi; Watt, April C; Tolaney, Sara M; Dillon, Deborah A; Li, Wei; Ramm, Susanne; Palmer, Adam C; Yuzugullu, Haluk; Varadan, Vinay; Tuck, David; Harris, Lyndsay N; Wong, Kwok-Kin; Liu, X Shirley; Sicinski, Piotr; Winer, Eric P; Krop, Ian E; Zhao, Jean J

    2016-03-14

    Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer. PMID:26977878

  14. Antitumor activity of phenethyl isothiocyanate in HER2-positive breast cancer models

    PubMed Central

    2012-01-01

    Background HER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells. Methods MDA-MB-231 and MCF-7 breast cancer cells stably transfected with HER2 (high HER2 (HH)) were used in this study. The effect of PEITC was evaluated using cytotoxicity and apoptosis assay in these syngeneic cells. Western blotting was used to delineate HER2 signaling. SCID/NOD mice were implanted with MDA-MB-231 (HH) xenografts. Results Our results show that treatment of MDA-MB-231 and MCF-7 cells with varying concentrations of PEITC for 24 h extensively reduced the survival of the cells with a 50% inhibitory concentration (IC50) of 8 μM in MDA-MB-231 and 14 μM in MCF-7 cells. PEITC treatment substantially decreased the expression of HER2, epidermal growth factor receptor (EGFR) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr-705. The expression of BCL-2-associated × (BAX) and BIM proteins were increased, whereas the levels of B cell lymphoma-extra large (BCL-XL) and X-linked inhibitor of apoptosis protein (XIAP) were significantly decreased in both the cell lines in response to PEITC treatment. Substantial cleavage of caspase 3 and poly-ADP ribose polymerase (PARP) were associated with PEITC-mediated apoptosis in MDA-MB-231 and MCF-7 cells. Notably, transient silencing of HER2 decreased and overexpressing HER2 increased the effects of PEITC. Furthermore, reactive oxygen species (ROS) generation, mitochondrial depolarization and apoptosis by PEITC treatment were much higher in breast cancer cells expressing higher levels of HER2 (HH) as compared to parent cell lines. The IC50 of PEITC following 24 h of treatment was

  15. HER2-positive, trastuzumab-resistant metastatic esophageal cancer presenting with brain metastasis after durable response to dual HER2 blockade: a case report

    PubMed Central

    Gelbspan, Deborah; Weitz, David; Markman, Maurie; Quan, Walter

    2014-01-01

    We here report a case of a patient diagnosed with human epithelial growth factor receptor 2 (HER2)-amplified esophageal adenocarcinoma. The patient responded well to trastuzumab-based chemotherapy initially, but progressed with liver metastases. Her treatment was then switched to dual HER2 blockade with both trastuzumab and lapatinib in combination with capecitabine. She tolerated therapy and responded remarkably well with radiographic resolution of liver metastases. Unfortunately, she developed multiple brain metastases in the absence of extracranial progression. Discordant negative expression of HER2 and subclonal mutations in brain lesions were discovered, which, at least in part, explained her brain metastases in the presence of capecitabine and lapatinib, as both agents are known to be able to cross the blood brain barrier. The potential mechanism for dual HER2 blockade is discussed in the context of HER2-positive, trastuzumab-resistant, advanced esophageal cancer. The incidence of brain metastasis in advanced gastro-esophageal cancer has been reported to be extremely low, but is expected to increase with more effective systemic therapy. The intratumoral heterogeneity between the metastases, local recurrences and the primary tumor is definitely noteworthy. PMID:25436131

  16. [Efficacy and Safety of Pertuzumab for HER2-Positive Metastatic Breast Cancer].

    PubMed

    Yamamura, Jun; Kamigaki, Shunji; Hamakawa, Takuya; Hoshino, Hiromitsu; Nakata, Ken; Yamamoto, Tameyoshi; Ikeda, Naoki; Kawase, Tomono; Tsujie, Masaki; Kimura, Yutaka; Ozato, Hiroki

    2015-06-01

    The CLEOPATRA trial showed a significant improvement in the progression-free survival (PFS) and overall survival of patients with HER2-positive first-line metastatic breast cancer (MBC) who were treated with pertuzumab (PER), trastuzumab (TRA), and docetaxel (DTX), compared to those treated with placebo, TRA, and DTX. PER was approved in 2013 for treating HER2-positive MBC in Japan. Herein, we present the retrospective review of data from 10 HER2-positive MBC patients who received PER in our hospital between September 2013 and August 2014.T he median age was 52 years (range, 45-66 years), and 7 patients were positive for ER.Six patients had not received any previous chemotherapy for their metastatic disease, while the others had received comparatively heavy pretreatment doses of chemotherapy.Our patients received the PER, TRA, and DTX regimen, although 2 patients were treated without DTX. Four patients experienced a partial response, 6 patients experienced stable disease (SD), and 3 patients experienced SD for ≥6 months. The response rate was 40%, and the clinical benefit rate was 70%.The median PFS was 7.3 months (range, 2.5-11.5 months). Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients, respectively; no Grade 4 adverse events were observed, and thus, the regimen was well tolerated. Further clinical research seems to be warranted for developing new treatment strategies involving PER for HER2-positive MBC. PMID:26199243

  17. 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

  18. 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. PMID:27583026

  19. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

    PubMed Central

    Ferrari, Anthony; Vincent-Salomon, Anne; Pivot, Xavier; Sertier, Anne-Sophie; Thomas, Emilie; Tonon, Laurie; Boyault, Sandrine; Mulugeta, Eskeatnaf; Treilleux, Isabelle; MacGrogan, Gaëtan; Arnould, Laurent; Kielbassa, Janice; Le Texier, Vincent; Blanché, Hélène; Deleuze, Jean-François; Jacquemier, Jocelyne; Mathieu, Marie-Christine; Penault-Llorca, Frédérique; Bibeau, Frédéric; Mariani, Odette; Mannina, Cécile; Pierga, Jean-Yves; Trédan, Olivier; Bachelot, Thomas; Bonnefoi, Hervé; Romieu, Gilles; Fumoleau, Pierre; Delaloge, Suzette; Rios, Maria; Ferrero, Jean-Marc; Tarpin, Carole; Bouteille, Catherine; Calvo, Fabien; Gut, Ivo Glynne; Gut, Marta; Martin, Sancha; Nik-Zainal, Serena; Stratton, Michael R.; Pauporté, Iris; Saintigny, Pierre; Birnbaum, Daniel; Viari, Alain; Thomas, Gilles

    2016-01-01

    HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal–basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage–fusion–bridge mechanism. PMID:27406316

  20. 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,

  1. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

    PubMed

    Ferrari, Anthony; Vincent-Salomon, Anne; Pivot, Xavier; Sertier, Anne-Sophie; Thomas, Emilie; Tonon, Laurie; Boyault, Sandrine; Mulugeta, Eskeatnaf; Treilleux, Isabelle; MacGrogan, Gaëtan; Arnould, Laurent; Kielbassa, Janice; Le Texier, Vincent; Blanché, Hélène; Deleuze, Jean-François; Jacquemier, Jocelyne; Mathieu, Marie-Christine; Penault-Llorca, Frédérique; Bibeau, Frédéric; Mariani, Odette; Mannina, Cécile; Pierga, Jean-Yves; Trédan, Olivier; Bachelot, Thomas; Bonnefoi, Hervé; Romieu, Gilles; Fumoleau, Pierre; Delaloge, Suzette; Rios, Maria; Ferrero, Jean-Marc; Tarpin, Carole; Bouteille, Catherine; Calvo, Fabien; Gut, Ivo Glynne; Gut, Marta; Martin, Sancha; Nik-Zainal, Serena; Stratton, Michael R; Pauporté, Iris; Saintigny, Pierre; Birnbaum, Daniel; Viari, Alain; Thomas, Gilles

    2016-01-01

    HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism. PMID:27406316

  2. Treatment of brain metastases from HER-2-positive breast cancer: current status and new concepts.

    PubMed

    Bartolotti, Marco; Franceschi, Enrico; Brandes, Alba A

    2013-11-01

    Breast cancer is the second most common source of brain metastases (BM). The incidence of BM in breast cancer patients has increased over the past decade, especially among patients with HER-2-positive breast cancer. This is probably due to how aggressive the HER-2-positive disease is but also to the prolongation of survival obtained with current treatments, which allow good control of extracranial disease but are unable to cross the blood-brain barrier. At present, whole-brain radiotherapy, surgery and radiosurgery/stereotactic radiotherapy represent the cornerstone of treatment for BM, while the role of pharmacological therapy remains uncertain. Lapatinib demonstrated activity against BM from HER-2-positive breast cancer in small Phase II and retrospective studies, mainly in combination with capecitabine, and cases of dramatic responses to such treatment are present in literature. In this review we focus on the available clinical data regarding the treatment of BM from HER-2-positive breast cancer and on new concepts about the treatment and evaluation of the CNS response. PMID:24156325

  3. Src, a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

    PubMed Central

    Peiró, G; Ortiz-Martínez, F; Gallardo, A; Pérez-Balaguer, A; Sánchez-Payá, J; Ponce, J J; Tibau, A; López-Vilaro, L; Escuin, D; Adrover, E; Barnadas, A; Lerma, E

    2014-01-01

    Background: Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas. Methods: We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome. Results: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab. Conclusions: Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients. PMID:24937674

  4. [Pertuzumab (Perjeta®) approval in HER2-positive metastatic breast cancers].

    PubMed

    Sabatier, Renaud; Gonçalves, Anthony

    2014-01-01

    Fifteen to 20% of breast cancers display HER2 amplification. Many therapeutic successes have been obtained for this subtype in the last decade since trastuzumab approval for metastatic and localized diseases. Pertuzumab, a new anti-HER2 antibody, has been approved in 2013 by the European Medicine Agency. This drug can be used in combination with trastuzumab and docetaxel for the first line treatment of metastatic or locally recurrent non resecable HER2-positive breast cancers not previously treated by chemotherapy or HER2-inhibitors in the metastatic setting. This approval has been done after the CLEOPATRA trial results. This was a randomized, double-blind, multicentre, phase III trial evaluating the standard treatment (trastuzumab plus docetaxel) associated to pertuzumab or placebo. The authors have reported a statistically significant and clinically relevant benefit for the pertuzumab-based treatment. Median progression-free survival was 18.4 for the pertuzumab arm versus 12.5 months for the control group (p<0.001). They also observed benefits concerning the secondary endpoints: overall response rate and overall survival. Patients receiving pertuzumab presented more frequent diarrhea and febrile neutropenia but no increase in cardiac events. This drug has already been evaluated in the neoadjuvant setting with a FDA approval recently obtained. Its use in the adjuvant setting is under evaluation. PMID:25091659

  5. 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

  6. Her-2 Positive Gastric Cancer Presented with Thrombocytopenia and Skin Involvement: A Case Report

    PubMed Central

    Arslan, Deniz; Tatlı, Ali Murat; Goksu, Sema Sezgin; Başsorgun, Cumhur İbrahim; Coskun, Hasan Senol; Bozcuk, Hakan; Savaş, Burhan

    2014-01-01

    Gastric cancer is the 5th most frequent cancer around the world and the 3rd most frequent reason of deaths due to cancer. Every year, about 1 million new cases are taking place, with varying geographical distribution. Gastric cancer is often metastatic to liver, lungs, and bones in hematogenous way, to peripheral lymph nodes in lymphogenous way, and to peripheral tissues in adjacency way, yet bone marrow (BM) and cutaneous metastasis are quite seldom. Pancytopenia is a more frequent finding identified in BM metastasis of solid organ cancers, and isolated thrombocytopenia is less often. The human epidermal growth factor 2 (HER-2) is positive in gastric cancer at a rate of 7–34%. Here, we have presented our HER-2 positive gastric cancer incident which presented with BM and cutaneous metastasis, and has no 18F-fluoro-2-deoxi-D-glucose (FDG) involvement except bone metastases. PMID:25045559

  7. In vivo targeting of HER2-positive tumor using 2-helix affibody molecules.

    PubMed

    Ren, Gang; Webster, Jack M; Liu, Zhe; Zhang, Rong; Miao, Zheng; Liu, Hongguang; Gambhir, Sanjiv S; Syud, Faisal A; Cheng, Zhen

    2012-07-01

    Molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression has drawn significant attention because of the unique role of the HER2 gene in diagnosis, therapy and prognosis of human breast cancer. In our previous research, a novel cyclic 2-helix small protein, MUT-DS, was discovered as an anti-HER2 Affibody analog with high affinity through rational protein design and engineering. MUT-DS was then evaluated for positron emission tomography (PET) of HER2-positive tumor by labeling with two radionuclides, 68Ga and 18F, with relatively short half-life (t1/2<2 h). In order to fully study the in vivo behavior of 2-helix small protein and demonstrate that it could be a robust platform for labeling with a variety of radionuclides for different applications, in this study, MUT-DS was further radiolabeled with 64Cu or 111In and evaluated for in vivo targeting of HER2-positive tumor in mice. Design 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated MUT-DS (DOTA-MUT-DS) was chemically synthesized using solid phase peptide synthesizer and I2 oxidation. DOTA-MUT-DS was then radiolabeled with 64Cu or 111In to prepare the HER2 imaging probe (64Cu/111In-DOTA-MUT-DS). Both biodistribution and microPET imaging of the probe were evaluated in nude mice bearing subcutaneous HER2-positive SKOV3 tumors. DOTA-MUT-DS could be successfully synthesized and radiolabeled with 64Cu or 111In. Biodistribution study showed that tumor uptake value of 64Cu or 111In-labeled DOTA-MUT-DS was 4.66±0.38 or 2.17±0.15%ID/g, respectively, in nude mice bearing SKOV3 xenografts (n=3) at 1 h post-injection (p.i.). Tumor-to-blood and tumor-to-muscle ratios for 64Cu-DOTA-MUT-DS were attained to be 3.05 and 3.48 at 1 h p.i., respectively, while for 111In-DOTA-MUT-DS, they were 2.04 and 3.19, respectively. Co-injection of the cold Affibody molecule ZHER2:342 with 64Cu-DOTA-MUT-DS specifically reduced the SKOV3 tumor uptake of the probe by 48%. 111In

  8. 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

  9. Pertuzumab: in the first-line treatment of HER2-positive metastatic breast cancer.

    PubMed

    Keating, Gillian M

    2012-02-12

    The humanized monoclonal antibody pertuzumab is the first in a new class of drugs, the human epidermal growth factor receptor (HER) dimerization inhibitors. Given that pertuzumab binds to a different epitope of the HER2 extracellular domain than trastuzumab, combination therapy with pertuzumab plus trastuzumab may result in more comprehensive blockade of HER2 signalling than can be achieved with trastuzumab alone. The efficacy of adding pertuzumab to trastuzumab plus docetaxel for the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, multinational, phase III CLEOPATRA trial. Both independently assessed progression-free survival (primary endpoint) and investigator-assessed progression-free survival were significantly improved in patients receiving pertuzumab plus trastuzumab and docetaxel compared with those receiving placebo plus trastuzumab and docetaxel. The prespecified interim analysis of survival revealed a strong trend towards a survival benefit associated with pertuzumab, although this was not considered statistically significant. The objective response rate was higher with pertuzumab than with placebo. Intravenous pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the CLEOPATRA trial. PMID:22316351

  10. Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options

    PubMed Central

    Jiang, Hanfang; Rugo, Hope S.

    2015-01-01

    Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) remains an incurable disease, and approximately 25% of patients with HER2+ early breast cancer still relapse after adjuvant trastuzumab-based treatment. HER2 is a validated therapeutic target that remains relevant throughout the disease process. Recently, a number of novel HER2 targeted agents have become available, including lapatinib (a small molecule tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor), pertuzumab (a new anti-HER2 monoclonal antibody) and ado-trastuzumab emtansine (T-DM1, a novel antibody–drug conjugate), which provide additional treatment options for patients with HER2+ MBC. The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or T-DM1 compared with standard HER2 targeted therapy. Here we review the clinical development of approved and investigational targeted agents for the treatment of HER2+ MBC, summarize the latest results of important clinical trials supporting use of these agents in the treatment of HER2+ MBC, and discuss how these results impact therapeutic options in clinical practice. PMID:26557900

  11. EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

    PubMed Central

    Zhu, Weidong; Phan, Quynh T.; Boontheung, Pinmanee; Solis, Norma V.; Loo, Joseph A.; Filler, Scott G.

    2012-01-01

    The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans, in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3- and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts. PMID:22891338

  12. 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

  13. First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer.

    PubMed

    Blumenthal, Gideon M; Scher, Nancy S; Cortazar, Patricia; Chattopadhyay, Somesh; Tang, Shenghui; Song, Pengfei; Liu, Qi; Ringgold, Kimberly; Pilaro, Anne M; Tilley, Amy; King, Kathryn E; Graham, Laurie; Rellahan, Barbara L; Weinberg, Wendy C; Chi, Bo; Thomas, Colleen; Hughes, Patricia; Ibrahim, Amna; Justice, Robert; Pazdur, Richard

    2013-09-15

    On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues. PMID:23801166

  14. t-Darpp overexpression in HER2-positive breast cancer confers a survival advantage in lapatinib

    PubMed Central

    Christenson, Jessica L.; Denny, Erin C.; Kane, Susan E.

    2015-01-01

    Drug resistance is a major barrier to successful cancer treatment. For patients with HER2-positive breast cancer who initially respond to therapy, the majority develop resistance within one year of treatment. Patient outcomes could improve significantly if we can find and exploit common mechanisms of acquired resistance to different targeted therapies. Overexpression of t-Darpp, a truncated form of the dual kinase/phosphatase inhibitor Darpp-32, has been linked to acquired resistance to trastuzumab, a front-line therapy for HER2-positive breast cancer. Darpp-32 reverses t-Darpp's effect on trastuzumab resistance. In this study, we examined whether t-Darpp could be involved in resistance to lapatinib, another HER2-targeted therapeutic. Lapatinib-resistant SKBR3 cells (SK/LapR) showed a marked change in the Darpp-32:t-Darpp ratio toward a predominance of t-Darpp. Overexpression of t-Darpp alone was not sufficient to confer lapatinib resistance, but cells that overexpress t-Darpp partially mimicked the molecular resistance phenotype observed in SK/LapR cells exposed to lapatinib. SK/LapR cells failed to down-regulate Survivin and failed to induce BIM accumulation in response to lapatinib; cells overexpressing t-Darpp exhibited only the failed BIM accumulation. t-Darpp knock-down reversed this phenotype. Using a fluorescence-based co-culture system, we found that cells overexpressing t-Darpp formed colonies in lapatinib within 3–4 weeks, whereas parental cells in the same co-culture did not. Overall, t-Darpp appears to mediate a survival advantage in lapatinib, possibly linked to failed lapatinib-induced BIM accumulation. t-Darpp might also be relevant to acquired resistance to other cancer drugs that rely on BIM accumulation to induce apoptosis. PMID:26430732

  15. Phosphorylation of Ser78 of Hsp27 correlated with HER-2/neu status and lymph node positivity in breast cancer

    PubMed Central

    Zhang, Daohai; Wong, Lee Lee; Koay, Evelyn SC

    2007-01-01

    Background Abnormal amplification/expression of HER-2/neu oncogene has been causally linked with tumorigenesis and metastasis in breast cancer and associated with shortened overall survival of patients. Recently, heat shock protein 27 (Hsp27) was reported to be highly expressed in HER-2/neu positive tumors and cell lines. However, putative functional links between phosphorylation of Hsp27 with HER-2/neu status and other clinicopathological features remain to be elucidated. Results Comparative phosphoproteomic studies of HER-2/neu positive and -negative breast tumors revealed that Hsp27, one of the identified phosphoproteins, was highly phosphorylated in HER-2/neu positive tumors. The extent of Hsp27 phosphorylation at its Ser15, Ser78 and Ser82 residues were further evaluated with site-specific antibodies in tumor samples by tissue lysate array- and tissue microarray-based analyses, and in the BT474 breast cancer cell line treated with heregulin α1 (HRG α1) or the p38 MAPK inhibitor, SB203580. The tissue lysate array study indicated that only the level of pSer78 in HER-2/neu positive tumors was more than 2-fold that in HER-2/neu negative tumors. Treatment of BT474 cells with HRG α1 and SB203580 indicated that Ser78 phosphorylation was mainly regulated by the HER-2/neu-p38 MAPK pathway. Immunohistochemical staining of sections from a tissue microarray with 97 breast tumors showed that positive staining of pSer78 significantly correlated with HER-2/neu (p = 0.004) and lymph node positivity (p = 0.026). Conclusion This investigation demonstrated the significant correlation of enhanced phosphorylation of the Ser78 residue of Hsp27 with HER-2/neu and lymph node positivity in breast cancer. PMID:17697330

  16. Activity of T-DM1 in HER-2 positive central nervous system breast cancer metastases

    PubMed Central

    Torres, Sofia; Maralani, Pejman; Verma, Sunil

    2014-01-01

    A 55-year-old woman with metastatic human epidermal growth factor receptor 2 (HER-2) positive breast cancer (BC) to the lungs and bones was diagnosed with central nervous system (CNS) metastases in November 2011. The MRI showed a right parietal lobe mass with adjacent leptomeningeal disease and several small bilateral cerebellar metastases. She was treated with whole brain irradiation (WBI), followed by capecitabine and lapatinib (December 2011-March 2013) and trastuzumab and lapatinib (May 2013-August 2013). Then, the brain MRI showed progression. In the absence of significant neurological symptoms, we postponed WBI and closely monitored for the development of neurological symptoms. Systemic treatment with trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab, was initiated in September 2013 to control systemic disease. Unexpectedly, after two cycles of treatment the brain MRI showed a decrease in size of CNS metastases. This case report suggests possible activity of T-DM1 in HER-2 positive BC with CNS metastases. PMID:25123575

  17. HER-2/neu protein-receptor-positive breast carcinoma: an immunologic perspective.

    PubMed

    Brown, R E; Bernath, A M; Lewis, G O

    2000-07-01

    Immunotherapy using a monoclonal antibody against the human epidermal growth factor receptor 2 protein, HER-2/neu, has proven to be clinically efficacious in about one-half of breast cancer patients who exhibit strong (3+) plasmalemmal immunoreactivity for this protein. The tumoricidal effect of this antibody relies in part upon antibody-dependent cell-mediated cytotoxicity. This report provides observations on certain factors or circumstances which could have an impact on this aspect of the therapeutic approach. These include: (1) concurrent medications; (2) the composition (immunophenotype) of peritumoral lymphocytes and the generally limited numbers of intratumoral T-lymphocytes/natural killer (NK) cells, monocytes, and neutrophilic granulocytes; (3) the presence of circulating HER-2/neu antigens which might bind the exogenous antibody and lead to immune complex formation; (4) the variable co-expression in the tumor of cytokines known to downregulate NK cell function (ie, transforming growth factor-beta1 [TGF-beta1] and platelet-derived growth factor [PDGF]-AB); and (5) the tumoral and/or stromal immunoreactivity for angiotensin-converting enzyme, which forms a part of one of the pathways for the activation of latent TGF-beta1 and for the biosynthesis of PDGF-AB. These observations provide an immunologic perspective for the use of monoclonal antibody therapy in HER-2/neu protein-receptor-positive breast carcinoma and suggest a role for the clinical laboratory in identifying potential avenues for additional manipulations of the immune system in individual cases in order to enhance the therapeutic response. PMID:10945564

  18. Trastuzumab-mediated selective delivery for platinum drug to HER2-positive breast cancer cells.

    PubMed

    Huang, Rong; Sun, Yu; Gao, Qihe; Wang, Qiucui; Sun, Baiwang

    2015-10-01

    Oxaliplatin is used widely as an anticancer drug for clinical treatment. However, its applications are limited because of its poor selectivity. In this work, we described the design, synthesis, and characterization of conjugates combining trastuzumab with a platinum (IV) analog of oxaliplatin, in which the trastuzumab acted as an active targeting agent for HER2-positive cancer cells. Indirect enzyme-linked immunosorbent assay and immunofluorescence study indicated the platinum (IV)-trastuzumab conjugates retained specific binding activity to HER2 overexpressed SK-BR-3 cells. In the presence of ascorbic acid, platinum (IV)-trastuzumab conjugates were reduced to platinum (II) analogs, which could bind to and unwind PUC19 DNA in a manner similar to oxaliplatin. The cytotoxic study was tested on three breast cell lines: SK-BR-3, MCF-7, and MDA-MB-231. Platinum (IV)-trastuzumab conjugates showed promising antiproliferative activity against SK-BR-3 cells, but significantly decreased the inhibition to MDA-MB-231 and MCF-7 cells. The flow cytometric analysis showed that the conjugates arrested the cell cycle mainly at the G2/M phase and killed the cells through an apoptotic pathway. PMID:26186063

  19. Inhibition of fatty acid synthase suppresses U-2 OS cell invasion and migration via downregulating the activity of HER2/PI3K/AKT signaling pathway in vitro

    SciTech Connect

    Wang, Tao Fang; Wang, Heng; Peng, Ai Fen; Luo, Qing Feng; Liu, Zhi Li; Zhou, Rong Ping; Gao, Song; Zhou, Yang; Chen, Wen Zhao

    2013-10-18

    Highlights: •We investigate the relationship between FASN and HER2 or p-HER2 by IHC in OS tissues. •We construct FASN-specific RNAi plasmid. •Inhibiting FASN down-regulates HER2/PI3K/AKT cell signaling in U-2 OS. •Inhibiting FASN blocks U-2 OS cell invasion and migration. -- Abstract: FASN plays an important role in the malignant phenotype of various tumors. Our previous studies show that inhibition FASN could induce apoptosis and inhibit proliferation in human osteosarcoma (OS) cell in vivo and vitro. The aim in this study was to investigate the effect of inhibition FASN on the activity of HER2/PI3K/AKT axis and invasion and migration of OS cell. The expression of FASN, HER2 and p-HER2(Y1248) proteins was detected by immunohistochemistry in OS tissues from 24 patients with pulmonary metastatic disease, and the relationship between FASN and p-HER2 as well as HER2 was investigated. The results showed that there was a positive correlation between FASN and HER2 as well as p-HER2 protein expression. The U-2 OS cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid. FASN mRNA was measured by RT-PCR. Western blot assays was performed to examine the protein expression of FASN, HER2, p-HER2(Y1248), PI3K, Akt and p-Akt (Ser473). Migration and invasion of cells were investigated by wound healing and transwell invasion assays. The results showed that the activity of HER2/PI3K/AKT signaling pathway was suppressed by inhibiting FASN. Meanwhile, the U-2OS cells migration and invasion were also impaired by inhibiting the activity of FASN/HER2/PI3K/AKT. Our results indicated that inhibition of FASN suppresses OS cell invasion and migration via down-regulation of the “HER2/PI3K/AKT” axis in vitro. FASN blocker may be a new therapeutic strategy in OS management.

  20. Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer.

    PubMed

    Bhargava, Rohit; Dabbs, David J; Beriwal, Sushil; Yildiz, Isil A; Badve, Preeti; Soran, Atilla; Johnson, Ronald R; Brufsky, Adam M; Lembersky, Barry C; McGuire, Kandace P; Ahrendt, Gretchen M

    2011-03-01

    Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptor-negative/HER2+ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER)+/HER2+ tumors demonstrate pathologic complete response in ∼ 8% of cases and is generally limited to weak-to-moderate ER+/HER2+ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2+ tumors. A list of HER2+ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2+ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score ≤10]/HER2+), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER+ [H-score 11-199]/HER2+), and Luminal A-HER2 Hybrid (LAHH; strong ER+[H-score ≥200]/HER2+). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2+ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting. PMID:21102420

  1. The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer.

    PubMed

    Wang, Qiwei; Zhang, Xiaotian; Shen, Enyun; Gao, Jing; Cao, Fengqi; Wang, Xiaojuan; Li, Yilin; Tian, Tiantian; Wang, Jingyuan; Chen, Zuhua; Wang, Jiayuan; Shen, Lin

    2016-09-28

    The anti-HER2 monoclonal antibody trastuzumab is central to the treatment of HER2-positive gastric cancer (GC); however, its responses are limited. HER3 seems to be the preferred dimerization partner with HER2 and is emerging as a key target for complete blockade of downstream pathways and better clinical response. In this study, we report that novel anti-HER3 antibodies (1A5-3D4) that can neutralize multiple modes of HER3 activation, combined with trastuzumab, exhibited synergistic inhibitory effect on the cell proliferation in HER2-positive GC cell lines. Follow-up studies revealed that the combination treatment significantly inhibited phosphorylation of HER3 as well as AKT and ERK signals. In vivo experiments further showed that the anti-tumor effect of trastuzumab was enhanced by its combination with 1A5-3D4 in NCI-N87 xenograft and patient derived xenografts (PDX). Particularly in an HER2-negative whereas neuregulin1 (a ligand of HER3) positive PDX, the combination was also superior to monotherapy. 1A5-3D4 in combination with trastuzumab exhibits a synergistic inhibitory effect on tumor activity, suggesting that targeting both HER2 and HER3 resulted in an improved treatment effects on HER2-positive GC. PMID:27317872

  2. Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer

    ClinicalTrials.gov

    2016-06-23

    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

  3. Chemotherapy Less Toxic to the Heart May Be Option for Some Women with HER2-Positive Breast Cancer

    Cancer.gov

    A nonanthracycline-containing chemotherapy regimen combined with the targeted therapy trastuzumab may be an option for some women with HER2-positive breast cancer, according to results from the BCIRG-006 trial.

  4. Activity of T-DM1 in Her2-positive breast cancer brain metastases.

    PubMed

    Bartsch, Rupert; Berghoff, Anna S; Vogl, Ursula; Rudas, Margaretha; Bergen, Elisabeth; Dubsky, Peter; Dieckmann, Karin; Pinker, Katja; Bago-Horvath, Zsuzsanna; Galid, Arik; Oehler, Leopold; Zielinski, Christoph C; Gnant, Michael; Steger, Guenther G; Preusser, Matthias

    2015-10-01

    Brain metastases (BM) are frequently diagnosed in metastatic Her2-positive breast cancer. Local treatment remains the standard of care but lapatinib plus capecitabine was recently established as systemic therapy option. Due to a disruption of the blood-brain/tumour-barrier at metastatic sites, even large molecules may penetrate into the central nervous system (CNS). Here, we report on the activity of T-DM1 in Her2-positive breast cancer BM. T-DM1 was administered at a dose of 3.6 mg once every 3 weeks as primary systemic therapy for BM or upon documented CNS progression after initial local treatment. Thus, this study allowed for the appraisal of T-DM1 activity in BM. Restaging was conducted every 12 weeks with MRI or whenever symptoms of disease progression occurred. Ten patients were included; in two asymptomatic subjects, T-DM1 was administered as primary therapy, while eight had progressive BM. All patients had received prior treatment with trastuzumab, six had already received lapatinib, and three pertuzumab as well. Three patients had partial remission of BM, and two patient had stable disease lasting for ≥6 months; two further patients had stable disease for <6 months while three progressed despite treatment. At 8.5 months median follow-up, intracranial PFS was 5 months, and median OS from initiation of T-DM1 was not reached. Local treatment of BM remains the standard of care; lapatinib plus capecitabine is currently the best established systemic therapy option. Still, T-DM1 apparently offers relevant clinical activity in BM and further investigation is warranted. PMID:26303828

  5. Monitoring Afatinib Treatment in HER2-Positive Gastric Cancer with 18F-FDG and 89Zr-Trastuzumab PET

    PubMed Central

    Janjigian, Yelena Y.; Viola-Villegas, Nerissa; Holland, Jason P.; Divilov, Vadim; Carlin, Sean D.; Gomes-DaGama, Erica M.; Chiosis, Gabriela; Carbonetti, Gregory; de Stanchina, Elisa; Lewis, Jason S.

    2016-01-01

    We evaluated the ability of the PET imaging agent 89Zr-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib. Methods Using 89Zr-trastuzumab, 18F-FDG, or 3′-deoxy-3′-18F-fluorothymidine (18F-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using 89Zr-trastuzumab and 18F-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies. Results Although 18F-FDG uptake in NCI-N87 tumors did not change, a decrease in 89Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 ± 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 ± 3.4%ID/g, respectively; P < 0.05). 89Zr-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment. Conclusion Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. 89Zr-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib. PMID:23578997

  6. Radiolabeled Affibody-Albumin Bioconjugates for HER2 Positive Cancer Targeting

    PubMed Central

    Hoppmann, Susan; Miao, Zheng; Liu, Shuanglong; Liu, Hongguang; Ren, Gang; Bao, Ande; Cheng, Zhen

    2011-01-01

    Affibody molecules have received significant attention in the fields of molecular imaging and drug development. However, Affibody scaffolds display an extremely high renal uptake, especially when modified with chelators and then labeled with radiometals. This unfavorable property may impact their use as radiotherapeutic agents in general and as imaging probes for the detection of tumors adjacent to kidneys in particular. Herein, we present a simple and generalizable strategy for reducing the renal uptake of Affibody molecules while maintaining their tumor uptake. Human serum albumin (HSA) was consecutively modified by 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DOTA-NHS ester) and the bifunctional crosslinker sulfosuccinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (Sulfo-SMCC). The HER2 Affibody analog, Ac-Cys-ZHER2:342, was covalently conjugated with HSA, and the resulting bioconjugate DOTA-HSA-ZHER2:342 was further radiolabeled with 64Cu and 111In and evaluated in vitro and in vivo. Radiolabeled DOTA-HSA-ZHER2:342 conjugates displayed a significant and specific cell uptake into SKOV3 cell cultures. Positron emission tomography (PET) investigations using 64Cu-DOTA-HSA-ZHER2:342 were performed in SKOV3 tumor-bearing nude mice. High tumor uptake values (> 14% ID/g at 24 h and 48 h) and high liver accumulations but low kidney accumulations were observed. Biodistribution studies and single-photon emission computed tomography (SPECT) investigations using 111In-DOTA-HSA-ZHER2:342 validated these results. At 24 h post injection, the bio distribution data revealed high tumor (16.26% ID/g) and liver uptake (14.11% ID/g) but relatively low kidney uptake (6.06% ID/g). Blocking studies with co-injected, non-labeled Ac-Cys-ZHER2:342 confirmed the in vivo specificity of HER2. Radiolabeled DOTA-HSA-ZHER2:342 Affibody conjugates are promising SPECT and PET-type probes for the imaging of HER2 positive cancer. More importantly

  7. Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells.

    PubMed

    Oak, Prajakta S; Kopp, Florian; Thakur, Chitra; Ellwart, Joachim W; Rapp, Ulf R; Ullrich, Axel; Wagner, Ernst; Knyazev, Pjotr; Roidl, Andreas

    2012-12-15

    A major obstacle in the successful treatment of cancer is the occurrence of chemoresistance. Cancer cells surviving chemotherapy and giving rise to a recurrence of the tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2(high) and HER2(low) cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2(low) cell fraction. Accordingly, HER2(low) cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in matrigel. Xenografts from subcutaneously injected HER2(low) sorted cells exihibited earlier onset but slower growth of tumors and an increase in stem cell markers compared to tumors developed from the HER2(high) fraction. Treatment of mammospheres with salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells. Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with trastuzumab and salinomycin was superior to single treatment with each drug. Thus, targeting HER2 expressing tumors with anti-HER2 therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy. PMID:22511343

  8. Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer

    PubMed Central

    Yu, Anthony F.; Yadav, Nandini U.; Lung, Betty Y.; Eaton, Anne A.; Thaler, Howard T.; Hudis, Clifford A.; Dang, Chau T.; Steingart, Richard M.

    2016-01-01

    Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified (n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p<0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p<0.0001) and trastuzumab (62 vs. 67 %, p<0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients. PMID:25552363

  9. Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer.

    PubMed

    Roy, Vivek; Perez, Edith A

    2009-11-01

    HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti-HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood-brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti-HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available. PMID:19887469

  10. Systemic Therapy for HER2-Positive Central Nervous System Disease: Where We Are and Where Do We Go From Here?

    PubMed

    Teplinsky, Eleonora; Esteva, Francisco J

    2015-10-01

    Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at an increased risk of developing brain metastases. The incidence and prevalence of central nervous system (CNS) disease are increasing due to improved survival, which can be attributed to better systemic therapies for extracranial disease. The current standard of care for brain metastases includes a combination of surgery and/or radiation. Systemic therapies are typically reserved for patients with intracranial progression following radiation, due to their limited ability to cross the blood-brain barrier. None of the available anti-HER2 agents (trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1)) are currently approved for the treatment of brain metastases. Research is underway evaluating novel anti-HER2 agents, which have demonstrated CNS activity. This article discusses the current data on using anti-HER2 therapies to treat CNS disease as well as the newer anti-HER2 agents, which may overcome the current challenges faced in treating brain metastases in the HER2-positive patient population. PMID:26314739

  11. 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. PMID:26507543

  12. 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. PMID:27265303

  13. A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

    PubMed Central

    Papadakis, Emmanouil; Robson, Natalia; Yeomans, Alison; Bailey, Sarah; Laversin, Stephanie; Beers, Stephen; Sayan, A. Emre; Ashton-Key, Margaret; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Packham, Graham; Cutress, Ramsey

    2016-01-01

    Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID:26958811

  14. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

    PubMed Central

    Kulhari, Hitesh; Pooja, Deep; Shrivastava, Shweta; Kuncha, Madhusudana; Naidu, V. G. M.; Bansal, Vipul; Sistla, Ramakrishna; Adams, David J.

    2016-01-01

    Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem. PMID:27052896

  15. Infracentimetric HER-2 positive breast tumours—review of the literature

    PubMed Central

    da Fonseca Reis Silva, Danilo; Ribeiro, Joana M

    2015-01-01

    Breast cancer is the most common malignant neoplasm in the world among women. As a result of the dissemination of population screening programmes, about half of non-metastatic breast cancers are now diagnosed at stage I. 10–15% of T1abN0 tumours over-express human epidermal growth factor (HER-2). These tumours have a globally excellent prognosis, however, treatment with chemotherapy and/or targeted therapy may further improve outcomes in selected cases. In this article, we will review studies with information on prognosis and benefit of adjuvant therapy for T1abN0 HER-2+ breast cancer. PMID:26635897

  16. Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer

    ClinicalTrials.gov

    2016-09-15

    Estrogen Receptor Positive; HER2/Neu Positive; Progesterone Receptor Positive; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  17. 18F-fluorodeoxyglucose (FDG) PET/CT after two cycles of neoadjuvant therapy may predict response in HER2-negative, but not in HER2-positive breast cancer

    PubMed Central

    Mo, Miao; Bao, Xiao; Zhang, Yingjian; Liu, Guangyu; Zhang, Jun; Geng, Daoying

    2015-01-01

    The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. 18FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab. PMID:26336821

  18. Polymalic acid nanobioconjugate for simultaneous inhibition of tumor growth and immunostimulation in HER2/neu-positive breast cancer✩

    PubMed Central

    Ding, Hui; Helguera, Gustavo; Rodríguez, José A.; Markman, Janet; Luria-Pérez, Rosendo; Gangalum, Pallavi; Portilla-Arias, Jose; Inoue, Satoshi; Daniels-Wells, Tracy R.; Black, Keith; Holler, Eggehard; Penichet, Manuel L.; Ljubimova, Julia Y.

    2013-01-01

    Breast cancer remains the second leading cause of cancer death among women in the United States. The breast cancer prognosis is particularly poor in case of tumors overexpressing the oncoprotein HER2/neu. A new nanobioconjugate of the Polycefin family of anti-cancer drugs based on biodegradable and non-toxic polymalic acid (PMLA) was engineered for a multi-pronged attack on HER2/neu-positive breast cancer cells. An antibody cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensuring the delivery of IL-2 to the tumor microenvironment. Antisense oligonucleotides (AON) were conjugated to the nanodrug to inhibit the expression of vascular tumor protein laminin-411 in order to block tumor angiogenesis. It is shown that the nanobioconjugate was capable of specifically binding human HER2/neu and retaining the biological activity of IL-2. We also showed the uptake of the nanobioconjugate by HER2/neu-positive breast cancer cells and enhanced tumor targeting in vivo. In addition, the nanobioconjugate was capable of eliciting anti-tumor activity in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu. Both IgG1 and IgG2a levels were significantly increased in animals treated with the PMLA-fusion nanobioconjugate compared to animals treated with the antibody–cytokine fusion protein alone or control animals, indicative of the induction of a humoral (TH2) and cell-mediated (TH1) immune responses. Animal survival in vivo was significantly longer after treatment with leading nanobioconjugate with fusion [anti-HER2/neu IgG3-(IL-2)] antibody, p < 0.05. The combination of these molecules on a single polymeric platform is expected to act through direct elimination of cancer cells, inhibition of tumor angiogenesis, and orchestration of a

  19. Triple-Negative or HER2-Positive Status Predicts Higher Rates of Locoregional Recurrence in Node-Positive Breast Cancer Patients After Mastectomy

    SciTech Connect

    Wang Shulian; Li Yexiong; Song Yongwen; Wang Weihu; Jin Jing; Liu Yueping; Liu Xinfan; Yu Zihao

    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: 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.

  20. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer

    PubMed Central

    2014-01-01

    Introduction The purpose of this study was to retrospectively explore the relationship between human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) expression and efficacy in patients receiving trastuzumab plus docetaxel (HT) or trastuzumab emtansine (T-DM1). Methods Patients with HER2-positive, locally advanced or metastatic breast cancer (MBC) were randomly assigned to HT (n = 70) or T-DM1 (n = 67). HER2 status was assessed locally using immunohistochemistry or fluorescence in situ hybridization and confirmed retrospectively by central testing. HER2 mRNA expression was assessed using quantitative reverse transcriptase polymerase chain reaction. Results HER2 mRNA levels were obtained for 116/137 patients (HT = 61; T-DM1 = 55). Median pretreatment HER2 mRNA was 8.9. The risk of disease progression in the overall population was lower with T-DM1 than with HT (hazard ratio (HR) = 0.59; 95% confidence interval (CI) 0.36 to 0.97). This effect was more pronounced in patients with HER2 mRNA ≥ median (HR = 0.39; 95% CI 0.18 to 0.85) versus < median (HR = 0.85; 95% CI 0.44 to 1.67). In the T-DM1 arm, median progression-free survival (PFS) was not reached in patients with HER2 mRNA ≥ median and was 10.6 months in patients with HER2 mRNA < median. In the HT arm, PFS was 8.8 versus 9.8 months in patients with HER2 mRNA ≥ median versus < median, respectively. The effect of HER2 mRNA expression on objective response rates was less pronounced. Conclusions This exploratory analysis suggests that while overall, patients with HER2-positive MBC show improved PFS with T-DM1 relative to HT, the effect is enhanced in patients with tumor HER2 mRNA ≥ median. Trial registration ClinicalTrials.gov NCT00679341 PMID:24887458

  1. Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients

    PubMed Central

    Duchnowska, Renata; Wysocki, Piotr J.; Korski, Konstanty; Czartoryska-Arłukowicz, Bogumiła; Niwińska, Anna; Orlikowska, Marlena; Radecka, Barbara; Studziński, Maciej; Demlova, Regina; Ziółkowska, Barbara; Merdalska, Monika; Hajac, Łukasz; Myśliwiec, Paulina; Zuziak, Dorota; Dębska-Szmich, Sylwia; Lang, Istvan; Foszczyńska-Kłoda, Małgorzata; Karczmarek-Borowska, Bożenna; Żawrocki, Anton; Kowalczyk, Anna; Biernat, Wojciech; Jassem, Jacek

    2016-01-01

    Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors. PMID:26623720

  2. PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers

    PubMed Central

    Stanley, Jennifer; Klepczyk, Lisa; Keene, Kimberly; Wei, Shi; Li, Yufeng; Forero, Andres; Grizzle, William; Wielgos, Monica; Brazelton, Jason; LoBuglio, Albert F.; Yang, Eddy S.

    2015-01-01

    Purpose Previous studies have shown that basal breast cancers, which may have an inherent “BRCAness” phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-kB pathway. In this study, we assessed PARP1 and phospho-p65, a marker of activated NF-kB levels in human breast cancer tissues. Methods PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using the cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. Results In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41%) HER2+, 32/81 (40%) basal, and 75/324 (23%) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p=0.003, p=0.027, p=0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p<0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho-p65 expression (p<0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p<0.0001) was noted. Conclusions These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due

  3. Autophagy and Apoptotic Crosstalk: Mechanism of Therapeutic Resistance in HER2-Positive Breast Cancer

    PubMed Central

    Zambrano, Joelle; Yeh, Elizabeth S.

    2016-01-01

    While breast cancer patients benefit from the use of HER2 inhibitors, many fail therapy and become resistant to treatment, indicating a critical need to prevent treatment failure. A number of studies have emerged that highlight the catabolic process of autophagy in breast cancer as a mechanism of resistance to chemotherapy and targeted inhibitors. Furthermore, recent research has begun to dissect how autophagy signaling crosstalks with apoptotic signaling. Thus, a possible strategy in fighting resistance is to couple targeting of apoptotic and autophagy signaling pathways. In this review, we discuss how cellular response by autophagy circumvents cell death to promote resistance of breast cancers to HER2 inhibitors, as well as the potential avenues of therapeutic intervention. PMID:26997868

  4. 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. PMID:27017242

  5. Transition probabilities of HER2-positive and HER2-negative breast cancer patients treated with Trastuzumab obtained from a clinical cancer registry dataset

    PubMed Central

    Pobiruchin, Monika; Bochum, Sylvia; Martens, Uwe M.; Kieser, Meinhard; Schramm, Wendelin

    2016-01-01

    Records of female breast cancer patients were selected from a clinical cancer registry and separated into three cohorts according to HER2-status (human epidermal growth factor receptor 2) and treatment with or without Trastuzumab (a humanized monoclonal antibody). Propensity score matching was used to balance the cohorts. Afterwards, documented information about disease events (recurrence of cancer, metastases, remission of local/regional recurrences, remission of metastases and death) found in the dataset was leveraged to calculate the annual transition probabilities for every cohort. PMID:27054173

  6. Transition probabilities of HER2-positive and HER2-negative breast cancer patients treated with Trastuzumab obtained from a clinical cancer registry dataset.

    PubMed

    Pobiruchin, Monika; Bochum, Sylvia; Martens, Uwe M; Kieser, Meinhard; Schramm, Wendelin

    2016-06-01

    Records of female breast cancer patients were selected from a clinical cancer registry and separated into three cohorts according to HER2-status (human epidermal growth factor receptor 2) and treatment with or without Trastuzumab (a humanized monoclonal antibody). Propensity score matching was used to balance the cohorts. Afterwards, documented information about disease events (recurrence of cancer, metastases, remission of local/regional recurrences, remission of metastases and death) found in the dataset was leveraged to calculate the annual transition probabilities for every cohort. PMID:27054173

  7. Selective internalization of self-assembled artificial oil bodies by HER2/neu-positive cells

    NASA Astrophysics Data System (ADS)

    Chiang, Chung-Jen; Lin, Li-Jen; Lin, Che-Chin; Chang, Chih-Hsiang; Chao, Yun-Peng

    2011-01-01

    A novel delivery carrier was developed using artificial oil bodies (AOBs). Plant seed oil bodies (OBs) consist of a triacylglycerol matrix surrounded by a monolayer of phospholipids embedded with the storage protein oleosin (Ole). Ole consists of a central hydrophobic domain with two amphiphatic arms that extrude from the surface of OBs. In this study, a bivalent anti-HER2/neu affibody domain (ZH2) was fused with Ole at the C terminus. After overproduction in Escherichia coli, the fusion protein (Ole-ZH2) was recovered to assemble AOBs. The size of self-assembled AOBs was tailored by varying the oil/Ole-ZH2 ratio and pH to reach a nanoscale. Upon co-incubation with tumor cells, the nanoscale AOBs encapsulated with a hydrophobic fluorescence dye were selectively internalized by HER2/neu-overexpressing cells and displayed biocompatibility with the cells. In addition, the ZH2-mediated endosomal entry of AOBs occurred in a time- and AOB dose-dependent manner. The internalization efficiency was as high as 90%. The internalized AOBs disintegrated at the non-permissive pH (e.g. in acidic endosomes) and the cargo dye was released. Results of in vitro study revealed a sustained and prolonged release profile. Taken together, our findings indicate the potential of AOBs as a delivery carrier.

  8. Targeted Delivery of Deoxycytidine Kinase to Her2-Positive Cells Enhances the Efficacy of the Nucleoside Analog Fludarabine

    PubMed Central

    Kay, Brian K.; Lavie, Arnon

    2016-01-01

    Cytotoxic drugs, such as nucleoside analogs and toxins, commonly suffer from off-target effects. One approach to mitigate this problem is to deliver the cytotoxic drug selectively to the intended site. While for toxins this can be achieved by conjugating the cell-killing moiety to a targeting moiety, it is not an option for nucleoside analogs, which rely on intracellular enzymes to convert them to their active triphosphorylated form. To overcome this limitation, and achieve site-targeted activation of nucleoside analogs, we fused the coding region of a prodrug-activating enzyme, deoxycytidine kinase (dCK), to affinity reagents that bind to the Her2 cell surface protein. We evaluated dCK fusions to an anti-Her2 affibody and Designed Ankyrin Repeat Protein (DARPin) for their ability to kill cancer cells by promoting the activation of the nucleoside analog fludarabine. Cell staining and flow cytometry experiments with three Her2 positive cancer cell lines (BT-474-JB, JIMT-1 and SK-OV-3) indicate dCK fusions binding and cellular internalization. In contrast, these reagents bind only weakly to the Her2 negative cell line, MCF-7. Cell proliferation assays indicate that SK-OV-3 and BT-474-JB cell lines exhibit significantly reduced proliferation rates when treated with targeting-module fused dCK and fludarabine, compared to fludarabine alone. These findings demonstrate that we have succeeded in delivering active dCK into the Her2-positive cells, thereby increasing the activation of fludarabine, which ultimately reduces the dose of nucleoside analog needed for cell killing. This strategy may help establish the therapeutic index required to differentiate between healthy tissues and cancer cells. PMID:27280468

  9. Ultrasound Targeted Apoptosis Imaging in Monitoring Early Tumor Response of Trastuzumab in a Murine Tumor Xenograft Model of Her-2Positive Breast Cancer11

    PubMed Central

    Wei, Xi; Li, Ying; Zhang, Sheng; Gao, Xiujun; Luo, Yi; Gao, Ming

    2014-01-01

    OBJECTIVE: Our study aimed to monitor the trastuzumab therapy response of murine tumor xenograft model with human epidermal growth factor receptor 2 (Her-2)–positive breast cancer using ultrasound targeted apoptosis imaging. METHODS: We prepared targeted apoptosis ultrasound probes by nanobubble (NB) binding with Annexin V. In vitro, we investigated the binding rate of NB–Annexin V with breast cancer apoptotic cells after the trastuzumab treatment. In vivo, tumor-bearing mice underwent ultrasound targeted imaging over 7 days. After imaging was completed, the tumors were excised to determine Her-2 and caspase-3 expression by immunohistochemistry (IHC). The correlation between parameters of imaging and histologic results was then analyzed. RESULTS: For seeking the ability of targeted NB binding with apoptotic tumor cells (Her-2 positive), we found that binding rate in the treatment group was higher than that of the control group in vitro (P = .001). There were no differences of tumor sizes in all groups over the treatment process in vivo (P = .98). However, when using ultrasound imaging to visualize tumors by targeted NB in vivo, we observed that the mean and peak intensities from NBs gradually increased in the treatment group after trastuzumab therapy (P = .001). Furthermore, these two parameters were significantly associated with caspase-3 expression of tumor excised samples (P = .0001). CONCLUSION: Ultrasound targeted apoptosis imaging can be a non-invasive technique to evaluate the early breast tumor response to trastuzumab therapy. PMID:24685547

  10. A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer.

    PubMed

    Curigliano, Giuseppe; Romieu, Gilles; Campone, Mario; Dorval, Thierry; Duck, Lionel; Canon, Jean-Luc; Roemer-Becuwe, Celia; Roselli, Mario; Neciosup, Silvia; Burny, Wivine; Callegaro, Andrea; de Sousa Alves, Pedro Miguel; Louahed, Jamila; Brichard, Vincent; Lehmann, Frédéric F

    2016-04-01

    The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2-overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease ≥26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients. PMID:26975189

  11. Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers.

    PubMed

    Tsang, Julia Y S; Hui, Suen-Wah; Ni, Yun-Bi; Chan, Siu-Ki; Yamaguchi, Rin; Kwong, Ava; Law, Bonita K B; Tse, Gary M

    2014-01-01

    The value for lymphocytic infiltration (LI) has been increasingly recognized for tumor assessment. In breast cancer, however, the overall significance of LI remains poorly defined, probably due to its heterogeneity. A large cohort of breast cancer was evaluated for the degree of LI and its association with traditional pathologic factors, biomarker expression, and cancer subtypes. The number of CD8 cytotoxic effector and FoxP3 regulatory T cell (Treg) was evaluated in those cases with high LI. High LI was associated with negative ER and PR but positive HER2 and EGFR expression (p < 0.001 for all). In ER-positive cancers, high LI was associated with poor prognostic features including higher grade, the presence of necrosis, and lymphovascular invasion (LVI) (p = 0.007 for LVI and <0.001 for the others). Conversely, LI correlated with smaller tumor size, a good prognostic feature (p = 0.046) in HER2+ ER-cancers. These observations suggested LI may show opposite prognostic values in different breast cancer subgroups. Interestingly, when the phenotype of LI in these subgroups was evaluated, a strong positive association with intratumoral accumulation of Treg was found in ER-positive cancers (p = 0.003, Rs = 0.319), while the opposite was observed in HER2+ ER-cancers (p < 0.001, Rs = -0.427). Also, in ER-positive cancers, positive associations between peri- and intra-tumoral distribution were found with both CD8 and Tregs (CD8: p < 0.001, Rs = 0.547; Treg: p = 0.001, Rs = 0.460). Nonetheless, in HER2+ ER-cancers, such strong association was found with CD8 (p < 0.001, Rs = 0.766) but not Tregs. The results may implicate a differential intratumoral migration of LI in different subtypes of breast cancer. In summary, the clinical value of LI in breast cancers could be subtype-dependent. In ER-positive cancers, high LI correlated with biologic parameters associated with poor prognosis, whereas in HER2 positive cancers, LI correlated with biologic

  12. Cost-effectiveness of lapatinib plus letrozole in her2-positive, hormone receptor–positive metastatic breast cancer in Canada

    PubMed Central

    Delea, T.E.; Amdahl, J.; Chit, A.; Amonkar, M.M.

    2013-01-01

    Background The cost-effectiveness of first-line treatment with lapatinib plus letrozole for postmenopausal women with hormone receptor–positive (hr+), human epidermal growth factor receptor 2–positive (her2+) metastatic breast cancer (mbc) has not been assessed from the Canadian health care system and societal perspectives. Methods A partitioned survival analysis model with 3 health states (alive, pre-progression; alive, post-progression; dead) was developed to estimate direct and indirect costs and quality-adjusted life years (qalys) with lapatinib–letrozole, letrozole, anastrozole, or trastuzumab–anastrozole as first-line treatment. Clinical inputs for lapatinib–letrozole and letrozole were taken from the EGF30008 trial (NCT00073528). Clinical inputs for anastrozole and trastuzumab–anastrozole were taken from a network meta-analysis of published studies. Drug costs were obtained from the manufacturer’s price list, the Quebec list of medications, and imsBrogan. Other costs were taken from the Ontario Health Insurance Plan’s Schedule of Benefits and Fees and published studies. A 10-year time horizon was used. Costs and qalys were discounted at 5% annually. Deterministic and probabilistic sensitivity analyses were performed to assess the effects of changes in model parameters. Results Quality-adjusted life years gained with lapatinib–letrozole were 0.236 compared with trastuzumab–anastrozole, 0.440 compared with letrozole, and 0.568 compared with anastrozole. Assuming a health care system perspective, incremental costs were $5,805, $67,029, and $67,472 respectively. Given a cost per qaly threshold of $100,000, the probability that lapatinib–letrozole is preferred was 21% compared with letrozole, 36% compared with anastrozole, and 68% compared with trastuzumab–anastrozole. Results from the societal perspective were similar. Conclusions In postmenopausal women with hr+/her2+ mbc receiving first-line treatment, lapatinib–letrozole may not be

  13. Nab-paclitaxel and trastuzumab combination: a promising approach for neoadjuvant treatment in HER2-positive breast cancer

    PubMed Central

    Ricciardi, Giuseppina Rosaria Rita; Franchina, Tindara; Russo, Alessandro; Schifano, Silvia; Ferraro, Giuseppa; Adamo, Vincenzo

    2016-01-01

    Neoadjuvant therapy is a well-established approach for the treatment of locally advanced or inflammatory breast cancer (BC) and has been increasingly used in recent years not only as a management strategy but also as a research tool. Recently, nanoparticle albumin-bound paclitaxel (nab-paclitaxel)/trastuzumab combinations have been associated with promising activity in different clinical settings. In the present case, we report a complete pathological response after neoadjuvant treatment with the trastuzumab/nab-paclitaxel combination in a locally advanced human epidermal growth factor receptor 2 (HER2)-positive BC patient, with a good toxicity profile. This combination may represent a valid therapeutic option in the neoadjuvant therapy for HER2-positive locally advanced BC. PMID:27499629

  14. HSP90 expression and its association with wighteone metabolite response in HER2-positive breast cancer cells

    PubMed Central

    CAO, ZHONG-WEI; ZENG, QIAN; PEI, HAI-JIANG; REN, LI-DONG; BAI, HAI-ZHEN; NA, RI-NA

    2016-01-01

    It is well known that heat shock protein 90 (HSP90) overexpression is correlated with poor prognosis and chemo-resistance in human malignant cancers. At the same time, wighteone, or 6-prenyl-5,7,4′-trihydroxyisoflavone, a major isoflavone component of the ornamental tall tree Erythrina suberosa, has been demonstrated to exhibit a potent anti-proliferative effect on human leukemia HL-60 cancer cell lines. In this study, the effects of wighteone on the proliferation of HER2-positive breast cancer cells were investigated, and the action mechanism was explored. MCF-7 HER2-positive breast cancer cells were treated with various concentrations of wighteone. The growth inhibitory rate of the cells was calculated by MTT assay, apoptosis was detected by flow cytometry, and the expression level of HSP90 was assessed by western blot analysis. The addition of wighteone at concentrations ranging from 1–10 g/ml in the medium for 48 h had a marked inhibition on the proliferation of HER2-positive cancer cell lines. The growth inhibitory rates with 0.5, 2 or 8 mM wighteone were significantly higher compared with the control group. Apoptosis in the wighteone-treated cells was also significantly higher compared with the control group. The expression level of HSP90 in the wighteone group was significantly lower than that in the control group. Our findings demonstrated that wighteone effectively inhibited the proliferation of HER2-positive cancer cell lines, and this is considered to be the result of downregulating HSP90 receptor and downstream signaling. PMID:27313682

  15. Response evaluation after primary systemic therapy of Her2 positive breast cancer – an observational cross-sectional study

    PubMed Central

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

    2015-01-01

    Aim 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. Methods 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. Results 10 patients (38.5%) in Group 1 and 8 (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 (PET/CT Method 2) differentiated pCR from non-pCR more accurately in both groups (Group 1: sens = 77.8%, spec = 100%, 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

  16. Peptide-functionalized ZCIS QDs as fluorescent nanoprobe for targeted HER2-positive breast cancer cells imaging.

    PubMed

    Michalska, Martyna; Florczak, Anna; Dams-Kozlowska, Hanna; Gapinski, Jacek; Jurga, Stefan; Schneider, Raphaël

    2016-04-15

    In this paper, the synthesis of alloyed CuInZnxS2+x quantum dots (ZCIS QDs), their transfer into aqueous solution via a polymer coating technique, and the use of these nanocrystals to selectively target HER2-positive cells, are reported. By optimizing first the ZnS shell deposition process onto the CuInS2 core, and next the encapsulation of the dots with the amphiphilic poly(maleic anhydride-alt-1-octadecene) (PMAO) polymer, water-dispersible ZCIS QDs were successfully prepared. The nanocrystals with a photoluminescence quantum yield of 35% were purified via centrifugation and ultracentrifugation and high quality nanoparticles with narrow size distributions and surface charges were obtained. After verifying the biocompatibility of PMO-coated ZCIS QDs, we coupled these nanocrystals with the LTVSPWY peptide and demonstrated via MTT assay that both bare and the peptide-linked QDs exhibit low cytotoxicity. The HER2-mediated delivery of the peptide-linked QDs was confirmed by confocal microscopy. This study indicates that as engineered QDs can efficiently be used as fluorescent nanoprobes for selective labelling of HER2-positive SKBR3 cancer cells. PMID:26850146

  17. Selective anticancer activity of hirsutine against HER2positive breast cancer cells by inducing DNA damage.

    PubMed

    Lou, Chenghua; Yokoyama, Satoru; Saiki, Ikuo; Hayakawa, Yoshihiro

    2015-04-01

    Hirsutine is one of the major alkaloids isolated from plants of the Uncaria genus and is known for its cardioprotective, anti‑hypertensive and anti-arrhythmic activities. We recently reported that hirsutine is an anti-metastatic phytochemical by targeting NF-κB activation in a murine breast cancer model. In the present study, we further examined the clinical utility of hirsutine against human breast cancer. Among six distinct human breast cancer cell lines, hirsutine showed strong cytotoxicity against HER2-positive/p53-mutated MDA-MB‑453 and BT474 cell lines. Conversely, HER2-negative/p53 wild‑type MCF-7 and ZR-75-1 cell lines showed resistance against hirsutine-induced cytotoxicity. Hirsutine induced apoptotic cell death in the MDA-MB-453 cells, but not in the MCF-7 cells, through activation of caspases. Furthermore, hirsutine induced the DNA damage response in the MDA-MB-453 cells, but not in the MCF-7 cells, as highlighted by the upregulation of γH2AX expression. Along with the induction of the DNA damage response, the suppression of HER2, NF-κB and Akt pathways and the activation of the p38 MAPK pathway in the MDA-MB-453 cells were observed. Considering that there was no difference between MDA-MB-453 and MCF-7 cells in regards to irinotecan‑induced DNA damage response, our present results indicate the selective anticancer activity of hirsutine in HER2-positive breast cancer by inducing a DNA damage response. PMID:25672479

  18. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer

    PubMed Central

    Minuti, G; Cappuzzo, F; Duchnowska, R; Jassem, J; Fabi, A; O'Brien, T; Mendoza, A D; Landi, L; Biernat, W; Czartoryska-Arłukowicz, B; Jankowski, T; Zuziak, D; Zok, J; Szostakiewicz, B; Foszczyńska-Kłoda, M; Tempińska-Szałach, A; Rossi, E; Varella-Garcia, M

    2012-01-01

    Background: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). Methods: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. Results: MET FISH-positive cases (N=36, mean ⩾3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0% P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN ⩾3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8% P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately. Conclusion: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC. PMID:22850551

  19. Restoring anti-oncodriver Th1 responses with dendritic cell vaccines in HER2/neu-positive breast cancer: progress and potential.

    PubMed

    De La Cruz, Lucy M; Nocera, Nadia F; Czerniecki, Brian J

    2016-10-01

    HER2/neu is expressed in the majority of in situ breast cancers, but maintained in 20-30% of invasive breast cancer (IBC). During breast tumorigenesis, there is a progressive loss of anti-HER2 CD4(pos) Th1 (anti-HER2Th1) from benign to ductal carcinoma in situ, with almost complete loss in IBC. This anti-HER2Th1 response can predict response to neoadjuvant therapy, risk of recurrence and disease-free survival. Vaccines consisting of HER2-pulsed type I polarized dendritic cells (DC1) administered during ductal carcinoma in situ and early IBC can efficiently correct anti-HER2Th1 response and have clinical impact on the disease. In this review, we will discuss the role of anti-HER2Th1 response in the three phases of immunoediting during HER2 breast cancer development and opportunities for reversing these processes using DC1 vaccines alone or in combination with standard therapies. Correcting the anti-HER2Th1 response may represent an opportunity for improving outcomes and providing a path to eliminate escape variants. PMID:27605070

  20. A novel luciferase based reporter system to monitor activation of the ErbB2/Her2/neu pathway non-invasively during radiotherapy

    PubMed Central

    Wolf, Frank; Li, Wenrong; Li, Fang; Li, Chuan-Yuan

    2010-01-01

    Purpose To develop a split-luciferase based reporter system that allows for non-invasive monitoring of activation of the Her2/neu pathway in vivo in a quantitative and sensitive manner. Methods and Materials Fusion proteins of the ErbB2/Her2/neu receptor to the N-terminal fragment of luciferase as well as of its downstream binding partner Shc to the C-terminal fragment of luciferase have been engineered based on the rationale that upon activation and binding of the Her2 receptor molecule to Shc, luciferase function will be reconstituted. Thus the resulting bioluminescence signals can serve as a surrogate measure of receptor activation. Results We show that our reporter systems functions well in vitro in breast cancer cells and in vivo in xenograft tumors. In particular, the activities of Her2/neu in xenograft tumors could be monitored serially for an extended period of time after radiotherapy. Conclusions We believe that the novel ErbB2/Her2/neu reporter presented here is a powerful tool to study the biology of the Her2-neu pathway in vitro as well as in vivo. It should also facilitate the development and rapid evaluation of new Her2/neu targeted therapeutics. PMID:20934271

  1. A stable explant culture of HER2/neu invasive carcinoma supported by alpha-Smooth Muscle Actin expressing stromal cells to evaluate therapeutic agents

    PubMed Central

    Piechocki, Marie P

    2008-01-01

    Background To gain a better understanding of the effects of therapeutic agents on the tumor microenvironment in invasive cancers, we developed a co-culture model from an invasive lobular carcinoma. Tumor cells expressing HER2/neu organize in nests surrounded by alpha-Smooth Muscle Actin (α-SMA) expressing tumor stroma to resemble the morphology of an invading tumor. This co-culture, Mammary Adenocarcinoma Model (MAM-1) maintains a 1:1 ratio of HER2/neu positive tumor cells to α-SMA-reactive stromal cells and renews this configuration for over 20 passages in vitro. Methods We characterized the cellular elements of the MAM-1 model by microarray analysis, and immunocytochemistry. We developed flow cytometric assays to evaluate the relative responses of the tumor and stroma to the tyrosine kinase inhibitor, Iressa. Results The MAM-1 gene expression profile contains clusters that represent the ErbB-2 breast cancer signature and stroma-specific clusters associated with invasive breast cancers. The stability of this model and the ability to antigenically label the tumor and stromal fractions allowed us to determine the specificity of Iressa, a receptor tyrosine kinase inhibitor, for targeting the tumor cell population. Treatment resulted in a selective dose-dependent reduction in phospho-pMEK1/2 and pp44/42MAPK in tumor cells. Within 24 h the tumor cell fraction was reduced 1.9-fold while the stromal cell fraction increased >3-fold, consistent with specific reductions in phospho-pp44/42 MAPK, MEK1/2 and PCNA in tumor cells and reciprocal increases in the stromal cells. Erosion of the tumor cell nests and augmented growth of the stromal cells resembled a fibrotic response. Conclusion This model demonstrates the specificity of Iressa for HER2/neu expressing tumor cells versus the tumor associated myofibroblasts and is appropriate for delineating effects of therapy on signal transduction in the breast tumor microenvironment and improving strategies that can dually or

  2. The effect of trastuzumab-based chemotherapy in small node-negative HER2-positive breast cancer.

    PubMed

    van Ramshorst, Mette S; van der Heiden-van der Loo, Margriet; Dackus, Gwen M H E; Linn, Sabine C; Sonke, Gabe S

    2016-07-01

    The prognosis of patients with stage II-III Human Epidermal growth factor Receptor 2 (HER2)-positive breast cancer has significantly improved since the addition of trastuzumab to (neo-)adjuvant chemotherapy. Several reports have shown that small (≤2 cm), node-negative, HER2-positive tumors have a relatively poor prognosis and these patients increasingly receive trastuzumab-based chemotherapy. We aimed to provide evidence for this approach in a population-based cohort. All T1N0M0 HER2-positive breast cancer patients diagnosed between 2006 and 2012 were identified from the Netherlands Cancer Registry. Patient, tumor, and treatment characteristics were recorded. Kaplan-Meier statistics were used for overall survival (OS) and breast cancer-specific survival (BCSS) estimations overall and in T1a, T1b, and T1c tumors separately. Cox regression analyses were performed to account for imbalances in baseline characteristics between treated and untreated patients. A total of 3512 patients were identified: 385 with T1a, 800 with T1b, and 2327 with T1c tumors. Forty-five percent of patients received chemotherapy and/or trastuzumab: 92 % received both. Chemotherapy and/or trastuzumab significantly improved 8-year OS (95 vs. 84 %; hazard ratio [HR] 0.29; 95 % confidence interval [CI] 0.21-0.41, P < 0.001). The effect remained significant in multivariable analyses (HR 0.35; 95 % CI 0.23-0.52, P < 0.001). BCSS was also improved with systemic treatment in univariable (96 vs. 92 %; HR 0.41; 95 % CI 0.27-0.63, P < 0.001) and multivariable analyses (HR 0.31; 95 % CI 0.19-0.53, P < 0.001). Treatment effect on OS and BCSS was similar in T1a, T1b, and T1c tumors. Chemotherapy and/or trastuzumab improves OS and BCSS and can be considered in all patients with small node-negative HER2-positive breast cancer. PMID:27357813

  3. Numerical assessment of radiation binary targeted therapy for HER-2 positive breast cancers: advanced calculations and radiation dosimetry

    NASA Astrophysics Data System (ADS)

    Sztejnberg Gonçalves-Carralves, Manuel L.; Jevremovic, Tatjana

    2007-07-01

    In our previous publication (Mundy et al 2006 Phys. Med. Biol. 51 1377) we have described the theoretical assessment of our novel approach in radiation binary targeted therapy for HER-2 positive breast cancers and summarized the future directions in this area of research. In this paper we advanced the numerical analysis to show the detailed radiation dose distribution for various neutron sources in combination with the required boron concentration and allowed radiation skin doses. We once again proved the feasibility of the concept and will use these data and conclusions to start with the experimental verifications.

  4. Analytical validation and interobserver reproducibility of EnzMet GenePro: a second-generation bright-field metallography assay for concomitant detection of HER2 gene status and protein expression in invasive carcinoma of the breast.

    PubMed

    Downs-Kelly, Erinn; Pettay, James; Hicks, David; Skacel, Marek; Yoder, Brian; Rybicki, Lisa; Myles, Jonathan; Sreenan, Joseph; Roche, Patrick; Powell, Richard; Hainfeld, James; Grogan, Thomas; Tubbs, Raymond

    2005-11-01

    Fluorescence in situ hybridization (FISH) has both excellent sensitivity and specificity in detecting HER2 gene amplification in invasive breast carcinoma. FISH has not been widely implemented in clinical practice because of reagent costs and the special instrumentation and expertise required to perform and integrate the assay. Immunohistochemistry (IHC) for HER2 protein is widely used, but false-positive and false-negative results are problematic. We developed a bright-field assay to visualize HER2 gene amplification and concomitant HER2 protein expression (EnzMet GenePro). This assay detects HER2 gene amplification via deposition of metallic silver by enzyme metallographytrade mark (EnzMettrade mark, Nanoprobes, Yaphank, NY) combined with HER2 protein detection by IHC using alkaline phosphatase and fast red K substrate visualization (CB11;Ventana, Tucson, AZ). The assay was performed on 94 invasive breast carcinomas, for which FISH (PathVysiontrade mark, Vysis, Downer's Grove, IL), conventional IHC (CB11), and enzyme metallography (EnzMettrade mark) results were known. The EnzMettrade mark component of the assay was scored as either HER2 gene amplified, polysomic, or nonamplified. The IHC component was scored using the conventional FDA scale of 0 to 3+. Concordance of the EnzMet component of the assay versus FISH was assessed and showed an excellent correlation (Pearson coefficient of 0.95; P < 0.001). The combination of gene and protein detection (EnzMet GenePro) displayed a specificity of 100% and an accuracy of 92.6% (95% confidence interval 85.3-97.0), facilitated recognition of gene/protein discordances, and allowed for efficient interpretation of the slide by conventional light microscopy. The interobserver kappa for each component was excellent (IHC, kappa = 0.94; and EnzMettrade mark, kappa = 0.96). EnzMet is the first bright-field ISH assay in our experience that routinely and nonambiguously detects endogenous HER2 signals, essential for a reliable

  5. First-Line Treatment Patterns and Clinical Outcomes in Patients With HER2-Positive and Hormone Receptor-Positive Metastatic Breast Cancer From registHER

    PubMed Central

    Kaufman, Peter A.; Brufsky, Adam M.; Mayer, Musa; Yood, Marianne Ulcickas; Yoo, Bongin; Quah, Cheng; Yardley, Denise; Rugo, Hope S.

    2013-01-01

    Background. Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. Methods. registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. Results. HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22–0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27–1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42–0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36–0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54–1.21; adjusted OS HR: 0.48, 95% CI: 0.26–0.89). Conclusions. These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged

  6. [Complete Response in a Patient with HER2-Positive Gastric Cancer and Multiple Lung Metastases with Trastuzumab-Containing Chemotherapy].

    PubMed

    Nakata, Wachiko; Tokuyama, Nobuyuki; Yagioka, Hiroshi; Suyama, Yuki; Ogura, Keiji

    2016-05-01

    We report the case ofa 79-year-old Japanese woman diagnosed with human epidermal growth factor receptor 2(HER2)- positive gastric cancer ofthe cardia with multiple lung metastases that showed complete response to trastuzumab-containing chemotherapy. First, we administered tegafur/gimeracil/oteraci(l S-1)and cisplatin(CDDP)concurrently to the patient. Next, we switched to trastuzumab in combination with capecitabine and CDDP because gastric cancer tissue indicated HER2-positivity. Considering the patient's age and renal function, the dose of CDDP was decreased to 50% after starting the medication. Before the 2nd course of trastuzumab-containing chemotherapy, oral mucositis(Grade 3)and hand-foot syndrome (Grade 1)were observed. Therefore, a one-step dose reduction ofcapecitabine was necessary. After the 4th course, the primary gastric tumor was no longer visible endoscopically. After the 7th course, computed tomography(CT)showed the disappearance ofall lung metastases. Accordingly, the patient was considered to be completely responsive to the medication. After the 12th course, recurrence of the tumor was not identified and at the request of the patient, the trastuzumab-containing chemotherapy was discontinued. Regular follow-up showed no evidence ofrecurrence 8 months after discontinuing treatment and the patient was in good condition 21 months after her initial diagnosis. PMID:27210096

  7. Roles of the ER-α36-EGFR/HER2 positive regulatory loops in tamoxifen resistance.

    PubMed

    Yin, Li; Wang, Zhao-Yi

    2016-07-01

    Tamoxifen provided a successful treatment for ER-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to tamoxifen therapy. Extensive researches were conducted to understand the molecular mechanisms involved in tamoxifen resistance, and have revealed that multiple signaling molecules and pathways such as EGFR and HER2 are involved in tamoxifen resistance. Currently, the mechanisms by which tamoxifen sensitive breast cancer cells acquire these signaling pathways and develop tamoxifen resistance have not been elucidated. The identification of ER-α36, a variant of ER-α, that is able to mediate agonist activity of tamoxifen provided great insights into the underlying mechanisms of tamoxifen resistance. In this review, we will discuss the biological function and the possible underlying mechanisms of ER-α36 in tamoxifen resistance and specifically illustrate a novel cross-talk mechanism; positive regulatory loops between the ER-α36 and EGFR/HER2 in tamoxifen resistance. The function and the underlying mechanisms of ER-α36 in tamoxifen resistance of the breast cancer stem/progenitor cells will also be discussed. Finally, we will postulate a novel approach to restore tamoxifen sensitivity in tamoxifen resistant breast cancer cells. PMID:26884313

  8. [A case of effective lapatinib/capecitabine therapy for HER2-positive breast cancer with multiple brain metastases].

    PubMed

    Fujita, Yoshifumi; Mizuta, Naruhiko; Sakaguchi, Koichi; Nakatsukasa, Katsuhiko; Imai, Aya; Umeda, Yoshimi; Hamaoka, Asako; Morita, Midori; Shouji, Mari; Goto, Mariko; Taguchi, Tetsuya

    2012-11-01

    A 63-year-old woman was suffering from HER2-positive and hormone receptor-negative breast cancer with bone metastasis. She received 16 cycles of paclitaxel(PTX 80mg/m2)plus trastuzumab(TRA 2mg/kg)on a 7-day cycle, and zoledronic acid(ZOL 4mg/body every 28 days), resulting in a near clinical complete response(cCR). Two years later, the patient complained of dizziness and nausea, and magnetic resonance imaging revealed multiple brain metastases. The prior treatments with PTX and TRA were changed to lapatinib(LAP)(orally at 1, 250mg/day every day)and capecitabine(CAP)(orally at 2, 000mg/m2 every day for 2 weeks, followed by a 1-week rest interval as 1 cycle)because of the multiple brain metastases. After 4 cycles of treatment, the number of brain lesions and the tumor sizes were significantly reduced. After 7 cycles, however, magnetic resonance imaging revealed the deterioration of some brain lesions. After whole-brain irradiation(30 Gy in 10 fractions)was added to the treatment, the outcome was near cCR. In conclusion, combination therapy of Lap and Cap may be an effective treatment option for brain metastasis of HER2-positive breast cancer. PMID:23152022

  9. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

    PubMed Central

    Lam, Prudence B; Burga, Laura N; Wu, Bryan P; Hofstatter, Erin W; Lu, Kun Ping; Wulf, Gerburg M

    2008-01-01

    Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results Sixty-four samples (28.7%) stained positive for Her2 (IHC 3+), and 54% (122/223) of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5%) were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2 degradation, which could

  10. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?

    PubMed

    Arnould, L; Gelly, M; Penault-Llorca, F; Benoit, L; Bonnetain, F; Migeon, C; Cabaret, V; Fermeaux, V; Bertheau, P; Garnier, J; Jeannin, J-F; Coudert, B

    2006-01-30

    This study evaluated by immunohistochemistry (IHC) immune cell response during neoadjuvant primary systemic therapy (PST) with trastuzumab in patients with HER2-positive primary breast cancer. In all, 23 patients with IHC 3+ primary breast cancer were treated with trastuzumab plus docetaxel. Pathological complete and partial responses were documented for nine (39%) and 14 (61%) patients, respectively. Case-matched controls comprised patients treated with docetaxel-based PST without trastuzumab (D; n=23) or PST without docetaxel or trastuzumab (non-taxane, non-trastuzumab, NT-NT; n=23). All surgical specimens were blind-analysed by two independent pathologists, with immunohistochemical evaluation of B and T lymphocytes, macrophages, dendritic cells and natural killer (NK) cells. Potential cytolytic cells were stained for Granzyme B and TiA1. HER2 expression was also evaluated in residual tumour cells. Trastuzumab treatment was associated with significantly increased numbers of tumour-associated NK cells and increased lymphocyte expression of Granzyme B and TiA1 compared with controls. This study supports an in vivo role for immune (particularly NK cell) responses in the mechanism of trastuzumab action in breast cancer. These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer. PMID:16404427

  11. Low Concordance between Gene Expression Signatures in ER Positive HER2 Negative Breast Carcinoma Could Impair Their Clinical Application

    PubMed Central

    Laas, Enora; Mallon, Peter; Duhoux, Francois P.; Hamidouche, Amina; Rouzier, Roman; Reyal, Fabien

    2016-01-01

    Background Numerous prognostic gene expression signatures have been recently described. Among the signatures there is variation in the constituent genes that are utilized. We aim to evaluate prognostic concordance among eight gene expression signatures, on a large dataset of ER positive HER2 negative breast cancers. Methods We analysed the performance of eight gene expression signatures on six different datasets of ER+ HER2- breast cancers. Survival analyses were performed using the Kaplan–Meier estimate of survival function. We assessed discrimination and concordance between the 8 signatures on survival and recurrence rates The Nottingham Prognostic Index (NPI) was used to to stratify the risk of recurrence/death. Results The discrimination ability of the whole signatures, showed fair discrimination performances, with AUC ranging from 0.64 (95%CI 0.55–0.73 for the 76-genes signatures, to 0.72 (95%CI 0.64–0.8) for the Molecular Prognosis Index T17. Low concordance was found in predicting events in the intermediate and high-risk group, as defined by the NPI. Low risk group was the only subgroup with a good signatures concordance. Conclusion Genomic signatures may be a good option to predict prognosis as most of them perform well at the population level. They exhibit, however, a high degree of discordance in the intermediate and high-risk groups. The major benefit that we could expect from gene expression signatures is the standardization of proliferation assessment. PMID:26895349

  12. Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas.

    PubMed

    Martin-Castillo, Begoña; Lopez-Bonet, Eugeni; Cuyàs, Elisabet; Viñas, Gemma; Pernas, Sonia; Dorca, Joan; Menendez, Javier A

    2015-10-20

    Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes

  13. Cancer stem cell-driven efficacy of trastuzumab (Herceptin): towards a reclassification of clinically HER2-positive breast carcinomas

    PubMed Central

    Martin-Castillo, Begoña; Lopez-Bonet, Eugeni; Cuyàs, Elisabet; Viñas, Gemma; Pernas, Sonia; Dorca, Joan; Menendez, Javier A.

    2015-01-01

    Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24−/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24−/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24−/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24−/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of “Trojan horse” approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC

  14. FLT PET in Measuring Treatment Response in Patients With Newly Diagnosed Estrogen Receptor-Positive, HER2-Negative Stage I-III Breast Cancer

    ClinicalTrials.gov

    2016-06-02

    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

  15. ER-Poor and HER2-Positive: A Potential Subtype of Breast Cancer to Avoid Axillary Dissection in Node Positive Patients after Neoadjuvant Chemo-Trastuzumab Therapy

    PubMed Central

    Chen, Can-ming; Hu, Zhen; Hou, Yi-feng; Di, Gen-hong; Wu, Jiong; Shen, Zhen-zhou; Shao, Zhi-ming; Liu, Guang-yu

    2014-01-01

    Purpose The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer. Methods Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4–6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection. Results Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection. Conclusions ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary

  16. Testing for HER2 in Breast Cancer: A Continuing Evolution

    PubMed Central

    Shah, Sejal; Chen, Beiyun

    2011-01-01

    Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%–20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin) a “humanized” monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls. PMID:21188214

  17. 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. PMID:26324739

  18. The in vitro influences of epidermal growth factor and heregulin-β1 on the efficacy of trastuzumab used in Her-2 positive breast adenocarcinoma

    PubMed Central

    2013-01-01

    Background Human epidermal growth factor receptor-2 (Her-2) is over expressed in approximately 25-30% of all primary breast tumors resulting in a distinctive breast cancer subtype associated with a poor prognosis and a decrease in overall survival. Trastuzumab (Herceptin®), an anti-Her-2 monoclonal antibody, has dramatically altered the prognosis of Her-2 positive breast cancer. Trastuzumab is, however, associated with primary and acquired resistance. Aim and methods To investigate the in-vitro effects of trastuzumab on cell viability (tetrazolium conversion assay), cell cycling (propidium iodide staining), apoptosis (executioner caspases and annexin-V) and relative surface Her-2 receptor expression (anti-Her-2 affibody molecule) in Her-2-positive (SK-Br-3) and oestrogen receptor positive (MCF-7) breast adenocarcinoma cells and to determine potential augmentation of these effects by two endogenous ligands, epidermal growth factor (EGF) and heregulin-β1 (HRG- β1). Results Cell viability was decreased in SK-Br-3 cells by exposure to trastuzumab. This was associated with G1 accumulation and decreased relative surface Her-2 receptor density, supporting the cytostatic nature of trastuzumab in vitro. SK-Br-3 cells exposed to EGF and heregulin-β1 produced differential cell responses alone and in combination with trastuzumab, in some instances augmenting cell viability and cell cycling. Relative surface Her-2 receptor density was reduced substantially by trastuzumab, EGF and heregulin-β1. These reductions were amplified when ligands were used in combination with trastuzumab. Conclusion Cell type specific interactions of endogenous ligands appear to be dependent on absolute Her-receptor expression and cross activation of signaling pathways. This supports the notion that receptor density of Her-family members and multiplicity of growth ligands are of mutual importance in breast cancer cell proliferation and therefore also in resistance associated with trastuzumab. PMID

  19. Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis

    PubMed Central

    Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

    2016-01-01

    Background The anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab’s high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. Methods and Findings A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50–54 y; 95% CI 2.29–2.37) for the worst prognosis (ER−/PR−) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25–29 to 90–94 y (0.44 times for the age group 50–54 y; 95% CI 0.43–0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]–adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER−/PR− subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR− cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had

  20. Conserved E2F mediated metastasis in mouse models of breast cancer and HER2 positive patients

    PubMed Central

    Rennhack, Jonathan; Andrechek, Eran

    2015-01-01

    To improve breast cancer patient outcome work must be done to understand and block tumor metastasis. This study leverages bioinformatics techniques and traditional genetic screens to create a novel method of discovering potential contributors of tumor progression with a focus on tumor metastasis. A database of 1172 of expression data from a variety of mouse models of breast cancer was assembled and queried using previously defined oncogenic activity signatures. This analysis revealed high activity of the E2F family of transcription factors in the MMTV-Neu mouse model. A genetic cross of MMTV-Neu mice into an E2F1 null, E2F2 null, or E2F3 heterozygous background revealed significant changes in tumor progression specifically reductions in tumor latency and metastasis with E2F1 or E2F2 loss. These findings were found to be conserved in human HER2 positive patients. Patients with high E2F1 activity were shown to have worse outcomes such as relapse free survival and distant metastasis free survival. This study shows conserved mechanisms of tumor progression in human breast cancer subtypes and analogous mouse models and underlies the importance of increased research into the characterization of and comparisons between mouse and human tumors to identify which mouse models resemble each subtype of human breast cancer. PMID:26682278

  1. Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery

    ClinicalTrials.gov

    2013-05-07

    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

  2. Clinicopathological characteristics of patients with HER2-positive breast cancer and the efficacy of trastuzumab in the People’s Republic of China

    PubMed Central

    Zhou, Ping; Jiang, Yi-Zhou; Hu, Xin; Sun, Wei; Liu, Yi-Rong; Liu, Fang; Luo, Rong-Cheng; Shao, Zhi-Ming

    2016-01-01

    Objective The aim of this study was to describe the clinical features and outcomes of Chinese patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Method The clinical data and survival statuses of 732 patients with operable HER2-positive breast cancer who were treated at the Department of Breast Surgery of the Shanghai Cancer Center from January 1, 2007, to December 31, 2011, were collected. The patients were divided into two groups according to treatment with and without trastuzumab. Disease-free survival (DFS) and overall survival were calculated using the Kaplan–Meier method and log-rank test. The associations of the patient characteristics with prognosis were analyzed via Cox regression. Results A total of 732 women with HER2-positive breast cancer were included in this study, among whom 258 (35.2%) received trastuzumab. The median follow-up duration was 41 months. By the end of the follow-up period, 86 (12%) women experienced local recurrence or metastasis. Patients who received both anti-HER2 therapy and chemotherapy exhibited a longer DFS than those who received chemotherapy alone (P=0.001). Tumor size, lymph node status, and family history of breast cancer were associated with median DFS, and tumor size, lymph node status, clinical stage, age, and body mass index were associated with median overall survival. Patients who received both neoadjuvant chemotherapy and trastuzumab exhibited a higher rate of pathological complete remission. In the neoadjuvant group, the patients who received both anti-HER2 therapy and chemotherapy exhibited a longer DFS than those who received chemotherapy alone (P=0.049). Conclusion Significant clinical features were observed in the Chinese patients with HER2-positive breast cancer. Furthermore, targeted anti-HER2 therapy may improve the prognosis of these patients. PMID:27143924

  3. Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells.

    PubMed

    Carson, W E; Parihar, R; Lindemann, M J; Personeni, N; Dierksheide, J; Meropol, N J; Baselga, J; Caligiuri, M A

    2001-10-01

    The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p < 0.05). Lysis was less than 5% when targets were treated with either the non-humanized mu4D5 mAb or control huIgG. Lysis of rhu4D5-coated MCF-7Her2/neu cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene. PMID:11592078

  4. Subcutaneous Trastuzumab for HER2-positive Breast Cancer – Evidence and Practical Experience in 7 German Centers

    PubMed Central

    Jackisch, C.; Müller, V.; Dall, P.; Neumeister, R.; Park-Simon, T.-W.; Ruf-Dördelmann, A.; Seiler, S.; Tesch, H.; Ataseven, B.

    2015-01-01

    A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of 600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patientʼs point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centersʼ overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed. PMID:26166837

  5. Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature

    PubMed Central

    Firwana, Belal; Atassi, Bassel; Hasan, Rim; Hasan, Nour; Sukari, Ammar

    2012-01-01

    Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response. PMID:23826550

  6. Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature.

    PubMed

    Firwana, Belal; Atassi, Bassel; Hasan, Rim; Hasan, Nour; Sukari, Ammar

    2012-07-01

    Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response. PMID:23826550

  7. [HER2-Positive Advanced Gastric Cancer with Disseminated Intravascular Coagulation and Diffuse Bone Marrow Carcinomatosis Successfully Treated with S-1/Trastuzumab Chemotherapy--A Case Report].

    PubMed

    Senoo, Satoru; Mannami, Tomohiko; Tamura, Tomoki; Fujiwara, Nobukiyo; Ikeda, Genyo; Komoda, Minori; Ohtawa, Yasuyuki; Fujimoto, Yoshimi; Sato, Naohiro; Kambara, Takeshi; Waku, Toshihiko; Kenmotsu, Masaichi; Kurimoto, Etsuko; Okada, Toshiaki; Harita, Shingo; Sonobe, Hiroshi

    2015-12-01

    Trastuzumab, a humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has been proven to result in a survival benefit for the treatment of patients with HER2-positive advanced gastric cancer (AGC). However, data are lacking for the treatment of those with disseminated intravascular coagulation (DIC) and diffuse bone marrow carcinomatosis. A 77-year-old woman presented with back pain and fatigue since 2 months. Esophagogastroduodenoscopy showed a scirrhous lesion in the gastric corpus, which was biopsied and identified as signet-ring cell carcinoma with HER2 overexpression on immunohistochemistry. Laboratory testing, bone scintigraphy, and bone marrow biopsy were conducted, and she was diagnosed with HER2-positive AGC with DIC and diffuse bone marrow carcinomatosis. She underwent chemotherapy with the following regimen: oral administration of 80 mg/m2 S-1 for 2 weeks and 6 mg/kg trastuzumab infusion on day 6 every 3 weeks, which significantly improved the DIC. She was discharged from the hospital 73 days after admission and survived for 438 days after diagnosis. To the best of our knowledge, this is the first case report in which HER2-positive AGC complicated by DIC with diffuse bone marrow carcinomatosis was successfully treated with combined chemotherapy consisting of S-1 plus trastuzumab. PMID:26809307

  8. Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status

    PubMed Central

    Nuciforo, P. G.; Aura, C.; Holmes, E.; Prudkin, L.; Jimenez, J.; Martinez, P.; Ameels, H.; de la Peña, L.; Ellis, C.; Eidtmann, H.; Piccart-Gebhart, M. J.; Scaltriti, M.; Baselga, J.

    2015-01-01

    Background Assessment of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) might be an important tool in identifying human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients unlikely to derive benefit from anti-HER2 therapies. However, studies to date have failed to demonstrate its predictive role in any treatment setting. Patients and methods Prospectively collected baseline core biopsies from 429 early-stage HER2-positive breast cancer patients treated with trastuzumab, lapatinib, or their combination in the Neo-ALTTO study were stained using two anti-PTEN monoclonal antibodies (CST and DAKO). The association of PTEN status and PI3K pathway activation (defined as either PTEN loss and/or PIK3CA mutation) with total pathological complete response (tpCR) at surgery, event-free survival (EFS), and overall survival (OS) was evaluated. Results PTEN loss was observed in 27% and 29% of patients (all arms, n = 361 and n = 363) for CST and DAKO, respectively. PTEN loss was more frequently observed in hormone receptor (HR)-negative (33% and 36% with CST and DAKO, respectively) compared with HR-positive tumours (20% and 22% with CST and DAKO, respectively). No significant differences in tpCR rates were observed according to PTEN status. PI3K pathway activation was found in 47% and 48% of patients (all arms, n = 302 and n = 301) for CST and DAKO, respectively. Similarly, tpCR rates were not significantly different for those with or without PI3K pathway activation. Neither PTEN status nor PI3K pathway activation were predictive of tpCR, EFS, or OS, independently of treatment arm or HR status. High inter-antibody and inter-observer agreements were found (>90%). Modification of scoring variables significantly affected the correlation between PTEN and HR status but not with tpCR. Conclusion These data show that PTEN status determination is not a useful biomarker to predict resistance to trastuzumab and lapatinib-based therapies. The lack of

  9. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

    PubMed Central

    Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

    2015-01-01

    An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents. PMID:26609467

  10. Discovery and verification of protein differences between Er positive/Her2/neu negative breast tumor tissue and matched adjacent normal breast tissue.

    PubMed

    Weitzel, Lindsay-Rae B; Byers, Tim; Allen, Jenna; Finlayson, Christina; Helmke, Steve M; Hokanson, John E; Hunsucker, Stephen W; Murphy, James R; Newell, Keri; Queensland, Kelly M; Singh, Meenakshi; Wischmeyer, Paul E; Duncan, Mark W; Elias, Anthony

    2010-11-01

    This study was designed to quantify and identify differences in protein levels between tumor and adjacent normal breast tissue from the same breast in 18 women with stage I/II ER positive/Her2/neu negative invasive breast cancer. Eighteen separate difference gel electrophoresis (DIGE) gels were run (1 gel per patient). Relative quantification was based on DIGE analysis. After excision and tryptic digestion, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and peptide mass mapping were used to identify protein spots. Two hundred and forty-three spots were differentially abundant between normal and cancer tissues. Fifty spots were identified: 41 were over abundant and nine were less abundant in cancers than in normal breast tissue. Western blotting provided independent confirmation for three of the most biologically and statistically interesting proteins. All 18 gels were replicated by another technician and 32% of the differentially abundant proteins were verified by the duplicate analysis. Follow-up studies are now examining these proteins as biomarkers in blood. PMID:20087651

  11. Estrogen/Progesterone Receptor Negativity and HER2 Positivity Predict Locoregional Recurrence in Patients With T1a,bN0 Breast Cancer

    SciTech Connect

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

    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. 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.

  12. Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience

    PubMed Central

    Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Rogers, Jane E.; Mares, Jeannette Elizabeth; Blum, Mariela A.; Estrella, Jeannelyn; Matamoros, Aurelio; Sagebiel, Tara; Devine, Catherine E.; Badgwell, Brian D.; Lin, Quan D.; Das, Prajnan; Ajani, Jaffer A.

    2016-01-01

    Background Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. Methods HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. Results Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01–5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5–53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. Conclusions In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in

  13. Induction of Protective Anti-CTL Epitope Responses against HER-2-Positive Breast Cancer Based on Multivalent T7 Phage Nanoparticles

    PubMed Central

    Pouyanfard, Somayeh; Bamdad, Taravat; Hashemi, Hamidreza; Bandehpour, Mojgan; Kazemi, Bahram

    2012-01-01

    We report here the development of multivalent T7 bacteriophage nanoparticles displaying an immunodominant H-2kd-restricted CTL epitope derived from the rat HER2/neu oncoprotein. The immunotherapeutic potential of the chimeric T7 nanoparticles as anti-cancer vaccine was investigated in BALB/c mice in an implantable breast tumor model. The results showed that T7 phage nanoparticles confer a high immunogenicity to the HER-2-derived minimal CTL epitope, as shown by inducing robust CTL responses. Furthermore, the chimeric nanoparticles protected mice against HER-2-positive tumor challenge in both prophylactic and therapeutic setting. In conclusion, these results suggest that CTL epitope-carrying T7 phage nanoparticles might be a promising approach for development of T cell epitope-based cancer vaccines. PMID:23166703

  14. Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer

    PubMed Central

    Baselga, J.; Manikhas, A.; Cortés, J.; Llombart, A.; Roman, L.; Semiglazov, V. F.; Byakhov, M.; Lokanatha, D.; Forenza, S.; Goldfarb, R. H.; Matera, J.; Azarnia, N.; Hudis, C. A.; Rozencweig, M.

    2014-01-01

    Background Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet®) in combination with trastuzumabHerceptin® (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. Patients and Methods Patients were randomly assigned to NPLD (M, 50 mg/m2 every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m2 weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). Results One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47–0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42–0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. Conclusion(s) The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. Clinical trial number NCT00294996. PMID:24401928

  15. Vaccine Therapy With Sargramostim (GM-CSF) in Treating Patients With Her-2 Positive Stage III-IV Breast Cancer or Ovarian Cancer

    ClinicalTrials.gov

    2016-05-02

    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

  16. Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

    PubMed Central

    Palmieri, Carlo; Macpherson, Iain RJ; Yan, Kelvin; Ades, Felipe; Riddle, Pippa; Ahmed, Riz; Owadally, Waheeda; Stanley, Barbara; Shah, Deep; Gojis, Ondrej; Januszewski, Adam; Lewanski, Conrad; Asher, Rebecca; Lythgoe, Daniel; de Azambuja, Evandro; Beresford, Mark; Howell, Sacha J.

    2016-01-01

    Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC. PMID:26334099

  17. Treatment patterns, clinical outcomes and health care costs associated with her2-positive breast cancer with central nervous system metastases: a French multicentre observational study

    PubMed Central

    2013-01-01

    Background The population of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) who develop central nervous system (CNS) metastases is growing. Treatment strategies in this population are highly diverse. The objective of the study was to assess health care costs for the management of HER2 positive BC with CNS metastases. Methods This multicentre, retrospective, observational study was conducted on HER2-positive BC patients diagnosed with CNS metastases between 2006 and 2008. Data were extracted from patient medical records to estimate health care resource use. A partitioned estimator was used to adjust censoring costs by use of the Kaplan-Meier survival estimate. Results 218 patients were included and costs were estimated for 200 patients. The median time to detection of CNS metastases was 37.6 months. The first metastatic event involved the CNS in 39 patients, and this was the unique first metastatic site in 31 of these patients. Two years following diagnosis of CNS metastases, 70.3% of patients had died. The mean per capita cost of HER2-positive BC with CNS metastases in the first year following diagnosis was €35,735 [95% CI: 31,716-39,898]. The proportion of costs attributed to expensive drugs and those arising from hospitalisation were in the same range. Conclusion A range of individualised disease management strategies are used in HER2-positive BC patients with CNS metastases and the treatments used in the first months following diagnosis are expensive. The understanding of cost drivers may help optimise healthcare expenditure and inform the development of appropriate prevention policies. PMID:24176086

  18. 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. PMID:26833123

  19. [A long-surviving case of HER2-positive breast cancer with brain metastasis treated by multidisciplinary therapy].

    PubMed

    Sugimoto, Hitoshi; Nakagawa, Tsuyoshi; Sato, Takanobu; Nagahara, Makoto; Ishiba, Toshiyuki; Kasahara, Mai; Kawachi, Hiroshi; Kubota, Kazunori; Sugihara, Kenichi

    2012-11-01

    We present a case of a 55-year-old woman who visited our hospital aware of a lump in her right breast. We diagnosed it as bilateral breast cancer [Rt: ABCDE, T3N1M0, ER (-), PgR (-), HER2: 3+, Stage IIIA; Lt: C, T2N0M0, ER (-), PgR (-), HER2: 1+, Stage IIA]. She underwent NAC with EC followed by docetaxel. After cPR, an operation (Rt Bt+Ax, Lt Bp+Ax) was performed. Liver metastases were identified 9 months after the operation, and she was administered weekly paclitaxel+trastuzumab for 12 courses. After cPR, the treatment was changed to trastuzumab only. Because a cerebellar metastasis appeared in postoperative month 19, she underwent an operation using a gamma-knife. Because a new cerebellar metastasis appeared in postoperative month 26, she underwent another gamma-knife operation. Furthermore, liver metastases were diagnosed as PD, and treatment was changed to vinorelbine and trastuzumab. Because third new cerebellar metastasis appeared in postoperative month 45, she underwent another gamma-knife operation. Lung metastases were identified 59 months after the operation, and the therapy was changed to lapatinib and capecitabine. There was no subsequent growth of metastatic tumors, and good control was obtained. PMID:23267980

  20. Discovery of Hapten-Specific scFv from a Phage Display Library and Applications for HER2-Positive Tumor Imaging

    PubMed Central

    2015-01-01

    In this study, an anti-hapten antibody (single chain Fv, scFv) against a hapten probe was developed as a unique reporter system for molecular imaging or therapy. The hapten peptide (histamine-succinyl-GSYK, Him) was synthesized for phage displayed scFv affinity selection and for conjugation with cypate (Cy-Him) for in vivo near-infrared (NIR) optical imaging. Hapten-specific scFvs were affinity selected from the human single fold phage display scFv libraries (Tomlinson I + J) with high specificity and affinity. Utilizing HER2 targeting as a model system, the highest affinity scFv (clone J42) was recombinantly fused to an anti-HER2 affibody (scFv-L-Aff) with no loss of affinity of either protein. The functionality of the hapten-scFv reporter system was tested in vitro with a HER2-positive human breast cancer cell line, SK-BR3, and in vivo with SK-BR3 xenografts. ScFv-L-Aff mediated the binding of the hapten to HER2 on SK-BR3 cells and from tissue from the SK-BR3 xenograft; however, scFv-L-Aff did not mediate uptake of the hapten in the SK-BR3 xenografted tumors, presumably due to rapid internalization of the HER2/scFv-L-Aff complex. Our results suggest that this hapten-peptide and anti-hapten scFv can be a universal reporter system in a wide range of imaging and therapeutic applications. PMID:24898150

  1. ANG4043, a novel brain-penetrant peptide-mAb conjugate, is efficacious against HER2-positive intracranial tumors in mice.

    PubMed

    Regina, Anthony; Demeule, Michel; Tripathy, Sasmita; Lord-Dufour, Simon; Currie, Jean-Christophe; Iddir, Mustapha; Annabi, Borhane; Castaigne, Jean-Paul; Lachowicz, Jean E

    2015-01-01

    Anti-HER2 monoclonal antibodies (mAb) have been shown to reduce tumor size and increase survival in patients with breast cancer, but they are ineffective against brain metastases due to poor brain penetration. In previous studies, we identified a peptide, known as Angiopep-2 (An2), which crosses the blood-brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2-mAb conjugate penetrates the BBB with a rate of brain entry (Kin) of 1.6 × 10(-3) mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2-drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications. PMID:25492620

  2. Outcome of patients with HER2-positive breast cancer treated with or without adjuvant trastuzumab in the Finland Capecitabine Trial (FinXX)

    PubMed Central

    2014-01-01

    Background. Little information is available about survival outcomes of patients with HER2-positive early breast cancer treated with adjuvant capecitabine-containing chemotherapy with or without trastuzumab. Patients and methods. One thousand and five hundred patients with early breast cancer were entered to the Finland Capecitabine trial (FinXX) between January 2004 and May 2007, and were randomly assigned to receive either three cycles of adjuvant TX (docetaxel, capecitabine) followed by three cycles of CEX (cyclophosphamide, epirubicin, capecitabine; TX-CEX) or three cycles of docetaxel followed by three cycles of CEF (cyclophosphamide, epirubicin, fluorouracil; T-CEF). The primary endpoint was recurrence-free survival (RFS). The study protocol was amended in May 2005 while study accrual was ongoing to allow adjuvant trastuzumab for patients with HER2-positive cancer. Of the 284 patients with HER2-positive cancer accrued to FinXX, 176 (62.0%) received trastuzumab after amending the study protocol, 131 for 12 months and 45 for nine weeks. The median follow-up time was 6.7 years. Results. Patients with HER2-positive cancer who received trastuzumab had better RFS than those who did not (five-year RFS 89.2% vs. 75.9%; HR 0.41, 95% CI 0.23–0.72; p = 0.001). Patients treated with trastuzumab for 12 months or nine weeks had similar RFS. There was no significant interaction between trastuzumab administration and the type of chemotherapy. Four (2.3%) patients treated with trastuzumab had heart failure or left ventricular dysfunction, three of these received capecitabine. Conclusion. Adjuvant trastuzumab improves RFS of patients treated with TX-CEX or T-CEF. Few patients had cardiac failure. PMID:23957715

  3. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases.

    PubMed

    Lin, Nancy U; Eierman, Wolfgang; Greil, Richard; Campone, Mario; Kaufman, Bella; Steplewski, Klaudia; Lane, Stephen R; Zembryki, Denise; Rubin, Stephen D; Winer, Eric P

    2011-12-01

    Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥ 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity. PMID:21706359

  4. Kit for the preparation of (111)In-labeled pertuzumab injection for imaging response of HER2-positive breast cancer to trastuzumab (Herceptin).

    PubMed

    Lam, Karen; Scollard, Deborah A; Chan, Conrad; Levine, Mark N; Reilly, Raymond M

    2014-10-23

    We previously reported that (111)In-labeled pertuzumab imaged trastuzumab (Herceptin)-mediated changes in HER2 expression preclinically in breast cancer tumors. To advance (111)In-labeled pertuzumab to a Phase I/II clinical trial, a kit was designed for preparing this agent in a form suitable for human administration. Unit-dose kits containing pertuzumab modified with 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (BzDTPA) were prepared that labeled to high efficiency (>90%) with (111)In and met specifications for pharmaceutical quality. The kits were stable for 4 months and the final radiopharmaceutical was stable for 24h. Imaging studies demonstrated high and specific uptake in HER2-positive tumors in mice using this clinical kit formulation. PMID:25464190

  5. Tumor Heterogeneity in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Gastric Cancer Assessed by CT Texture Analysis: Association with Survival after Trastuzumab Treatment

    PubMed Central

    Yoon, Sung Hyun; Lee, Yoon Jin; Park, Jihoon; Kim, Jin Won; Lee, Hye Seung; Kim, Bohyoung

    2016-01-01

    Background Image texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment. Methods and Findings Patients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan–Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10−3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan–Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger

  6. Caveolin-1 Dependent Endocytosis Enhances the Chemosensitivity of HER-2 Positive Breast Cancer Cells to Trastuzumab Emtansine (T-DM1)

    PubMed Central

    Chung, Yuan-Chiang; Kuo, Jang-Fang; Wei, Wan-Chen; Chang, King-Jen; Chao, Wei-Ting

    2015-01-01

    The humanized monoclonal antibody-drug conjugate trastuzumab emtansine (T-DM1, Kadcyla) has been approved by the U.S. FDA to treat human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Despite its effectiveness in most patients, some are initially resistant or develop resistance. No biomarker of drug resistance to T-DM1 has been identified. Antibody-drug efficacy is associated with antibody internalization in the cell; therefore, cellular sensitivity of cells to the drug may be linked to cellular vesicle trafficking systems. Caveolin-1 is a 22 KD protein required for caveolae formation and endocytic membrane transport. In this study, the relationship between caveolin-1 expression and the chemosensitivity of HER-2-positive breast cancer cells to T-DM1 was investigated. Samples from 32 human breast cancer biopsy and normal tissue specimens were evaluated immunohistochemically for caveolin-1 expression. Caveolin-1 was shown to be expressed in 68% (22/32) of the breast cancer specimens. In addition, eight (72.7%, 8/11) HER-2 positive breast cancer specimens had a higher caveolin-1 expression than normal tissues. HER-2-positive BT-474 and SKBR-3 breast cancer cells that express low and moderate levels of caveolin-1, respectively, were treated with trastuzumab or its conjugate T-DM1. Cell viability and molecular localizations of caveolin-1, antibody and its conjugate were examined. Confocal microscopy showed that T-DM1 and caveolin-1 colocalized in SKBR-3 cells, which also were five times more sensitive to the conjugate in terms of cell survival than BT-474 cells, although T-DM1 also showed improved drug efficacy in BT-474 cells than trastuzumab treatment. Caveolin-1 expression in these lines was manipulated by transfection of GFP-tagged caveolin-1 or caveolin-1 siRNA. BT-474 cells overexpressing caveolin-1 were more sensitive to T-DM1 treatment than mock-transfected cells, whereas the siRNA-transfected SKBR-3 cells had decreased sensitivity

  7. Weekly Paclitaxel/Carboplatin/Trastuzumab Therapy Improves Pathologic Complete Remission in Aggressive HER2-Positive Breast Cancers, Especially in Luminal-B Subtype, Compared With a Once-Every-3-Weeks Schedule

    PubMed Central

    Yu, Ke-Da; Liu, Guang-Yu; Chen, Can-Ming; Li, Jian-Wei; Wu, Jiong; Lu, Jin-Song; Shen, Zhen-Zhou

    2013-01-01

    Background. The efficacy and tolerability of two different schedules of paclitaxel, carboplatin, and trastuzumab (PCarH) for HER2-positive, locally aggressive (stage IIB–IIIC) breast cancers were evaluated in this phase II trial. Methods. Patients were randomly assigned to receive either weekly (12 doses over 16 weeks) or once-every-3-weeks (4 doses over 12 weeks) treatment. The primary endpoint was pathologic complete remission (pCR) in the breast and axilla. To detect an assumed 35% pCR absolute difference between the two schedules, a minimum of 26 assessable patients in each group was required (two-sided α = 0.05, β = 0.2). Results. A total of 56 patients were enrolled (weekly group, n = 29; every-3-weeks group, n = 27). In the intent-to-treat analysis, pCR in the breast/axilla were found in 31 patients (55%; 95% confidence interval [CI]: 41%–69%). Compared with the every-3-weeks schedule, the weekly administration achieved higher pCR (41% vs. 69%; p = .03). After adjustment for clinical and pathological factors, the weekly administration was more effective than the every-3-weeks schedule, with hazard ratio of 0.3 (95% CI: 0.1–0.9; p = .03). Interestingly, weekly administration resulted in high pCR rates in both luminal-B (HER2-positive) and ERBB2+ tumors (67% vs. 71%; p = .78), whereas luminal-B (HER2-positive) tumors benefited less from the every-3-weeks schedule compared with the ERBB2+ tumors (21% vs. 62%, p = .03). These results remain after multivariate adjustment, showing weekly administration was more effective in the luminal-B (HER2-positive) subgroup (p = .02) but not in the ERBB2+ subgroup (p = .50). Conclusion. A more frequent administration might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype. Further studies to validate our findings are warranted. PMID:23635560

  8. Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models

    PubMed Central

    Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Zhang, Nan; Murakami, Takashi; Maawy, Ali; Mii, Sumiyuki; Uehara, Fuminari; Yamamoto, Mako; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

    2015-01-01

    We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient’s cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer. PMID:26047477

  9. Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma.

    PubMed

    Pierpaoli, Elisa; Damiani, Elisa; Orlando, Fiorenza; Lucarini, Guendalina; Bartozzi, Beatrice; Lombardi, Paolo; Salvatore, Carmela; Geroni, Cristina; Donati, Abele; Provinciali, Mauro

    2015-10-01

    Berberine (BBR) is a natural isoquinoline alkaloid with proven antiangiogenic and anticancer activities. We recently demonstrated that BBR and its synthetic derivative 13-(4-chlorophenylethyl)berberine iodide, NAX014, exert antiproliferative activity against HER2-overexpressing breast cancer cells, inducing apoptosis, modulating the expression of cell cycle checkpoint molecules involved in cell senescence, and reducing both HER2 expression and phosphorylation on tumor cells. In this study, we examined the anticancer properties of BBR and NAX014 in a transgenic mouse model which spontaneously develops HER2-positive mammary tumors. Repeated intraperitoneal injections of a safety dose (2.5mg/kg) of NAX014 delayed the development of tumors, reducing both the number and size of tumor masses. In vivo sidestream dark field videomicroscopy revealed a significant lower vessel density in mammary tumors from NAX014-treated mice in comparison with the control group. Immunohistochemical evaluation using CD34 antibody confirmed the reduced vessel density in NAX014 group. Statistically significant increase of senescence associated β-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals. Finally, NAX014 treatment decreased the level of perforine and granzyme mRNA in mammary tumors. Berberine did not show any statistically significant modulation in comparison with control mice. The results of the present study indicate that NAX014 is more effective than BBR in exerting anticancer activity delaying the development of mammary tumors in mice transgenic for the HER-2/neu oncogene. The antitumor efficacy of NAX014 is mainly related to its effect on tumor vascular network and on induction of tumor cell senescence. PMID:26168818

  10. Biologic and therapeutic role of HER2 in cancer.

    PubMed

    Ménard, Sylvie; Pupa, Serenella Marja; Campiglio, Manuela; Tagliabue, Elda

    2003-09-29

    Overexpression of the human epidermal growth factor-2 (HER2) oncogene in human breast carcinomas has been associated with a more aggressive course of disease. The reason for this association is still unclear, although it has been suggested to rest in increased proliferation, vessel formation, and/or invasiveness. Alternatively, prognosis may not be directly related to the presence of the oncoprotein on the cell membrane, but instead to the breast carcinoma subset identified by HER2 overexpression and characterized by a peculiar gene expression profile. HER2 has also been associated with sensitivity to anthracyclins and resistance to endocrine therapy, suggesting that tyrosine kinase receptor and hormone receptor pathways represent two major proliferation pathways exclusively active in breast carcinomas, one sensitive to chemotherapeutic drugs and the other to antiestrogens. HER2 currently represents one of the most appropriate targets for specific therapy. Indeed, trastuzumab, a monoclonal antibody directed against the extracellular domain of HER2, is therapeutically active in HER2-positive breast carcinomas. However, a consistent number of HER2-positive tumors is not responsive to HER2-driven therapy, indicating the need for a better understanding of the mechanism of action of this new biological drug in vivo. While preclinical studies suggest antibody-dependent cell cytotoxicity as the major mechanism, determination of NK activity at the time of treatment remains mandatory, especially in patients treated with immunosuppressive drugs. The efficacy of prophylactic vaccination has been fully demonstrated in preclinical models, whereas ongoing studies of active immunotherapy using a variety of vaccination regimens against HER2 in tumor-bearing mice and patients have met with only moderate success. PMID:14528282

  11. Protective effect of naturally occurring anti-HER2 autoantibodies on breast cancer.

    PubMed

    Tabuchi, Yukiko; Shimoda, Masafumi; Kagara, Naofumi; Naoi, Yasuto; Tanei, Tomonori; Shimomura, Atsushi; Shimazu, Kenzo; Kim, Seung Jin; Noguchi, Shinzaburo

    2016-05-01

    Anti-HER2-autoantibodies (HER2-AAbs) are found in breast cancer patients as well as healthy individuals. However, the clinical relevance of the antibodies is unknown. We established an enzyme-linked immunosorbent assay with high sensitivity and quantified serum HER2-AAbs in 100 healthy women, 100 untreated patients with ductal carcinoma in situ (DCIS), and 500 untreated patients with invasive breast carcinoma (IBC). The associations between the levels of HER2-AAbs and breast cancer risk, and recurrence-free survival, were examined. High levels of HER2-AAbs were significantly associated with a reduced risk of DCIS (odds ratio [OR] 0.19, P = 4.6 × 10(-7)) or IBC (OR 0.31, P = 3.7 × 10(-7)). Subgroup analysis of IBC revealed a stronger association of HER2-AAbs with a reduced risk of the hormone receptor (HR)(-)/HER2(+) subtype (OR 0.12) than the other subtypes (HR(+)/HER2(-) [OR = 0.32], HR(+)/HER2(+) [OR 0.38], and HR(-)/HER2(-) [OR 0.29]). When we set the cutoff of HER2-AAbs at 20 ng/mL, recurrence-free survival of HER2-AAb-positive patients (N = 74) was significantly better than that of HER2-AAb-negative patients (N = 426) (P = 0.015). Univariate and multivariate analyses demonstrated that HER2-AAbs, as well as histological grade, were independently and significantly (P = 0.0065 and 0.049, respectively) associated with recurrence-free survival. Our exploratory study suggests a protective effect of naturally occurring HER2-AAbs on the development of primary and recurrent breast cancer. Further studies on HER2-AAbs are warranted. PMID:27113738

  12. Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting

    ClinicalTrials.gov

    2014-03-03

    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

  13. The Promher Study: An Observational Italian Study on Adjuvant Therapy for HER2-Positive, pT1a-b pN0 Breast Cancer

    PubMed Central

    Gori, Stefania; Inno, Alessandro; Fiorio, Elena; Foglietta, Jennifer; Ferro, Antonella; Gulisano, Marcella; Pinotti, Graziella; Gubiotti, Marta; Cavazzini, Maria Giovanna; Turazza, Monica; Duranti, Simona; De Simone, Valeria; Iezzi, Laura; Bisagni, Giancarlo; Spazzapan, Simon; Cavanna, Luigi; Saggia, Chiara; Bria, Emilio; Cretella, Elisabetta; Vici, Patrizia; Santini, Daniele; Fabi, Alessandra; Garrone, Ornella; Frassoldati, Antonio; Amaducci, Laura; Saracchini, Silvana; Evangelisti, Lucia; Barni, Sandro; Gamucci, Teresa; Mentuccia, Lucia; Laudadio, Lucio; Zoboli, Alessandra; Marchetti, Fabiana; Bogina, Giuseppe; Lunardi, Gianluigi; Boni, Luca

    2015-01-01

    Background The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients. Methods Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted. Results Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001). Conclusions The majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. The choice of treatment type seems to be mainly influenced by tumor size, proliferation index, hormone receptor status and age. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant

  14. Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer.

    PubMed

    Doornebal, Chris W; Vrijland, Kim; Hau, Cheei-Sing; Coffelt, Seth B; Ciampricotti, Metamia; Jonkers, Jos; de Visser, Karin E; Hollmann, Markus W

    2015-08-01

    Morphine and other opioid analgesics are potent pain-relieving agents routinely used for pain management in patients with cancer. However, these drugs have recently been associated with a worse relapse-free survival in patients with surgical cancer, thus suggesting that morphine adversely affects cancer progression and relapse. In this study, we evaluated the impact of morphine on breast cancer progression, metastatic dissemination, and outgrowth of minimal residual disease. Using preclinical mouse models for metastatic invasive lobular and HER2 breast cancer, we show that analgesic doses of morphine do not affect mammary tumor growth, angiogenesis, and the composition of tumor-infiltrating immune cells. Our studies further demonstrate that morphine, administered in the presence or absence of surgery-induced tissue damage, neither facilitates de novo metastatic dissemination nor promotes outgrowth of minimal residual disease after surgery. Together, these findings indicate that opioid analgesics can be used safely for perioperative pain management in patients with cancer and emphasize that current standards of "good clinical practice" should be maintained. PMID:25734987

  15. Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model.

    PubMed

    Nakayama, Akiko; Takagi, Shinji; Yusa, Tadashi; Yaguchi, Masahiro; Hayashi, Akira; Tamura, Toshiya; Kawakita, Youichi; Ishikawa, Tomoyasu; Ohta, Yoshikazu

    2013-01-01

    Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase-expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases. PMID:23983820

  16. The efficiency and safety of trastuzumab and lapatinib added to neoadjuvant chemotherapy in Her2-positive breast cancer patients: a randomized meta-analysis

    PubMed Central

    Chen, Zhe-Ling; Shen, Yan-Wei; Li, Shu-Ting; Li, Chun-Li; Zhang, Ling-Xiao; Yang, Jiao; Lv, Meng; Lin, Ya-Yun; Wang, Xin; Yang, Jin

    2016-01-01

    Background The addition of human epidermal growth factor receptor 2 (Her2) therapies to neoadjuvant chemotherapy (NAC) during treatment of Her2-positive breast cancer has been proposed as an effective way to improve the prognosis. However, the treatment outcomes of adding trastuzumab, lapatinib, or both to NAC were not unequivocal in randomized clinical trials. Based on these data, a meta-analysis was performed. Objective The main objective was to evaluate the efficiency and safety of trastuzumab and lapatinib added to NAC for treatment of Her2-positive breast cancer. Methods ClinicalTrials.gov and PubMed were searched for randomized clinical trials that compared trastuzumab, lapatinib, or both, added to NAC. The main endpoint was a pathologically complete response (pCR) rate, in breast only or in breast and lymph nodes. The drug safety and the influence of hormone-receptor status, comparing the clinical response and the rate of breast conservation, were evaluated. Results A total of eight publications were included in the primary analysis, designed as two or three subgroups. The cumulative cases were 2,349 and the analyses of all the clinical trials showed that the pCR rate was significantly higher in the group receiving trastuzumab than that in the group with lapatinib, either in breast only (P=0.001) or in breast and lymph nodes (P=0.0001). Similar results could be seen in comparisons of the combination versus trastuzumab group. Further studies of subgroups divided into hormone receptor-positive or-negative patients showed that the addition of trastuzumab or dual Her2-targeted therapy significantly improved the pCR rate in patients who were hormone-insensitive. Regarding the toxic effects, we found more grade 3 and 4 toxic effects, such as diarrhea, skin disorder, and hepatic biochemical changes in the lapatinib and combination groups. No temporally significant differences were found when the clinical response and the rate of breast conservation in the groups

  17. Quantitative detection of HER2 protein concentration in breast cancer tissue does not increase the number of patients eligible for adjuvant HER2-targeted therapy.

    PubMed

    Bechmann, Troels; Olsen, Dorte Aalund; Jakobsen, Erik Hugger; Madsen, Jonna Skov; Brandslund, Ivan; Jylling, Anne Marie Bak; Steffensen, Karina Dahl; Jakobsen, Anders

    2013-04-01

    Human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer patients and is associated with an aggressive tumor and a poor prognosis. Currently, patients are selected for adjuvant HER2-targeted therapy based on HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). In this study, we assessed the clinical significance of tissue HER2 status determined by a quantitative immunoassay using ADVIA Centaur. We investigated the hypothesis that the clinical outcome is worse in a group of patients defined as tissue HER2-positive only by Centaur, but not treated with adjuvant HER2-targeted therapy, compared to patients defined as HER2-positive by IHC/FISH and therefore treated with adjuvant HER2-targeted therapy. Tumor tissue was obtained at primary surgery from 415 breast cancer patients between 2004 and 2010. HER2 status was determined by quantitative immunoassay of fresh-frozen tissue and by IHC/FISH of corresponding paraffin-embedded tissue. We compared the clinical outcome in four groups of patients defined by tissue HER2 status and adjuvant HER2-targeted therapy. The final analysis included 379 patients after a median follow-up of 3.9 years for invasive disease-free survival (IDFS) and 4.2 years for overall survival (OS). The quantitative Centaur assay defined a greater number of patients (100 patients, 26.4%) as HER2-positive than IHC/FISH (63 patients, 16.6%) (P<0.0001). No significant difference in IDFS (P=0.159) and OS (P=0.150) was observed among the four groups of patients. However, in the IHC/FISH-positive group without adjuvant HER2-targeted therapy (group 2), a significantly greater number of events was found compared to the Centaur-positive group without adjuvant HER2-targeted therapy (group 3) for both IDFS (P=0.025) and OS (P=0.020). Quantitative HER2 determination by Centaur did not define a new group of patients eligible for HER2-targeted therapy. Currently, tissue HER2 status defined

  18. First MNKs degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines.

    PubMed

    Ramalingam, Senthilmurugan; Gediya, Lalji; Kwegyir-Afful, Andrew K; Ramamurthy, Vidya P; Purushottamachar, Puranik; Mbatia, Hannah; Njar, Vincent C O

    2014-01-30

    Some retinoic acid metabolism blocking agents (RAMBAs) are known to exhibit a wide range of anticancer activities by mechanisms that are still not completely resolved. This study investigated the anticancer efficacy and mechanism(s) of novel RAMBA retinamides (RRs) in triple negative and Her-2 overexpressing breast cancer cells. Specifically, we examined the possibility that RRs affect the translational machinery in these breast cancer (BC) cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine209 phosphorylation by upstream MAPK-interacting kinases (Mnks). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating BCs, particularly for Her2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes. We report for the first time that the degradation of Mnk1 by RRs in BC cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, colonization, invasion, and migration and induce apoptosis. Most importantly, the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (cercosporamide and CGP57380). Furthermore, RRs potencies on peIF4E down-regulation and growth inhibition were superior to those of two clinically relevant retinoids and the Mnk inhibitors. Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk/eIF4E based therapeutic treatment of breast cancers. PMID:24504069

  19. First Mnks degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines

    PubMed Central

    Ramalingam, Senthilmurugan; Gediya, Lalji; Kwegyir-Afful, Andrew K.; Ramamurthy, Vidya P.; Purushottamachar, Puranik; Mbatia, Hannah; Njar, Vincent C. O.

    2014-01-01

    Some retinoic acid metabolism blocking agents (RAMBAs) are known to exhibit a wide range of anticancer activities by mechanisms that are still not completely resolved. This study investigated the anticancer efficacy and mechanism(s) of novel RAMBA retinamides (RRs) in triple negative and Her-2 overexpressing breast cancer cells. Specifically, we examined the possibility that RRs affect the translational machinery in these breast cancer (BC) cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine209 phosphorylation by upstream MAPK-interacting kinases (Mnks). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating BCs, particularly for Her2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes. We report for the first time that the degradation of Mnk1 by RRs in BC cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, colonization, invasion, and migration and induce apoptosis. Most importantly, the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (cercosporamide and CGP57380). Furthermore, RRs potencies on peIF4E down-regulation and growth inhibition were superior to those of two clinically relevant retinoids and the Mnk inhibitors. Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk/eIF4E based therapeutic treatment of breast cancers. PMID:24504069

  20. [A Case of Effective Whole-Brain Irradiation and Lapatinib/Capecitabine Combination Therapy for HER2-Positive Breast Cancer with Multiple Brain Metastases].

    PubMed

    Shibasaki, Masayuki; Tanabe, Asami; Toda, Tateo; Sakata, Hiroki; Ijichi, Masayoshi; Kusaka, Kouji; Bandai, Yasutsugu

    2015-06-01

    We report the case of a 48-year-old female patient with HER2-positive and hormone receptor-negative breast cancer with multiple liver metastases. She underwent 6 cycles of FEC followed by docetaxel plus trastuzumab (TZB), resulting in a clinical complete response. After 15 cycles of a TZB-containing regimen, she complained of dizziness and nausea, and imaging examinations revealed multiple brain metastases. Whole-brain irradiation(33.6 Gy) was performed, and the chemotherapy regimen was changed to lapatinib (LAP: orally at 1,250 mg/day, every day) and capecitabine (CAP: orally at 2,000 mg/m2, every day for 2 weeks, followed by a 1-week rest interval, as 1 cycle). After 6 weeks of the new treatment, magnetic resonance imaging revealed marked shrinkage of brain metastases. A clinical complete response was maintained for 19 months. While brain metastasis is an important problem with treatment with TZB, LAP is drawing attention because of its ability to pass the blood-brain barrier because of its small molecular weight. LAP/CAP combination therapy may be an effective treatment option for brain metastases of HER2-positive breast cancer in which TZB essentially has no effect. PMID:26199252

  1. HER-2/neu oncogene expression and proliferation in breast cancers.

    PubMed Central

    Bacus, S. S.; Ruby, S. G.; Weinberg, D. S.; Chin, D.; Ortiz, R.; Bacus, J. W.

    1990-01-01

    Amplification of the HER-2/neu proto-oncogene in breast cancer has been reported to correlate with poor patient prognosis. The proliferation, or growth fraction, of cells has also been shown to be of prognostic importance in breast cancer. A study was conducted to evaluate the correlation between HER-2/neu gene expression and proliferation in breast cancer. Quantitative immunohistochemical methods for the detection of the HER-2/neu protein expression and for assessing the proliferation fraction on frozen sections of tumor cells were used. The detection of epidermal growth factor receptor (EGFR) along with quantitative DNA ploidy analysis, also was performed on the same breast cancers. The results indicated two subgroups of invasive ductal carcinoma; 1) HER-2/neu overexpressing cases that were negative for EGFR expression and had low proliferation fraction, and a tetraploid DNA pattern (22 cases), and 2) other combinations of HER-2/neu expression and EGFR expression, with a high proliferation fraction and an aneuploid DNA pattern (38 cases). Eight cases of carcinoma in situ were positive for HER-2/neu overexpression and negative for EGFR expression, and had a high proliferation fraction and a tetraploid DNA pattern. Twenty-six cases of low-grade carcinoma exhibited low proliferation and a diploid DNA pattern. Images Figure 1 Figure 2 PMID:1973597

  2. Bilateral inflammatory metachronic ERBB2 (HER2/neu)-positive breast carcinoma: prolonged survival with combined chemotherapy and trastuzumab.

    PubMed

    Lázaro, Alicia; Casinello, Javier; Amorós, Almudena; Heredia, Miriam; López-Alfonso, Ana

    2008-09-01

    A patient with inflammatory breast carcinoma (IBC) diagnosed in the left breast responded to cisplatin and was treated with radical mastectomy and adjuvant therapy. Two years later C-erbB2-positive IBC was diagnosed in the right breast, and was treated with mastectomy and radiotherapy. Two years later skin metastases appeared, and trastuzumab was started initially as monotherapy, and later with paclitaxel and capecitabine. More than 12 years after diagnosis and 7 years after trastuzumab was started, the patient remains in complete clinical remission on trastuzumab and capecitabine. PMID:18796377

  3. Clinical efficacy and safety of T-DM1 for patients with HER2-positive breast cancer

    PubMed Central

    Ma, Bo; Ma, Qianqian; Wang, Hongqiang; Zhang, Guolei; Zhang, Huiying; Wang, Xiaohong

    2016-01-01

    Purpose The aim of this study was to evaluate the therapeutic efficacy and safety of trastuzumab emtansine (T-DM1) for the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer. Methods We performed a systemic review and meta-analysis of the relevant published clinical studies. A computerized search was performed for controlled clinical trials of T-DM1 in targeted treatment. Overall survival, progression-free survival, objective response rate, symptom progression free, and adverse events (AEs) were evaluated. Results Eight eligible trials with a total of 2,016 patients with breast cancer were included in the present meta-analysis. The treatment of patients with breast cancer with T-DM1 was associated with significantly increased overall and progression-free survival when compared with controls (P<0.0001). An analysis of the objective response rate and symptom progression free also demonstrated favorable results for T-DM1 treatment (P≤0.0001). There was no significant difference between the T-DM1 and control groups with respect to nonhematologic or hematologic AEs (P=0.99 and P=0.30, respectively). Conclusion Overall, T-DM1 is efficacious in the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer and low rates of AEs compared with controls. PMID:27013890

  4. Gigantoxin-4-4D5 scFv is a novel recombinant immunotoxin with specific toxicity against HER2/neu-positive ovarian carcinoma cells.

    PubMed

    Lv, Xinxin; Zhang, Jian; Xu, Rui; Dong, Yuguo; Sun, Aiyou; Shen, Yaling; Wei, Dongzhi

    2016-07-01

    Immunotoxins are a new class of antibody-targeted therapy in clinical development. Traditional immunotoxins that are constructed from the toxins of plants or bacteria need to be internalized to the cytoplasm and thus have limited antitumor efficacy. In the present study, we combined a recently reported sea anemone cytolysin Gigantoxin-4 with an anti-HER2/neu single-chain variable fragment 4D5 scFv to construct a novel immunotoxin. We fused a SUMO tag to the N-terminus of Gigantoxin-4-4D5 scFv and it was successfully expressed in Escherichia coli strain BL21 (DE3) in a soluble form. After purification, the purity of Gigantoxin-4-4D5 scFv reached 96 % and the yield was 14.3 mg/L. Our results demonstrated that Gigantoxin-4-4D5 scFv exerted a highly cytotoxic effect on the HER2/neu-positive ovarian carcinoma SK-OV-3 cell line. And the hemolytic activity was weaker, making it safe for normal cells. The results of immunofluorescence analysis showed that this novel immunotoxin could specifically bind to SK-OV-3 cells with no recognition of human embryonic kidney 293 cells. Scanning electron microscope observations and extracellular lactate dehydrogenase activity indicated that it could induce necrosis in SK-OV-3 cells by disrupting the cell membrane. Moreover, it could also mediate apoptosis of SK-OV-3 cells. PMID:27063011

  5. The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

    SciTech Connect

    Niwinska, Anna; Tacikowska, Malgorzata; Murawska, Magdalena

    2010-07-15

    Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

  6. Paclitaxel and Trastuzumab as Maintenance Therapy in Patients with HER2-Positive Metastatic Breast Cancer Who Underwent High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation.

    PubMed

    Cheng, Yee Chung; Rondón, Gabriela; Anderlini, Paolo; Khouri, Issa F; Champlin, Richard E; Ueno, Naoto T

    2013-01-01

    We examined the feasibility and safety of using paclitaxel and trastuzumab as maintenance therapy after high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (AHST) for patients with HER2-positive metastatic breast cancer. Ten patients (9 women and 1 man) were enrolled in the study. The median age was 46.5 years (range, 27-65 years). The median follow-up time was 1003 days (range, 216-2526 days). All patients had metastatic disease, but 2 had only bone metastasis. One patient had complete response, 6 had partial response and 3 had stable disease to the standard-dose chemotherapy prior to transplantation. The conditioning regimen consisted of cyclophosphamide, carmustine, and thiotepa. After AHST, patients received weekly paclitaxel for 12 doses and trastuzumab every 3 weeks for 1 year as maintenance therapy. All patients experienced successful engraftment. The only grade 4 toxic effects observed were leukopenia and thrombocytopenia. The most common grade 3 toxic effect was neutropenic fever. No treatment-related deaths were observed. The median progression-free survival time was 441 days, and the median overall survival time was 955 days. Two patients died in accidents while their disease remained in remission. Five patients died with disease progression. At the time of this report, 3 patients are alive with stable disease, 1 of whom has remained free of disease progression for 2526 days since transplantation. Our findings indicate that paclitaxel plus trastuzumab as maintenance therapy after HDC with AHST for patients with HER2-positive metastatic breast cancer not only is feasible and safe but also results in survival outcomes similar to historical results. PMID:24155780

  7. The Clinical Efficacy and Cardiotoxicity of Fixed-Dose Monthly Trastuzumab in HER2-Positive Breast Cancer: A Single Institutional Analysis

    PubMed Central

    Tsai, Tsung-Neng; Chen, Jia-Hong; Dai, Ming-Shen; Chang, Ping-Ying; Ho, Ching-Liang; Ye, Ren-Hua; Chung, Tsai-Rong; Chen, Yeu-Chin; Chao, Tsu-Yi

    2016-01-01

    Objective Trastuzumab-containing treatment regimens have been shown to improve survival outcomes in HER2-positive breast cancer (BC). It is much easier to infuse a fixed one-vial dose to every patient on a regular schedule in the general clinical setting. The aims of this study were evaluating the efficacy of a 440 mg fixed-dose of trastuzumab administered on a monthly infusion schedule, and the risk factors for cardiac events. Patients and methods We retrospectively reviewed data from 300 HER2-positive BC patients in our institute: 208 were early-stage BC patients undergoing adjuvant trastuzumab treatment, and 92 were metastatic BC patients treated with trastuzumab infusions until disease progression. There were 181 patients receiving regular trastuzumab infusions every 3 weeks (Q3W; 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks), and the other 119 patients were treated monthly with a fixed 440 mg dose (QM; fixed 440 mg every 4 weeks). Results The medians of progression-free survival (PFS) and overall survival (OS) in the adjuvant setting were not reached in both treatment groups. In the metastatic setting, there was no significant difference between groups in PFS or OS. The median time to significant cardiovascular (CV) dysfunction was 4.54 months. The incidence of congestive heart failure requiring medication in our cohort was 3.4%. Conclusion In our study, we found that fixed-dose monthly trastuzumab was feasible and effective. In addition, the CV risk was not higher with the fixed-dose protocol. This treatment modality could lower the cost and was easier to implement in clinical practice. Larger prospective randomized studies with longer-term follow up are needed to confirm our results. PMID:26953588

  8. Delay in initiation of adjuvant trastuzumab therapy leads to decreased overall survival and relapse-free survival in patients with HER2-positive non-metastatic breast cancer.

    PubMed

    Gallagher, Christopher M; More, Kenneth; Kamath, Tripthi; Masaquel, Anthony; Guerin, Annie; Ionescu-Ittu, Raluca; Gauthier-Loiselle, Marjolaine; Nitulescu, Roy; Sicignano, Nicholas; Butts, Elizabeth; Wu, Eric Q; Barnett, Brian

    2016-05-01

    Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6 months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6 months and ≤6 months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9 % initiated adjuvant trastuzumab within ≤6 months of diagnosis and 20.1 % initiated adjuvant trastuzumab >6 months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6 months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within ≤6 months of diagnosis (hazard ratios [95 % CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6 months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS. PMID:27107569

  9. [Radiotherapy for Alleviation of Paraparesis due to Leptomeningeal and Cauda Equina Metastasis of HER2-Positive Breast Cancer: A Case Report].

    PubMed

    Fujimoto, Shutaro; Iwasaki, Motoyuki; Ito, Masaki; Niiya, Yoshimasa; Itosaka, Hiroyuki; Mabuchi, Shouji; Nishioka, Takeshi; Echizenya, Hayato; Kasai, Kiyoshi

    2015-09-01

    Leptomeningeal metastasis is a rare entity and its diagnosis is often difficult. Moreover, evidence-based therapeutic strategies have not yet been established. A 52-year-old woman presented with high fever and was diagnosed with bacterial meningitis at first examination;although her fever was alleviated, she experienced motor weakness in both of her lower extremities. Ga scintigraphy highlighted the hot-spot areas of the disease in the cranial bone. She was then transferred to our department. Open biopsy of the skull showed metastasis of the cancer. Chest CT results indicated right breast cancer and Gd-DTPA imaging showed obvious enhancement of the pia mater around the conus medullaris and cauda equina. However, cerebrospinal fluid(CSF)cytological examination did not show the presence of any positive cells;consequently, mastectomy was performed in the thoracic surgical department. The severity of paraparesis and pain in her legs increased;however, repeat MRI 1 month later showed no evidence of any change. Therefore, we performed biopsy of the cauda equina and arachnoid lesions. The pathological diagnosis was metastasis of breast cancer with positive human epidermal growth factor receptor 2(HER2)immunological staining. The results of a repeat cytological examination of the CSF during the surgery were negative. Local radiotherapy(25 Gy/5 Fr)as a monotherapy was selected for the patient, because her family did not approve of the combination of radiotherapy and chemotherapy. The severity of both paraparesis and limb pain decreased immediately after the radiotherapy. PMID:26321696

  10. Overall survival benefit with pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer in CLEOPATRA, a randomised Phase 3 study

    PubMed Central

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

    2013-01-01

    Summary Background Primary results from the randomised, double-blind phase 3 study CLEOPATRA demonstrated significantly improved median progression-free survival (PFS) with pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive first-line metastatic breast cancer (MBC). Overall survival (OS) data at the primary analysis showed a strong trend in favour of the pertuzumab arm but did not reach statistical significance. Here we report confirmatory OS results after one additional year of follow-up. Methods Patients were randomly assigned to study treatment. OS and investigator-assessed PFS were analysed using the Kaplan-Meier approach and log-rank tests stratified by geographic region and prior treatment status. This trial is registered with ClinicalTrials.gov, NCT00567190. Findings In the intent-to-treat population (808 patients), 267 deaths had occurred at data cut-off (placebo arm: 154 of 406 [37·9%], pertuzumab arm: 113 of 402 [28·1%]). Treatment with pertuzumab plus trastuzumab plus docetaxel resulted in a 34% reduction in the risk of death during the course of the study (HR=0·66; 95% CI 0·52–0·84; p=0·0008). Median OS was 37·6 months in the placebo arm and was not yet reached in the pertuzumab arm. A descriptive follow-up analysis of investigator-assessed PFS showed a median PFS of 12·4 and 18·7 months in the placebo versus pertuzumab arm (HR=0·69; 95% CI 0·58–0·81). No new safety concerns were identified with one additional year of follow-up. Adverse events were similar to those reported at the primary analysis with respect to incidence, severity, and specificity. Interpretation This OS analysis demonstrated statistically significant and clinically meaningful survival benefit with pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive MBC. Updated analyses of investigator-assessed PFS and safety were consistent with the

  11. Ki-67 index as a prognostic factor of subsequent lapatinib-based therapy in HER2-positive metastatic breast cancer with resistance to trastuzumab

    PubMed Central

    Bian, Li; Wang, Tao; Zhang, Shao-hua; Zhang, Hui-qiang; Guo, Yun-fei; Du, Ge; Li, Wang; Wu, Shi-kai; Song, San-tai; Jiang, Ze-fei

    2014-01-01

    Prognostic factor analysis has been conducted to determine whether the parameters of clinical data and biomarkers would predict differential progression-free survival (PFS) or overall survival (OS) from lapatinib-based therapy in patients with primary or acquired resistance to trastuzumab. Treatment with lapatinib plus capecitabine for HER2-positive metastatic breast cancer (MBC) with primary or acquired resistance to trastuzumab was analyzed retrospectively. Tumor biomarkers, which came from the biopsies before the starting of lapatinib therapy, were evaluated by immunohistochemistry (IHC). Prognostic factors related to PFS or OS of the lapatinib therapy were assessed by univariate and multivariate analysis. Ki-67 index and liver metastases were the significant prognostic factors for predicting PFS of subsequent lapatinib therapy in the univariate analysis and the multivariate analysis. The risk for disease progression in patients who had a Ki-67 index < 40% was 59% less than that in patients had Ki-67 ≥ 40 (HR = 0.41, 95% CI, 0.23–0.74, P = 0.003). TTP of prior trastuzumab therapy, liver metastases, and the number of metastatic sites were three independent prognostic factors of subsequent lapatinib therapy. Ki-67 index was the significant prognostic factors for predicting PFS of the subsequent second line targeted therapy in patients with trastuzumab resistance. PMID:24424115

  12. Predictive Factors of Lapatinib and Capecitabine Activity in Patients with HER2-Positive, Trastuzumab-Resistant Metastatic Breast Cancer: Results from the Italian Retrospective Multicenter HERLAPAC Study

    PubMed Central

    Gori, Stefania; Inno, Alessandro; Rossi, Valentina; Turazza, Monica; Fiorio, Elena; Fabi, Alessandra; Bisagni, Giancarlo; Foglietta, Jennifer; Santini, Daniele; Pavese, Ida; Pellegrino, Arianna; Zambelli, Alberto; Vici, Patrizia; Leonardi, Vita; Barni, Sandro; Saracchini, Silvana; Bogina, Giuseppe; Marchetti, Fabiana; Duranti, Simona; Lunardi, Gianluigi; Montemurro, Filippo

    2016-01-01

    Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p<0.001). Multivariate analysis revealed the benefit of lapatinib-based therapy in terms of PFS and OS was significantly associated with time-to-progression (TTP) on prior first-line trastuzumab-based therapy. In particular, each additional month on first-line trastuzumab based therapy was associated with a reduction in hazard of progression and death after the initiation of lapatinib-based therapy of 2% and 4%, respectively. Conclusions A longer TTP to first line trastuzumab seems to predict a prolonged PFS and OS with subsequent lapatinib and capecitabine. PMID:27224517

  13. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies

    PubMed Central

    Morancho, Beatriz; Zacarias-Fluck, Mariano; Zhang, Junjie; Martínez-Barriocanal, Águeda; Navarro Jiménez, Alexandra; Aura, Claudia; Burgues, Octavio; Lluch, Ana; Cortés, Javier; Nuciforo, Paolo; Rubio, Isabel T.; Marangoni, Elisabetta; Deeds, James; Boehm, Markus; Schlegel, Robert; Tabernero, Josep; Mosher, Rebecca; Arribas, Joaquín

    2015-01-01

    A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies. PMID:26075403

  14. Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in HER2-positive patients with metastatic gastric cancer

    PubMed Central

    Takahashi, Naoki; Furuta, Koh; Taniguchi, Hirokazu; Sasaki, Yusuke; Shoji, Hirokazu; Honma, Yoshitaka; Iwasa, Satoru; Okita, Natsuko; Takashima, Atsuo; Kato, Ken; Hamaguchi, Tetsuya; Shimada, Yasuhiro; Yamada, Yasuhide

    2016-01-01

    HER2-overexpression in tumor tissue is observed in 6 to 23% of advanced gastric cancer (GC) cases, and trastuzumab is an active molecular drug for these patients. There are no data available on whether serum levels of ligands are associated with the response and resistance to trastuzumab in HER2-positive patients with metastatic GC. HER2 screening of 502 patients with advanced gastric cancer was performed in our institution. Among these patients, 84 patients (16.8%) were diagnosed as HER2-positive, and those who were treated with trastuzumab and met the inclusion criteria were enrolled in the present study. Serum levels of ligands that affect the HER2 signal pathway were measured by an enzyme-linked immunosorbent assay. Forty-six HER2-positive patients were enrolled in this study, and 26 patients (56.5%) achieved a partial response to treatment with trastuzumab. Among several ligands, the serum level of hepatocyte growth factor (HGF) was significantly lower in responders compared with that in non-responders (p = 0.014). Multivariate analyses showed that a high level of serum HGF was a poor prognostic factor for overall survival (OS) compared with low levels of HGF (adjusted HR: 3.857, 95% CI: 1.309–11.361, p = 0.014). Among 25 patients without initial disease progression on the treatment with trastuzumab, the mean value of serum HGF at disease progression was significantly higher than that at pre-treatment (p = 0.041). As novel findings, our study indicated that serum level of HGF was associated with tumor shrinkage and time to progression of trastuzumab in HER2-positive patients with metastatic GC. PMID:26716644

  15. Targeting HER2

    PubMed Central

    Wong, Karen J; Baidoo, Kwamena E; Nayak, Tapan K; Regino, Celeste AS; Garmestani, Kayhan; Brechbiel, Martin W

    2010-01-01

    The potential of the HER2-targeting antibody trastuzumab as a radioimmunoconjugate useful for both imaging and therapy was investigated. Conjugation of trastuzumab with the acyclic bifunctional chelator CHX-A″-DTPA yielded a chelate:protein ratio of 3.4 ± 0.3; the immunoreactivity of the antibody unaffected. Radiolabeling was efficient, routinely yielding a product with high specific activity. Tumor targeting was evaluated in mice bearing subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian and prostate carcinomas. High uptake of the radioimmunoconjugate, injected intravenously (i.v.), was observed in each of the models and the highest tumor %ID/g (51.18 ± 13.58) was obtained with the ovarian (SKOV-3) tumor xenograft. Specificity was demonstrated by the absence of uptake of 111In-trastuzumab by melanoma (A375) s.c. xenografts and 111In-HuIgG by s.c. LS-174T xenografts. Minimal uptake of i.v. injected 111In-trastuzumab in normal organs was confirmed in non-tumor-bearing mice. The in vivo behavior of 111In-trastuzumab in mice bearing intraperitoneal (i.p.) LS-174T tumors resulted in a tumor %ID/g of 130.85 ± 273.34 at 24 h. Visualization of tumor, s.c. and i.p. xenografts was achieved by γ-scintigraphy and PET imaging. Blood pool was evident as expected but cleared over time. The blood pharmacokinetics of i.v. and i.p. injected 111In-trastuzumab was determined in mice with and without tumors. The data from these in vitro and in vivo studies supported advancement of radiolabeled trastuzumab into two clinical studies, a Phase 0 imaging study in the Molecular Imaging Program of the National Cancer Institute and a Phase 1 radioimmunotherapy study at the University of Alabama. PMID:20716957

  16. 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

  17. Over 17-month complete clinical brain response with a well-tolerated lapatinib plus capecitabine combination in a very young patient afflicted by HER2-positive metastatic breast cancer.

    PubMed

    Sini, Valentina; Menghi, Antonello; Cursano, Maria Concetta; Mandolini, Pier Luca; Lanza, Rosina

    2013-01-01

    This report describes a case of ab initio metastatic HER2-positive breast cancer in a very young patient. The onset of breast cancer at such a young age is uncommon and could delay the diagnosis with unquestionable impact on the prognosis. Unfortunately, the patient experienced cerebral progression during first-line treatment. Indeed, brain metastases occur in about one-third of HER2-positive metastatic breast cancer patients during trastuzumab-based treatment. The small molecule lapatinib is active in established cerebral disease, and we report a complete brain response longer than expected, thanks to a well-tolerated, orally administered combination of lapatinib and capecitabine. PMID:24503802

  18. Safety and efficacy of the combination of T-DM1 with radiotherapy of the central nervous system in a patient with HER2-positive metastatic breast cancer: case study and review of the literature

    PubMed Central

    Borges, Giuliano Santos; Rovere, Rodrigo Kraft; Dias, Stéphanie Mereniuk Kappel; Chong, Fernando Henrique; Morais, Mayara dos Santos

    2015-01-01

    Approximately 35% of patients with confirmed HER2 breast cancer progress to metastases of the central nervous system (CNS). Total cerebral radiotherapy is considered as standard treatment for these cases; however, studies have shown that some chemotherapy drugs can be used during radiotherapy without significantly increasing its toxicity. In this article, we report the case of a patient with HER2-positive breast cancer who showed isolated progression of the illness in the CNS, which was observed during the treatment period using T-DM1 concomitantly with radiotherapy of the CNS without apparent toxicity of the combination and keeping the illness controlled. Through a review of the literature on the use of radiotherapy and chemotherapy with T-DM1 for the treatment of cerebral metastases in HER2-positive breast cancer, we describe the efficacy and tolerance of the concomitant application of these treatments. PMID:26557884

  19. 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

  20. Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status

    PubMed Central

    Soares, Maria; Ribeiro, Rita; Najmudin, Shabir; Gameiro, Andreia; Rodrigues, Rita; Cardoso, Fátima; Ferreira, Fernando

    2016-01-01

    HER2 is overexpressed in about 30% of feline mammary carcinomas (FMC) and in 15-30% of breast cancers. Women with HER2-positive breast tumors are associated with shorter survival. This study aimed to optimize the detection and quantification of serum HER2 (sHER2) in cats and to evaluate its potential in diagnosing cats with mammary carcinomas (MC) overexpressing HER2. A prospective study was conducted in 60 queens showing MC and 20 healthy animals. Pre-operative serum samples were collected for sHER2 quantification using two immunoassays: ELISA and Dot blot assay. sHER2 levels were compared with tissue HER2 status assessed by immunohistochemistry. Queens with FMC showed significantly higher mean levels of sHER2 by both ELISA and Dot blot assay. A significant difference in the sHER2 levels was also found between cats with HER2-positive MC and those with low-expressing HER2 MC. A significant correlation between sHER2 levels and tumor HER2 status was also found, particularly when ELISA was used (r = 0.58, p < 0.0001). The value of 10 ng/ml was proposed as the optimal cutoff for both immunoassays by ROC analysis. Like in humans, sHER2 levels are increased in cats with MC HER2-positive, strongly suggesting that evaluation of sHER2 levels can be very useful in feline oncology. The results show that ELISA and Dot blot assay can replace the immunohistochemistry technique, due to their efficacy and lower costs for diagnostic purposes and for monitoring the response to anti-HER2 therapies in cats. PMID:26909614

  1. Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status.

    PubMed

    Soares, Maria; Ribeiro, Rita; Najmudin, Shabir; Gameiro, Andreia; Rodrigues, Rita; Cardoso, Fátima; Ferreira, Fernando

    2016-04-01

    HER2 is overexpressed in about 30% of feline mammary carcinomas (FMC) and in 15-30% of breast cancers. Women with HER2-positive breast tumors are associated with shorter survival. This study aimed to optimize the detection and quantification of serum HER2 (sHER2) in cats and to evaluate its potential in diagnosing cats with mammary carcinomas (MC) overexpressing HER2. A prospective study was conducted in 60 queens showing MC and 20 healthy animals. Pre-operative serum samples were collected for sHER2 quantification using two immunoassays: ELISA and Dot blot assay. sHER2 levels were compared with tissue HER2 status assessed by immunohistochemistry. Queens with FMC showed significantly higher mean levels of sHER2 by both ELISA and Dot blot assay. A significant difference in the sHER2 levels was also found between cats with HER2-positive MC and those with low-expressing HER2 MC. A significant correlation between sHER2 levels and tumor HER2 status was also found, particularly when ELISA was used (r = 0.58, p < 0.0001). The value of 10 ng/ml was proposed as the optimal cutoff for both immunoassays by ROC analysis. Like in humans, sHER2 levels are increased in cats with MC HER2-positive, strongly suggesting that evaluation of sHER2 levels can be very useful in feline oncology. The results show that ELISA and Dot blot assay can replace the immunohistochemistry technique, due to their efficacy and lower costs for diagnostic purposes and for monitoring the response to anti-HER2 therapies in cats. PMID:26909614

  2. Real-world adjuvant TAC or FEC-D for HER2-negative node-positive breast cancer in women less than 50 years of age

    PubMed Central

    Lupichuk, S.; Tilley, D.; Kostaras, X.; Joy, A.A.

    2016-01-01

    Purpose We compared the efficacy, toxicity, and use of granulocyte colony–stimulating factor (g-csf) with tac (docetaxel–doxorubicin–cyclophosphamide) and fec-d (5-fluorouracil–epirubicin–cyclophosphamide followed by docetaxel) in women less than 50 years of age. Methods The study included all women more than 18 years but less than 50 years of age with her2-negative, node-positive, stage ii or iii breast cancer diagnosed in Alberta between 2008 and 2012 who received tac (n = 198) or fec-d (n = 274). Results The patient groups were well-balanced, except that radiotherapy use was higher in the tac group (91.9% vs. 79.9%, p < 0.001). At a median follow-up of 49.6 months, disease-free survival was 91.4% for tac and 92.0% for fec-d (p = 0.76). Overall survival (os) was 96% with tac and 95.3% with fec-d (p = 0.86).The incidences of grades 3 and 4 toxicities were similar in the two groups (all p > 0.05). Overall, febrile neutropenia (fn) was reported in 11.6% of tac patients and 15.7% of fec-d patients (p = 0.26). However, use of g-csf was higher in the tac group than in the fec-d group (96.4% vs. 71.5%, p < 0.001). Hospitalization for fn was required in 10.5% of tac patients and 13.0% of fec-d patients (p = 0.41). In g-csf–supported and –unsupported patients receiving tac, fn occurred at rates of 11.1% and 33.3% respectively (p = 0.08); in patients receiving the fec portion of fec-d, those proportions were 2.9% and 8.1% respectively (p = 0.24); and in patients receiving docetaxel after fec, the proportions were 4.1% and 17.6% respectively (p < 0.001). Conclusions In women less than 50 years of age receiving adjuvant tac or fec-d, we observed no differences in efficacy or other nonhematologic toxicities. Based on the timing and rates of fn, use of prophylactic g-csf should be routine for the docetaxel-containing portion of treatment; however, prophylactic g-csf could potentially be avoided during the fec portion of fec-d treatment. PMID:27330344

  3. Akt Inhibitor MK2206, Lapatinib Ditosylate, and Trastuzumab in Treating Patients With Locally Advanced or Metastatic HER2-Positive Breast , Gastric, or Gastroesophageal Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2013-09-27

    Adenocarcinoma of the Gastroesophageal Junction; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Stage IIIC Breast Cancer; Stage IIIC Esophageal Cancer; Stage IIIC Gastric Cancer; Stage IV Breast Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer

  4. Lapatinib Plus Capecitabine in Women with HER-2Positive Advanced Breast Cancer: Final Survival Analysis of a Phase III Randomized Trial

    PubMed Central

    Casey, Michelle; Oliva, Cristina; Newstat, Beth; Imwalle, Bradley; Geyer, Charles E.

    2010-01-01

    Objectives. A planned interim analysis of study EGF100151 prompted early termination of enrollment based on a longer time to progression with lapatinib and capecitabine than with capecitabine alone in patients with human epidermal growth factor receptor (HER)-2+ previously treated advanced breast cancer or metastatic breast cancer (MBC). Here, we report final analyses of overall survival. Patients and Methods. Women with HER-2+ MBC who progressed after regimens that included, but were not limited to, anthracyclines, taxanes, and trastuzumab, were randomized to lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2) or capecitabine monotherapy (2,500 mg/m2) on days 1–14 of a 21-day cycle. Results. At enrollment termination, 399 patients were randomized, and nine were being screened and were offered combination treatment. In total, 207 and 201 patients were enrolled to combination therapy and monotherapy, respectively. Thirty-six patients receiving monotherapy crossed over to combination therapy following enrollment termination. The median overall survival times were 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.71–1.08; p = .210). A Cox regression analysis considering crossover as a time-dependent covariate suggested a 20% lower risk for death for patients treated with combination therapy (HR, 0.80; 95% CI, 0.64–0.99; p = .043). The low incidence of serious adverse events was consistent with previously reported rates. Conclusions. Although premature enrollment termination and subsequent crossover resulted in insufficient power to detect differences in overall survival, exploratory analyses demonstrate a trend toward a survival advantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2+ MBC. PMID:20736298

  5. Efficacy and safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive breast cancer with brain metastases.

    PubMed

    Jacot, William; Pons, Elvire; Frenel, Jean-Sébastien; Guiu, Séverine; Levy, Christelle; Heudel, Pierre Etienne; Bachelot, Thomas; D'Hondt, Véronique; Darlix, Amélie; Firmin, Nelly; Romieu, Gilles; Thezenas, Simon; Dalenc, Florence

    2016-06-01

    Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2 + BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82 % presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72 % whole-brain radiation therapy). After a median follow-up of 8.1 months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44 %) and 6 patients achieved disease stabilization (59 % clinical benefit rate). Median PFS was 6.1 months (95 %CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17 %, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2 + BC patients with BM. These findings require a prospective validation. PMID:27167986

  6. Novel bright field molecular morphology methods for detection of HER2 gene amplification.

    PubMed

    Tubbs, Raymond; Pettay, James; Hicks, David; Skacel, Marek; Powell, Richard; Grogan, Tom; Hainfeld, James

    2004-08-01

    Profiling the amplification and over-expression of the HER2 gene is a key component for defining the prognosis and management of invasive breast carcinoma. Clinical laboratory testing for HER2 gene amplification and over expression has been complicated by an unacceptably high rate of false positive immunohistochemistry (IHC) results, poor reproducibility for the '2+' category of IHC scoring, and reluctant acceptance of alternative testing by fluorescence in situ hybridization (FISH) by the diagnostic pathology community. Novel chromogenic in situ hybridization (CISH) assays have been developed that utilize bright field microscopy and a conventional light microscope for interpretation, but the analytical sensitivity of first generation CISH systems has been problematic. Novel second generation in situ hybridization detection methods based upon polymerized lg detection chemistry, autometallography or enzyme metallography, have been developed that routinely detect endogenous HER2 signals in normal cells (on slide hybridization control) and HER2 signals in both non-amplified and amplified patterns of HER2 genomic signatures. By combining the strength of polymerized peroxidase-labeled antibodies and metallography for gene amplification, with the detection of expression of HER2 encoded protein by IHC on the same slide, both HER2 gene amplification and protein over-expression can be simultaneously evaluated on a cell-by-cell basis in each microscopic field of carcinoma. PMID:15614612

  7. Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer.

    PubMed

    Fleeman, Nigel; Bagust, Adrian; Beale, Sophie; Dwan, Kerry; Dickson, Rumona; Proudlove, Chris; Dundar, Yenal

    2015-01-01

    The National Institute for Health and Care Excellence (NICE) invited the manufacturer of pertuzumab (Roche) to submit evidence for the clinical and cost effectiveness of pertuzumab + trastuzumab + docetaxel for the treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic or locally recurrent unresectable breast cancer in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee's (AC) initial decision. At the time of writing, final guidance had not been published by NICE. The clinical evidence was mainly derived from an ongoing phase III randomised double-blind placebo-controlled international multicentre clinical trial (CLEOPATRA), designed to evaluate efficacy and safety in 808 patients, which compared pertuzumab + trastuzumab + docetaxel (pertuzumab arm) with placebo + trastuzumab + docetaxel (control arm). Both progression-free survival (PFS) and overall survival (OS) were analysed at two data cut-off points-May 2011 (median follow-up of 18 months) and May 2012 (median follow-up of 30 months). At both time points, PFS was significantly longer in the pertuzumab arm (18.5 months compared with 12.4 months in the control arm at the first data cut-off point and 18.7 versus 12.4 months at the second data cut-off point). Assessment of OS benefit suggested an improvement for patients in the pertuzumab arm with a strong trend towards an OS benefit at the second data cut-off point; however, due to the immaturity of the OS data, the magnitude of the OS benefit was uncertain. Importantly, cardiotoxicity was not increased in patients treated with a combination of pertuzumab + trastuzumab + docetaxel. The ERG's main concern with the

  8. The assessment of HER2 status in breast cancer: the past, the present, and the future.

    PubMed

    Nitta, Hiroaki; Kelly, Brian D; Allred, Craig; Jewell, Suzan; Banks, Peter; Dennis, Eslie; Grogan, Thomas M

    2016-06-01

    Humanized monoclonal anti-human growth factor receptor 2 (HER2) antibody trastuzumab was approved for HER2 positive breast cancer patient treatment 11 years after the demonstration of HER2 gene amplification associated with the HER2 protein overexpression in breast cancer in 1987. HER2 positive status of breast cancer patients is assessed by HER2 gene amplification with in situ hybridization (ISH) and/or HER2 protein overexpression with immunohistochemistry (IHC). Because the discordance between quantitative HER2 ISH and subjective, semi-quantitative HER2 IHC assay results is a well-recognized issue of HER2 testing, we developed an assay combining HER2 ISH and HER2 IHC assays (HER2 gene-protein assay; HER2 GPA) as one test on the same tissue section. HER2 GPA allows pathologists to score the HER2 gene and HER2 protein status simultaneously at the individual cell level. The possibility that HER2 GPA may become the next generation of HER2 testing is discussed, particularly for cases in which it is difficult to assess the HER2 status of breast cancer patients due to the HER2 heterogeneity. PMID:27061008

  9. High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy

    PubMed Central

    Aura, Claudia; Garrido-Castro, Ana; Vilaro, Marta; Peg, Vicente; Jimenez, José; Vicario, Rocio; Cecchi, Fabiola; Hoos, William; Burrows, Jon; Hembrough, Todd; Ferreres, Juan Carles; Perez-Garcia, José; Arribas, Joaquin; Cortes, Javier; Scaltriti, Maurizio

    2016-01-01

    Introduction Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. Methods Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. Results Absolute HER2 amol/μg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/μg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/μg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. Conclusion Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy. PMID:26422389

  10. Rapamycin Inhibits Multiple Stages of c-Neu/ErbB2-induced Tumor Progression in a Transgenic Mouse Model of HER2 Positive Breast Cancer

    PubMed Central

    Mosley, Jonathan D.; Poirier, John T.; Seachrist, Darcie D.; Landis, Melissa D.; Keri, Ruth A.

    2008-01-01

    Amplification of the HER2 (ErbB2, c-Neu) proto-oncogene in breast cancer is associated with poor prognosis and high relapse rates. HER2/ErbB2, in conjunction with ErbB3, signals through the Akt/PI3-K pathway and leads to the activation of mTOR, a critical mRNA translation regulator that controls cell growth. Gene expression analysis of mammary tumors collected from MMTV-c-Neu transgenic mice revealed that mRNA levels of several mTOR pathway members were either up-regulated (p85/PI3-K and p70S6K) or down-regulated (eIF4E-BP1) in a manner expected to enhance signaling through this pathway. Treatment of MMTV-c-Neu transgenic mice with the mTOR inhibitor rapamycin caused growth arrest and regression of primary tumors with no evidence of weight loss or generalized toxicity. The treatment effects were due to decreased proliferation, associated with reduced cyclin D1 expression, and increased cell death in primary tumors. While many of the dead epithelial cells had the histopathologic characteristics of ischemic necrosis, rapamycin treatment was not associated with changes in microvascular density or apoptosis. Rapamycin also inhibited cellular proliferation in lung metastases. In summary, data from this preclinical model of ErbB2/Neu-induced breast cancer demonstrate that inhibition of the mTOR pathway with rapamycin blocks multiple stages of ErbB2/Neu-induced tumorigenic progression. PMID:17699716

  11. HER2 immunohistochemistry significantly overestimates HER2 amplification in uterine papillary serous carcinomas.

    PubMed

    Mentrikoski, Mark J; Stoler, Mark H

    2014-06-01

    Recently, there have been numerous reports showing that HER2 overexpression or amplification occurs in a variable number of uterine papillary serous carcinoma (UPSC) cases, leading to a current clinical trial targeting this pathway. Although approved algorithms exist for scoring HER2 overexpression/amplification in breast and gastroesophageal carcinomas, scoring criteria and the optimal methodology for assessing HER2 in UPSC are currently unknown. Most frequently, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) breast carcinoma algorithms have been utilized for UPSC, wherein cases are screened with immunohistochemistry (IHC), followed by fluorescence in situ hybridization for equivocal cases. However, interpreting HER2 IHC can be prone to significant subjectivity, often leading to false-positive results. To better correlate HER2 IHC results with underlying amplification in UPSC, we compared HER2 overexpression by IHC with HER2 amplification with chromogenic in situ hybridization (CISH). A total of 69 cases of UPSC-57 pure and 12 mixed-were identified over a 10-year period. All were included in a tissue microarray, and HER2 IHC and CISH were performed. Each case was scored according to the most recent 2013, as well as the 2007, ASCO/CAP scoring guidelines for breast carcinoma. Whole-tissue sections were also examined in cases with amplification by CISH on initial screening, as well as an equal number of negative cases, to account for intratumoral heterogeneity. Nine (13%) cases showed HER2 amplification by CISH, whereas 14 (20%) and 28 (40%) cases showed overexpression with IHC when the 2007 or 2013 ASCO/CAP criteria were utilized, respectively. The overall concordance rate between CISH and IHC was 64% (9/14) with the 2007 ASCO/CAP criteria and 32% (9/28) with the 2013 ASCO/CAP criteria. Intratumoral heterogeneity was seen in 3 (33%) amplified cases. No additional amplified cases were identified on subsequent whole

  12. Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers

    PubMed Central

    Parise, Carol A.

    2014-01-01

    Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade. Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage. Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes. Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification. PMID:24955090

  13. Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43

    PubMed Central

    Siziopikou, Kalliopi P.; Anderson, Stewart J.; Cobleigh, Melody A.; Arthur, Douglas W.; Zheng, Ping; Mamounas, Eleftherios P.; Pajon, Eduardo R.; Behrens, Robert J.; Eakle, Janice F.; Leasure, Nick C.; Atkins, James N.; Polikoff, Jonathan A.; Seay, Thomas E.; McCaskill-Stevens, Worta J.; Rabinovitch, Rachel; Costantino, Joseph P.; Wolmark, Norman

    2016-01-01

    NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient’s pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust. PMID:24202240

  14. Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.

    PubMed

    Siziopikou, Kalliopi P; Anderson, Stewart J; Cobleigh, Melody A; Julian, Thomas B; Arthur, Douglas W; Zheng, Ping; Mamounas, Eleftherios P; Pajon, Eduardo R; Behrens, Robert J; Eakle, Janice F; Leasure, Nick C; Atkins, James N; Polikoff, Jonathan A; Seay, Thomas E; McCaskill-Stevens, Worta J; Rabinovitch, Rachel; Costantino, Joseph P; Wolmark, Norman

    2013-11-01

    NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust. PMID:24202240

  15. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial

    PubMed Central

    Buzdar, Aman U; Suman, Vera J; Meric-Bernstam, Funda; Leitch, A Marilyn; Ellis, Matthew J; Boughey, Judy C; Unzeitig, Gary; Royce, Melanie; McCall, Linda M; Ewer, Michael S; Hunt, Kelly K

    2014-01-01

    Summary Background Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30–65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy. Methods This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292. Findings From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56.5%, 95% CI 47.8–64.9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54.2%, 95% CI 45.7–62.6) who received concurrent

  16. 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.

  17. 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. PMID:24009064

  18. 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

  19. Quantitative measurements of HER2 and phospho-HER2 expression: correlation with pathologic response to neoadjuvant chemotherapy and trastuzumab

    PubMed Central

    2014-01-01

    Background Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy. Methods We evaluated core biopsy samples from 27 HER2+ breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy (BrUOG BR-211B (NCT00617942)). Tumor core biopsies were taken before initiation of treatment and 9–13 days after patients received "run-in" doses of either single agent trastuzumab or nab-paclitaxel. The AQUA method of quantitative immunofluorescence was used for analysis of in situ protein expression. Patients then received 18 weeks of treatment, followed by surgery to assess pathologic response to the neoadjuvant regimen. Results A HER2 score of 2111 by AQUA analysis has been shown to be equivalent to HER2 3+ by immunohistochemical staining in previous studies. Of 20 evaluable patients, 10 cases who achieved a pathologic complete response (pathCR) with neoadjuvant treatment had a mean HER2 level of 10251 compared with 4766 in the patients without pathCR (p = 0.0021). Measurement of phospho-HER2 showed no difference in pathCR vs non-pathCR groups. In 9 patients who had HER2 levels repeated after a single treatment with trastuzumab there was no evidence of a reduction in the HER2 or phospho-HER2 levels following that exposure. Conclusions High levels of HER2 are associated with achievement of a pathCR in the preoperative setting, while levels of Phospho-HER2 were not predictive of

  20. 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. PMID:27112931

  1. Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III, HER2-positive breast cancer patients: a phase 2, open-label, multicenter, randomized trial.

    PubMed

    Huang, Liang; Chen, Sheng; Yang, Wentao; Xu, Binghe; Huang, Tao; Yang, Hongjian; Zheng, Hong; Wang, Yongsheng; Song, Erwei; Zhang, Jin; Cui, Shude; Pang, Da; Tang, Lili; Lei, Yutao; Geng, Cuizhi; Shao, Zhiming

    2015-07-30

    This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH. PMID:26084292

  2. Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor–Positive, HER2-Negative Early Breast Cancer1

    PubMed Central

    Azim, Hamdy A.; Kassem, Loay; Treilleux, Isabelle; Wang, Qing; El Enein, Mona Abu; Anis, Shady E.; Bachelot, Thomas

    2016-01-01

    BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative (luminal) early breast cancer treated at Cairo university hospitals. METHODS: Next-generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 9 and 20). Immunohistochemistry was performed on tissue microarray blocks prepared from samples of 35 Egyptian luminal breast cancer patients in the pathology department of Centre Léon Bérard (CLB). The intensity and the percentage of stained tumor cells were integrated to define high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Patients were followed for a median of 4.7 years (2.1 to 6.9 years). Correlation was done between PI3K mutations and the immunohistochemistry expression of pAKT, LKB1, p4EBP1, and pS6 ribosomal protein (pS6RP) with the clinicopathologic features and disease free survival (DFS) of the patients. RESULTS: Median age at diagnosis was 51.3 years (range, 25 to 82 years). Tumors were larger than 20 mm in 79.2% of the cases, whereas 57.9% had axillary lymph node deposits. Only 12.3% of the patients had SBR grade I tumors, 50.8% had grade II, and 36.8% had grade III. ERs were negative in 6 patients (17%) after pathology review. Thirty-two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP, and 24 for PI3K mutations. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, nuclear p4EBP1, and cytoplasmic pS6RP expression was high in 65.6%, 62.5%, 62.5%, 68.8%, 42.4%, and 57.6%, respectively

  3. Moderate level of HER2 expression and its prognostic significance in breast cancer with intermediate grade.

    PubMed

    Ignatov, Tanja; Eggemann, Holm; Burger, Elke; Fettke, Franziska; Costa, Serban Dan; Ignatov, Atanas

    2015-06-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive marker of response to anti-HER2 therapy in breast cancer. Our goal was to analyze the prognostic significance of moderate expression of HER2 in breast cancer with intermediate differentiation grade. We performed a multicenter retrospective register study of 8494 patients with primary non-metastatic breast cancer admitted between 2000 and 2011 to eight Clinics in Saxony-Anhalt, federal state of Germany. Patients were divided into three groups according to their HER2 score: 4073 were classified as HER2 negative (HER2 0 and 1+), 822 HER2 moderate (HER2 2+/HER2), and 1238 HER2 positive (HER2 3+ or HER2 2+/HER2+). HER2-positive cases were excluded from analysis. Tumors with moderate HER2 (HER2 2+) expression demonstrated an aggressive behavior and worse patient survival compared with HER2 0 and 1+ status. HER2 2+ status was associated with shorter median overall survival (OS) (P < 0.0001) in breast cancer patients with an intermediate grade of differentiation. Comparing low-grade and high-grade tumors, HER2 moderate expression did not significantly influence patient survival. In multivariate analysis after adjustment for other prognostic factors HER2 2+ status remained an unfavorable prognostic factor for OS (HR 1.224, 95 % CI 1.059-1.415, P = 0.006) in breast cancer patients with an intermediate grade of differentiation. HER2 2+ status is an unfavorable prognostic factor regarding the OS of breast cancer patients with intermediate grade of differentiation and could be used to identify patients, who may benefit from adjuvant therapy. PMID:25926338

  4. Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.

    PubMed

    Cresti, Nicola; Lee, Joanne; Rourke, Emma; Televantou, Despina; Jamieson, David; Verrill, Mark; Boddy, Alan V

    2016-03-01

    Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease. PMID:26773371

  5. Treatment of older patients with HER2-positive metastatic breast cancer with pertuzumab, trastuzumab, and docetaxel: subgroup analyses from a randomized, double-blind, placebo-controlled phase III trial (CLEOPATRA).

    PubMed

    Miles, David; Baselga, José; Amadori, Dino; Sunpaweravong, Patrapim; Semiglazov, Vladimir; Knott, Adam; Clark, Emma; Ross, Graham; Swain, Sandra M

    2013-11-01

    Although the incidence of cancer increases with age, older patients are under-represented in cancer treatment trials, resulting in limited data availability in this patient population. Here we present results from pre-defined subgroup analyses conducted by age group (<65 vs ≥ 65 years) from a randomized, double-blind, placebo-controlled phase III trial in patients with HER2-positive metastatic breast cancer. Patients who had not received previous chemotherapy or biological therapy for HER2-positive locally recurrent, unresectable or metastatic breast cancer were randomly assigned to treatment with placebo, trastuzumab, and docetaxel or with pertuzumab, trastuzumab, and docetaxel. Primary endpoint was independently assessed progression-free survival. We performed pre-specified subgroup analyses of progression-free survival according to age. The study is registered with ClinicalTrials.gov, NCT00567190. 808 patients were enrolled. Of those, 127 patients were 65 years of age or older (placebo arm: 67, pertuzumab arm: 60). Patients in both age groups experienced progression-free survival benefit with treatment in the pertuzumab arm (<65 years: HR: 0.65; 95 % CI 0.53-0.80; ≥65 years: HR: 0.52; 95 % CI 0.31-0.86). Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the older age group. The efficacy and safety data reported in CLEOPATRA suggest that the combined use of pertuzumab, trastuzumab, and docetaxel should not be limited by patient age. PMID:24129974

  6. Cardiac Tolerability of Pertuzumab Plus Trastuzumab Plus Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer in CLEOPATRA: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

    PubMed Central

    Ewer, Michael S.; Cortés, Javier; Amadori, Dino; Miles, David; Knott, Adam; Clark, Emma; Benyunes, Mark C.; Ross, Graham; Baselga, José

    2013-01-01

    Introduction. We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). Patients and Methods. Left ventricular ejection fraction (LVEF) ≥50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m2 q3w. Results. The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff. Conclusion. The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible. PMID:23475636

  7. Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

    PubMed Central

    N.Tinianow, Jeff; Pandya, Darpan N.; Pailloux, Sylvie L.; Ogasawara, Annie; Vanderbilt, Alexander N.; Gill, Herman S.; Williams, Simon-P.; Wadas, Thaddeus J.; Magda, Darren; Marik, Jan

    2016-01-01

    A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89Zr; subsequently, it was used as a bi-functional chelator for preparation of 89Zr-labeled antibodies. Quantitative chelation of 89Zr4+ with the octadentate ligand forming 89ZrL complex was achieved under mild conditions within 15 minutes. The 89Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89Zr4+ from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89Zr-labeled monoclonal antibodies for immunoPET studies. PMID:26941844

  8. Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial.

    PubMed

    Müller, Volkmar; Gade, Stephan; Steinbach, Bettina; Loibl, Sibylle; von Minckwitz, Gunter; Untch, Michael; Schwedler, Kathrin; Lübbe, Kristina; Schem, Christian; Fasching, Peter A; Mau, Christine; Pantel, Klaus; Schwarzenbach, Heidi

    2014-08-01

    Trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate, whether altered expression levels of potentially relevant microRNAs (miRs) in serum are associated with response to trastuzumab or lapatinib. Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21. PMID:25086636

  9. 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

  10. HER story: the next chapter in HER-2-directed therapy for advanced breast cancer.

    PubMed

    Verma, Sunil; 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

  11. 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. PMID:23443928

  12. EGFR/HER2 inhibitors effectively reduce the malignant potential of MDR breast cancer evoked by P-gp substrates in vitro and in vivo.

    PubMed

    Jin, Yiting; Zhang, Wei; Wang, Hongying; Zhang, Zijing; Chu, Chengyu; Liu, Xiuping; Zou, Qiang

    2016-02-01

    Multidrug resistance (MDR) induced by chemotherapy in breast cancer frequently leads to tumor invasion, metastasis and poor clinical outcome. We preliminarily found that the epidermal growth factor receptor (EGFR) is involved in enhancing the malignant potential of MDR breast cancer cells, but the mechanism remains unclear. In the present study, we demonstrated in vitro and in vivo that EGFR/HER2 promote the invasive and metastatic abilities of MDR breast cancer. More importantly, a new function of EGFR/HER2 inhibitors was revealed for the first time, which could improve the treatment efficacy of breast cancer by reversing the MDR process rather than by inhibiting tumor growth. Firstly, using quantitative real‑time PCR and western blot analysis, we found that overexpression of EGFR/HER2 in MCF7/Adr cells upregulated CD147 and MMP2/9 at both the transcription and protein expression levels, which promoted tumor cell migration, as determined using an in vitro invasion assay. Secondly, the upregulated levels of CD147 and MMP2/9 were decreased when EGFR/HER2 activity was inhibited, and therefore tumor invasion was also significantly inhibited. These phenomena were also demonstrated in nude mouse assays. Additionally, in MDR breast cancer patients, we found that overexpression of EGFR and P‑gp levels led to shorter overall survival (OS) and disease‑free survival (DFS) by IHC assays and Kaplan‑Meier survival analysis. In conclusion, EGFR/HER2 play a crucial role in enhancing CD147 and MMP expression to establish favorable conditions for invasion/metastasis in MDR breast cancer. The scope of application of EGFR/HER2 inhibitors may be expanded in EGFR/HER2positive patients. We suggest that MDR breast cancer patients may benefit from novel therapies targeting EGFR/HER2. PMID:26718028

  13. Identification of Targetable HER2 Aberrations in Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Birkeland, Andrew C.; Yanik, Megan; Tillman, Brittny N.; Scott, Megan V.; Foltin, Susan K.; Mann, Jacqueline E.; Michmerhuizen, Nicole L.; Ludwig, Megan L.; Sandelski, Morgan M.; Komarck, Christine M.; Carey, Thomas E.; Prince, Mark E.P.; Bradford, Carol R.; McHugh, Jonathan B.; Spector, Matthew E.; Brenner, J. Chad

    2016-01-01

    Importance HER2 is an important drug target in breast cancer, where anti-HER2 therapy has been shown to lead to improvements in disease recurrence and overall survival. HER2 status in head and neck squamous cell carcinoma (HNSCC) has not been well studied. Identification of HER2 positive tumors and characterization of response to HER2 therapy could lead to targeted treatment options in HNSCC. Objective To identify HER2 aberrations in HNSCCs and investigate potential for HER2 targeted therapy in HNSCCs. Design, Setting, and Participants Retrospective case series of patients with laryngeal and oral cavity SCC enrolled in the University of MichiganSPORE. Publically available sequencing data(TCGA) was reviewed to identify additional mutations and overexpression in HER2 in HNSCC. Established HNSCC cell lines were used for follow-up in vitro analysis. Interventions Using targeted, amplicon-based sequencing with the Oncomine Cancer Panel, we assessed the copy number and mutation status of commonly altered genes in HNSCCs. Immunohistochemical staining was performed on tissue microarrays of HNSCCs to assess expression of HER2. Western blotting for HNSCC cell line HER2 expression, and cell survival assays after treatment with HER2 inhibitors were performed. Main Outcomes and Measures Prevalence of HER2 genetic aberrations and HER2 overexpression in laryngeal and oral cavity squamous cell carcinomas (SCCs). Prevalence of HER2 aberrations in HNSCC in TCGA. HER2 protein expression in HNSCC cell lines. Response of HNSCC cell lines to targeted HER2 inhibitors. Results Forty-two laryngeal SCC samples were screened by targeted sequencing, of which 4 were positive for HER2 amplification. Two samples identified with sequencing showed HER2 overexpression on immunohistochemistry. Two of 94 oral cavity SCC samples were positive for HER2 on immunohistochemistry. Analysis of 288 patients from publicly available HNSCC sequencing data revealed 9 amplifications in HER2. Protein expression

  14. High cell-surface density of HER2 deforms cell membranes.

    PubMed

    Chung, Inhee; Reichelt, Mike; Shao, Lily; Akita, Robert W; Koeppen, Hartmut; Rangell, Linda; Schaefer, Gabriele; Mellman, Ira; Sliwkowski, Mark X

    2016-01-01

    Breast cancers (BC) with HER2 overexpression (referred to as HER2 positive) progress more aggressively than those with normal expression. Targeted therapies against HER2 can successfully delay the progression of HER2-positive BC, but details of how this overexpression drives the disease are not fully understood. Using single-molecule biophysical approaches, we discovered a new effect of HER2 overexpression on disease-relevant cell biological changes in these BC. We found HER2 overexpression causes deformation of the cell membranes, and this in turn disrupts epithelial features by perturbing cell-substrate and cell-cell contacts. This membrane deformation does not require receptor signalling activities, but results from the high levels of HER2 on the cell surface. Our finding suggests that early-stage morphological alterations of HER2-positive BC cells during cancer progression can occur in a physical and signalling-independent manner. PMID:27599456

  15. p53 status as effect modifier of the association between pre-treatment fasting glucose and breast cancer outcomes in non diabetic, HER2 positive patients treated with trastuzumab

    PubMed Central

    Maugeri-Saccà, Marcello; Melucci, Elisa; Benedetto, Anna Di; Lauro, Luigi Di; Pizzuti, Laura; Sergi, Domenico; Terrenato, Irene; Esposito, Luca; Iannuzzi, Carmelina Antonella; Pasquale, Raffaella; Botti, Claudio; Fuhrman, Barbara; Giordano, Antonio

    2014-01-01

    Mounting evidence supports the role of p53 in metabolic processes involved in breast carcinogenesis. We investigated whether p53 status affects the association of pre-treatment fasting glucose with treatment outcomes in 106 non diabetic, HER2 positive breast cancer patients treated with trastuzumab. p53 status was validated against gene sequencing of selected codons in 49 patients. The Kaplan–Meier method and log rank test were used to compare survival by categories of fasting glucose in the overall population and separate settings. Cox models included age and body mass index. Direct sequencing confirmed the lack of mutations in 73.7% of p53 negative patients and their presence in 53.3% of p53 positive cases. At 66 months, 88.3% of patients with glucose ≤ 89.0 mg/dl (median value) did not experiment disease progression compared with 70.0% in the highest category (p=0.034), with glucose being an independent predictor (p=0.046). Stratified analysis confirmed this association in p53 negative patients only (p=0.01). In the early setting, data suggested longer disease free survival in p53 negative patients in the lowest glucose category (p=0.053). In our study, p53 status acted as effect modifier of the investigated association. This may help differentiate target sub-groups and affect outcomes interpretation in similarly characterized patients. PMID:25071015

  16. 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

  17. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.

    PubMed

    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

    2011-03-01

    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 nontransformed 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. 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, the 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 patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab. PMID:21324925

  18. Therapeutic strategies and mechanisms of tumorigenesis of HER2-overexpressing breast cancer.

    PubMed

    Emde, Anna; Köstler, Wolfgang J; Yarden, Yosef

    2012-12-01

    The receptor tyrosine kinase HER2 is overexpressed in approximately 25% of breast cancers. HER2 acts as a signal amplifier for its siblings, namely three different transmembrane receptors that collectively bind with 11 distinct growth factors of the EGF family. Thus, overexpression of HER2 confers aggressive invasive growth in preclinical models and in patients. Specific therapies targeting HER2 include monoclonal antibodies, antibody-drug conjugates, small molecule tyrosine kinase inhibitors, as well as heat shock protein and sheddase inhibitors. Two of these drugs have shown impressive - yet mostly transient - efficacy in patients with HER2 overexpressing breast cancer. We highlight the biological roles of HER2 in breast cancer progression, and overview the available therapeutic armamentarium directed against this receptor-kinase molecule. Focusing on the mechanisms that confer resistance to individual HER2 targeting agents, we envisage therapeutic approaches to delay or overcome the evolvement of resistance in patients. PMID:20951604

  19. Even With Very Small Breast Tumors, Studies Find HER2 Status Matters | Division of Cancer Prevention

    Cancer.gov

    Two retrospective studies have found that women with HER2-positive breast tumors (that is, tumors that produce too much of the HER2 protein) that are 1 centimeter or smaller had a higher risk of their disease returning within 5 years than women with similarly small HER2-negative tumors. |

  20. The role of HER2 in cancer therapy and targeted drug delivery

    PubMed Central

    Tai, Wanyi; Mahato, Rubi; Cheng, Kun

    2010-01-01

    HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, various artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details. PMID:20385184

  1. 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. PMID:17646988

  2. HER2 status and disparities in luminal breast cancers.

    PubMed

    Holowatyj, Andreana N; Ruterbusch, Julie J; Ratnam, Manohar; Gorski, David H; Cote, Michele L

    2016-08-01

    National Comprehensive Care Network guidelines for adjuvant treatment of invasive breast cancer are based on HER2 and hormone receptor (HR) status, where HR+ disease encompasses all estrogen receptor (ER)+ and/or progesterone receptor (PR)+ tumors. We sought to explore clinical and demographic differences among patients with HR+ breast cancer subtypes, and the role of HER2 status, age, race/ethnicity, and socioeconomic status (SES) in disease risk. We evaluated breast cancer subtype distribution, defined by HR and HER2 status, using patient clinical, demographic, and socioeconomic characteristics. Differences in HR categories by demographic and tumor characteristics were examined using chi-squared tests. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) to quantify associations between breast cancer HR status and demographic factors. We found that differences in HR+ (ER-/PR+ vs. ER+/PR- or ER+/PR+) tumor biology are likely clinically significant and may play a role in breast cancer, regardless of HER2 status. While clinical and patient characteristics differed within each luminal subtype, we found disparities in SES only among Luminal A (HR+/HER2-) tumors. Among HR+/HER2- cases, we observed that ER-/PR+ patients tend to live in areas of higher poverty (OR = 1.20, 95% CI = 1.03-1.40) and are 70% more likely to be aged 50 years or older. However, this pattern was not found in women with Luminal B (HR+/HER2+) disease (Poverty OR = 0.98, 95% CI = 0.76-1.27; Age OR = 1.01, 95% CI = 0.81-1.26). Racial/ethnic disparities among non-Hispanic black and Hispanic women persisted across HR+/HER2- cases compared to non-Hispanic white women. Our findings suggest that while race/ethnicity and SES are correlated, each plays an independent role in contributing to disease among Luminal A tumors. Further study is needed to investigate how tumor biology, race/ethnicity, and socioeconomic disparities among HR+/HER2

  3. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications

    PubMed Central

    Iqbal, Nida; Iqbal, Naveed

    2014-01-01

    Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2. PMID:25276427

  4. Marked heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma.

    PubMed

    Buza, Natalia; Hui, Pei

    2013-12-01

    Significant heterogeneity of HER2 protein expression has been recently observed in HER2 positive endometrial serous carcinomas. Tumor cells with HER2 overexpression and/or gene amplification in a heterogeneous tumor may represent a biologically more aggressive subclone that is clinically relevant to prognosis and potential targeted therapy. To correlate with HER2 protein heterogeneity, we investigated the heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma. A total of 17 endometrial serous carcinomas with heterogeneous HER2 protein expression were selected for the study, including nine cases with a 3+ and eight cases with a 2+ immunohistochemical score. Initial reflex HER2 FISH was available for seven of the eight 2+ cases, five of which showed HER2/NEU gene amplification. All 17 cases underwent repeat FISH targeting larger tumor tissue areas. Ten cases (72%) displayed striking heterogeneity of HER2/NEU gene copy number in the form of cluster amplification. Diffuse HER2 amplification was observed in four cases, no amplification was seen in three tumors. In cases with cluster amplification, HER2 protein overexpression by immunohistochemistry closely correlated at the cellular level with HER2/NEU gene amplification. In conclusion, the significant percentage of cases with heterogeneous HER2/NEU gene amplification indicates that the existing HER2 testing guidelines designed for breast cancer may not be applicable to endometrial serous carcinoma. Clinical testing on multiple different tumor samples or large tumor tissue sections is recommended for both immunohistochemistry and FISH assessment of HER2 status. Direct comparison with the HER2 immunostaining pattern may be helpful in detecting HER2 amplified areas in a heterogeneous tumor. PMID:24123408

  5. Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer

    PubMed Central

    2010-01-01

    Background We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC. Methods HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses. Results Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group. Conclusions These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC. PMID:20178580

  6. Efficacy and Safety of HER2-Targeted Agents for Breast Cancer with HER2-Overexpression: A Network Meta-Analysis

    PubMed Central

    Yu, Qiuyan; Zhu, Zhenli; Liu, Yan; Zhang, Jun; Li, Ke

    2015-01-01

    Background Clinical trials of human epidermal growth factor receptor 2 (HER2)-targeted agents added to standard treatment have been efficacious for HER2-positive (HER2+) advanced breast cancer. To our knowledge, no meta-analysis has evaluated HER2-targeted therapy including trastuzumab emtansine (T-DM1) and pertuzumab for HER2-positive breast caner and ranked the targeted treatments. We performed a network meta-analysis of both direct and indirect comparisons to evaluate the effect of adding HER2-targeted agents to standard treatment and examined side effects. Methods We performed a Bayesian-framework network meta-analysis of randomized controlled trials to compare 6 HER2-targeted treatment regimens and 1 naïve standard treatment (NST, without any-targeted drugs) in targeted treatment of HER2+ breast cancer in adults. These treatment regimens were T-DM1, LC (lapatinib), HC (trastuzumab), PEC (pertuzumab), LHC (lapatinib and trastuzumab), and PEHC (pertuzumab and trastuzumab). The main outcomes were overall survival and response rates. We also examined side effects of rash, LVEF (left ventricular ejection fraction), fatigue, and gastrointestinal disorders, and performed subgroup analysis for the different treatment regimens in metastatic or advanced breast cancer. Results We identified 25 articles of 21 trials, with data for 11,276 participants. T-DM1 and PEHC were more efficient drug regimens with regard to overall survival as compared with LHC, LC, HC and PEC. The incidence of treatment-related rash occurs more frequently in the patients who received LC treatment regimen than PEHC and T-DM1 and HC. In subgroup analysis, T-DM1 was associated with increased overall survival as compared with LC and HC. PEHC was associated with increased overall response as compared with LC, HC, and NST. Conclusions Overall, the regimen of T-DM1 as well as pertuzumab in combination with trastuzumab and docetaxel is efficacious with fewer side effects as compared with other regimens

  7. HER2 Dimerization Inhibitor Pertuzumab – Mode of Action and Clinical Data in Breast Cancer

    PubMed Central

    Harbeck, Nadia; Beckmann, Matthias W.; Rody, Achim; Schneeweiss, Andreas; Müller, Volkmar; Fehm, Tanja; Marschner, Norbert; Gluz, Oleg; Schrader, Iris; Heinrich, Georg; Untch, Michael; Jackisch, Christian

    2013-01-01

    Summary The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment. PMID:24715843

  8. HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer.

    PubMed

    Harbeck, Nadia; Beckmann, Matthias W; Rody, Achim; Schneeweiss, Andreas; Müller, Volkmar; Fehm, Tanja; Marschner, Norbert; Gluz, Oleg; Schrader, Iris; Heinrich, Georg; Untch, Michael; Jackisch, Christian

    2013-03-01

    The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in particular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastuzumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combination of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2-positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment. PMID:24715843

  9. Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study.

    PubMed

    Martin, Miguel; Brase, Jan C; Ruiz, Amparo; Prat, Aleix; Kronenwett, Ralf; Calvo, Lourdes; Petry, Christoph; Bernard, Philip S; Ruiz-Borrego, Manuel; Weber, Karsten E; Rodriguez, César A; Alvarez, Isabel M; Segui, Miguel A; Perou, Charles M; Casas, Maribel; Carrasco, Eva; Caballero, Rosalía; Rodriguez-Lescure, Alvaro

    2016-02-01

    There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2-) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2- patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan-Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2- BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability. PMID:26909792

  10. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer

    PubMed Central

    Mohd Sharial, M. S. N.; Crown, J.; Hennessy, B. T.

    2012-01-01

    Background Approximately 15%–23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed. Design A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease. Results Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer. Conclusions Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer. PMID:22865781

  11. Detection of truncated HER2 forms in formalin-fixed, paraffin-embedded breast cancer tissue captures heterogeneity and is not affected by HER2-targeted therapy.

    PubMed

    Krüger, Juliane M; Thomas, Marlene; Korn, René; Dietmann, Gabriele; Rutz, Christoph; Brockhoff, Gero; Specht, Katja; Hasmann, Max; Feuerhake, Friedrich

    2013-08-01

    Truncated forms of HER2, previously identified in subsets of HER2-positive breast cancer, originate from proteolytic extracellular domain (ECD) cleavage or alternative translation initiation. They lack ECD but may retain intracellular domain functionality, potentially associated with unfavorable prognosis, metastasis, and decreased sensitivity to antibody-based HER2-targeted therapy. To study the distribution of truncated HER2 in breast cancer, we detected loss of membrane-bound ECD independently of its molecular origin in paraffin sections, combining multispectral unmixing of chromogenic duplex IHC for HER2 ECD and intracellular domain with advanced image analysis. HER2 C-terminal fragment 611-transfected MCF7 and 4-aminophenylmercuric acetate-treated SKBR3 cell lines were used as controls. Applying a prototype work flow to whole sections, paired surgical resection/core needle biopsy samples, and paired samples from 69 patients of a phase 2 neoadjuvant clinical trial, we observed unexpected heterogeneity of ECD loss at the single-cell level, and in different areas of individual tumors, indicating that extent and localization of HER2 ECD loss add relevant information to averaging truncated HER2 across whole sections. We show acceptable run-to-run variation (coefficient of variation, <0.15), image analysis results in moderate agreement with conventional slide assessment (Cohen's κ = 0.59), and no obvious interference with previous HER2-ECD-targeted therapy. We conclude that duplex IHC and digital image processing extend current approaches of truncated HER2 detection. PMID:23727348

  12. Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with Cu-labeled trastuzumab PET.

    PubMed

    Paudyal, Pramila; Paudyal, Bishnuhari; Hanaoka, Hirofumi; Oriuchi, Noboru; Iida, Yashuhiko; Yoshioka, Hiroki; Tominaga, Hideyuki; Watanabe, Satoshi; Watanabe, Shigeki; Ishioka, Noriko S; Endo, Keigo

    2010-04-01

    Non-small cell lung carcinomas (NSCLC) overexpress the Her2/neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/neu overexpressing breast cancer. However, its therapeutic use in Her2/neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of (64)Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/neu expression was performed in NCI-H2170 tumor-bearing mice with (64)Cu-DOTA-trastuzumab PET and (64)Cu-DOTA-IgG. In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/neu positive NCI-H2170 cells, while no binding was seen in the Her2/neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of (64)Cu-DOTA-trastuzumab in the Her2/neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4 +/- 1.4% and 23.2 +/- 5.1% injection dose/gram (% ID/g), respectively). PET imaging of Her2/neu negative NCI-H520 tumors showed much less uptake of (64)Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of (64)Cu-DOTA-trastuzumab was significantly higher than that of (64)Cu-DOTA-IgG (P < 0.0001). (64)Cu-DOTA-trastuzumab showed a very clear image of a Her2/neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. PMID:20219072

  13. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial

    PubMed Central

    Harbeck, N.; Iyer, S.; Turner, N.; Cristofanilli, M.; Ro, J.; André, F.; Loi, S.; Verma, S.; Iwata, H.; Bhattacharyya, H.; Puyana Theall, K.; Bartlett, C. H.; Loibl, S.

    2016-01-01

    Background In the PALOMA-3 study, palbociclib plus fulvestrant demonstrated improved progression-free survival compared with fulvestrant plus placebo in hormone receptor-positive, HER2− endocrine-resistant metastatic breast cancer (MBC). This analysis compared patient-reported outcomes (PROs) between the two treatment groups. Patients and methods Patients were randomized 2 : 1 to receive palbociclib 125 mg/day orally for 3 weeks followed by 1 week off (n = 347) plus fulvestrant (500 mg i.m. per standard of care) or placebo plus fulvestrant (n = 174). PROs were assessed on day 1 of cycles 1–4 and of every other subsequent cycle starting with cycle 6 using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. High scores (range 0–100) could indicate better functioning/quality of life (QoL) or worse symptom severity. Repeated-measures mixed-effect analyses were carried out to compare on-treatment overall scores and changes from baseline between treatment groups while controlling for baseline. Between-group comparisons of time to deterioration in global QoL and pain were made using an unstratified log-rank test and Cox proportional hazards model. Results Questionnaire completion rates were high at baseline and during treatment (from baseline to cycle 14, ≥95.8% in each group completed ≥1 question on the EORTC QLQ-C30). On treatment, estimated overall global QoL scores significantly favored the palbociclib plus fulvestrant group [66.1, 95% confidence interval (CI) 64.5–67.7 versus 63.0, 95% CI 60.6–65.3; P = 0.0313]. Significantly greater improvement from baseline in pain was also observed in this group (−3.3, 95% CI −5.1 to −1.5 versus 2.0, 95% CI −0.6 to 4.6; P = 0.0011). No significant differences were observed for other QLQ-BR23 functioning domains, breast or arm symptoms. Treatment with palbociclib plus fulvestrant significantly delayed deterioration in global QoL (P < 0.025) and pain (P < 0.001) compared with fulvestrant alone. Conclusion

  14. Trastuzumab Emtansine for Treating HER2-Positive, Unresectable, Locally Advanced or Metastatic Breast Cancer After Treatment with Trastuzumab and a Taxane: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    PubMed

    Squires, Hazel; Stevenson, Matt; Simpson, Emma; Harvey, Rebecca; Stevens, John

    2016-07-01

    The National Institute for Health and Care Excellence (NICE) invited the manufacturer of trastuzumab emtansine (T-DM1) (Kadcyla(®); Roche) to submit evidence of its clinical and cost-effectiveness for treating human epidermal growth factor receptor 2 (HER2)-positive, unresectable, locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield were the independent Evidence Review Group (ERG) who produced a critical review of the company's submission to NICE. The ERG also independently searched for relevant evidence and modified the submitted decision analytic model to produce a revised estimate of cost-effectiveness and examine the impact of altering some of the key assumptions. The clinical effectiveness data were taken from two randomised controlled trials that reported a significant advantage in progression-free survival (PFS) for T-DM1 over lapatinib in combination with capecitabine (EMILIA trial), and over the treatment of physician's choice (TH3RESA trial). A network meta-analysis suggested T-DM1 was the best treatment in terms of both overall survival and PFS compared with lapatinib in combination with capecitabine; trastuzumab in combination with capecitabine; and capecitabine monotherapy. Adverse event (AE) data were taken from a pooled analysis of additional trials of T-DM1 as a single agent. The most common grade 3 or greater AEs for T-DM1 were thrombocytopenia and hepatotoxicity. Following the clarification process, the manufacturer reported a deterministic incremental cost-effectiveness ratio (ICER) for T-DM1 compared with lapatinib in combination with capecitabine of £167,236, the latter of which was estimated to have an ICER of £49,798 compared with capecitabine monotherapy. The ERG produced similar values of £166,429 and £50,620 respectively. All other comparators were dominated. During the appraisal, the

  15. Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer

    PubMed Central

    Jung, Hae Hyun; Choi, Yoon-La; Ahn, TaeJin; Park, Kyunghee; Lee, Aeri; Do, In-Gu; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Woong-Yang; Im, Young-Hyuck

    2015-01-01

    In women with metastatic breast cancer (MBC), introduction of the anti-HER2 (human epidermal growth factor receptor-2) directed therapies including trastuzumab, pertuzumab, lapatinib, and/or trastuzumab-DM1 has markedly improved overall survival. However, not all cases of HER2-positive breast tumours derive similar benefit from HER2-directed therapy, and a significant number of patients experience disease progression because of primary or acquired resistance to anti-HER2-directed therapies. We integrated genomic and clinicopathological analyses in a cohort of patients with refractory breast cancer to anti-HER2 therapies to identify the molecular basis for clinical heterogeneity. To study the molecular basis underlying refractory MBC, we obtained 36 MBC tumours tissues and used next-generation sequencing to investigate the mutational and transcriptional profiles of 83 genes. We focused on HER2 mutational sites and HER2 pathways to identify the roles of HER2 mutations and the HER2 pathway in the refractoriness to anti-HER2 therapies. Analysis using massively parallel sequencing platform, CancerSCAN™, revealed that HER2 mutations were found in six of 36 patients (16.7%). One patient was ER (estrogen receptor)-positive and HER2-negative and the other five HER2 mutated patients were HER2-positive and HR (hormone receptor)-negative. Most importantly, four of these five patients did not show any durable clinical response to HER2-directed therapies. The HER2 pathway score obtained through transcriptional analyses identified that Growth Receptor Biding protein 2 (GRB2) was the most significantly down regulated gene in the HER2 mutated samples. Detection of HER2 mutations using higher deep DNA sequencing may identify a predictive biomarker of resistance to HER2-directed therapy. Functional validation is warranted. PMID:26397225

  16. Prognostic Significance of HER-2 Status in Women With Inflammatory Breast Cancer

    PubMed Central

    Dawood, Shaheenah; Broglio, Kristine; Gong, Yun; Yang, Wei-Tse; Cristofanilli, Massimo; Kau, Shu-Wan; Meric-Bernstam, Funda; Buchholz, Thomas A.; Hortobagyi, Gabriel N; Gonzalez-Angulo, Ana M.

    2015-01-01

    BACKGROUND Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC. METHODS In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics. RESULTS A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46–1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34–0.93 [P = .024]) compared with patients with HER-2-negative disease. CONCLUSIONS HER-2 status, in the absence of trastuzumab, did not appear to

  17. Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China

    PubMed Central

    Shen, Guo-Shuang; Zhao, Jiu-Da; Zhao, Jun-Hui; Ma, Xin-Fu; Du, Feng; Kan, Jie; Ji, Fa-Xiang; Ma, Fei; Zheng, Fang-Chao; Wang, Zi-Yi; Xu, Bing-He

    2016-01-01

    AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection. METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors. RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival. CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population. PMID:27340357

  18. Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab

    PubMed Central

    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

    2011-01-01

    Background: 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. Methods: 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. Results: 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). Conclusion: 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. PMID:21915118

  19. X-ray CT guided fault-free photothermal ablation of metastatic lymph nodes with ultrafine HER-2 targeting W18O49 nanoparticles.

    PubMed

    Huo, Da; He, Jian; Li, Hui; Huang, Ai J; Zhao, Hui Y; Ding, Yin; Zhou, Zheng Y; Hu, Yong

    2014-11-01

    Designing high accuracy in the diagnosing and fault-freely eliminating lymphatic metastasis of breast malignancy, to avoid the invasiveness and complications caused by traditional assays, is of great therapeutic importance. To this end, theranostic W18O49 nanoparticles targeting to human epidermal growth receptor 2 (HER-2) over-expressed breast malignancy were synthesized via polyol method. By taking advantage of their high X-ray attenuating and photothermotherapy potency, lymph nodes in the mice bearing HER-2 positive metastasis could be clearly distinguished under CT guidance and selectively eliminated by laser ablation. The therapeutic efficacy was further confirmed by the significantly extended survival period. These finding evidenced the potential of these nanoparticles for imaging guided photothermal ablation of HER-2 positive breast malignancy. PMID:25112934

  20. Survival Improvement in Korean Breast Cancer Patients Due to Increases in Early-Stage Cancers and Hormone Receptor Positive/HER2 Negative Subtypes: A Nationwide Registry-Based Study

    PubMed Central

    You, Jee Man; Kim, Yun Gyoung; Moon, Hyeong-Gon; Nam, Seok Jin; Lee, Jong Won; Lim, Woosung; Lee, Mi-Ri; Noh, Dong-Young

    2015-01-01

    Purpose The aim of this study was to investigate whether the observed changes over time in the survival rates vary according to the intrinsic subtypes of breast cancer diagnosed. Methods Data from 46,320 breast cancer patients in the Korean Breast Cancer Registry who underwent surgery between 1999 and 2006 were reviewed. Among them, results from 25,887 patients with available data about the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were analyzed. Patients were classified into two cohorts according to the year in which they underwent surgery: 1999-2002 and 2003-2006. Results The patients treated in the latter time period showed significantly better overall survival (OS) compared with those in the former period when adjusted for follow-up duration. The proportion of hormone receptor+/HER2-subtype and stage I breast cancer were significantly higher in the latter period (47.4% vs. 54.6%, p<0.001; 31.0% vs. 39.6%, p<0.001, respectively). Improvement in OS between the former and latter periods was seen in all subtypes of breast cancer, including triple-negative cancers (all p-values <0.001 in univariate and multivariate analyses). Conclusion Improvement in survival in Korean breast cancer patients over the study years is being observed in all subtypes of breast cancer, implying that increases in both early-stage detection and the proportion of less aggressive cancers contribute to this improvement. PMID:25834605

  1. Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

    PubMed Central

    Brufsky, Adam M

    2014-01-01

    Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer. PMID:25125981

  2. PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2

    PubMed Central

    Wishart, G C; Bajdik, C D; Dicks, E; Provenzano, E; Schmidt, M K; Sherman, M; Greenberg, D C; Green, A R; Gelmon, K A; Kosma, V-M; Olson, J E; Beckmann, M W; Winqvist, R; Cross, S S; Severi, G; Huntsman, D; Pylkäs, K; Ellis, I; Nielsen, T O; Giles, G; Blomqvist, C; Fasching, P A; Couch, F J; Rakha, E; Foulkes, W D; Blows, F M; Bégin, L R; van't Veer, L J; Southey, M; Nevanlinna, H; Mannermaa, A; Cox, A; Cheang, M; Baglietto, L; Caldas, C; Garcia-Closas, M; Pharoah, P D P

    2012-01-01

    Background: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. Methods: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. Results: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. Conclusion: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients. PMID:22850554

  3. HER2 status in advanced gastric carcinoma: A retrospective multicentric analysis from Sicily

    PubMed Central

    IENI, A.; BARRESI, V.; GIUFFRÈ, G.; CARUSO, R.A.; LANZAFAME, S.; VILLARI, L.; SALOMONE, E.; ROZ, E.; CABIBI, D.; FRANCO, V.; CERTO, G.; LABATE, A.; NAGAR, C.; MAGLIOLO, E.; BROGGI, B.; FAZZARI, C.; ITALIA, F.; TUCCARI, G.

    2013-01-01

    According to the ToGA trial, HER2 has been shown to be predictive for the success of treatment with trastuzumab in advanced gastric cancer (AGC). A number of studies have analyzed HER-2/neu overexpression in gastric carcinoma and identified the rate of HER2 positivity to be markedly varied. To date, the prevalence of HER2 overexpression in Sicilian people with AGC is unknown. Therefore, in the present study, a retrospective immunohistochemical analysis of HER2 was performed in a cohort of 304 AGC samples that were obtained from the archives of 10 Sicilian anatomopathological diagnostic units in order to verify the positive rate of HER2-positive cases. Furthermore, the characteristics of histotype, grade, stage and Ki-67 expression were also analyzed. HER2 overexpression was encountered in 17.43% of all the gastric adenocarcinomas, which was consistent with the results that have been reported elsewhere in the literature. A progressive increase in HER2 overexpression was observed, from the poorly cohesive histotype to the tubular adenocarcinomas and gastric hepatoid adenocarcinomas. HER2 overexpression was significantly associated with a high grade, advanced stage and high Ki-67 labeling index. Further investigations performed jointly by pathologists and oncologists within the geographical area of the present study should confirm that the association of trastuzumab with chemotherapy results in an improvement of survival in patients with AGC. PMID:24260051

  4. 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

  5. Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case.

    PubMed

    Saito, Takuya; Kondo, Chihiro; Shitara, Kohei; Ito, Yuichi; Saito, Noriko; Ikehara, Yuzuru; Yatabe, Yasushi; Yamamichi, Keigo; Tanaka, Hideo; Nakanishi, Hayao

    2015-06-01

    Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2-positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab. PMID:25828363

  6. A general approach to prepare conjugated polymer dot embedded silica nanoparticles with a SiO2@CP@SiO2 structure for targeted HER2-positive cellular imaging

    NASA Astrophysics Data System (ADS)

    Geng, Junlong; Liu, Jie; Liang, Jing; Shi, Haibin; Liu, Bin

    2013-08-01

    We report on a one-step synthesis of conjugated polymer (CP) embedded silica nanoparticles (NPs) with a SiO2@CP@SiO2 structure by combination of a precipitation method and a modified Stöber approach. Four types of CPs are employed to demonstrate the versatility of the developed strategy, yielding fluorescent silica NPs with emission across the visible spectrum. Field emission transmission electron microscopy investigation reveals that the entanglement between hydrophobic CPs and the aminopropyl groups of 3-aminopropyl triethoxysilane contributes to the successful encapsulation of CPs into a silica matrix. The synthesized NPs exhibit excellent physical stability and good photostability. In addition, they have amine groups on surfaces, which benefit further conjugation for biological applications. Through reaction with a peptide (GGHAHFG) that is specific to the HER2 receptor, the synthesized NPs have been successfully applied for targeted cellular imaging of HER2-overexpressed SKBR-3 breast cancer cells. Along with its high quantum yield and benign biocompatibility, the developed CP embedded silica NPs have great potential for applications in biological imaging.We report on a one-step synthesis of conjugated polymer (CP) embedded silica nanoparticles (NPs) with a SiO2@CP@SiO2 structure by combination of a precipitation method and a modified Stöber approach. Four types of CPs are employed to demonstrate the versatility of the developed strategy, yielding fluorescent silica NPs with emission across the visible spectrum. Field emission transmission electron microscopy investigation reveals that the entanglement between hydrophobic CPs and the aminopropyl groups of 3-aminopropyl triethoxysilane contributes to the successful encapsulation of CPs into a silica matrix. The synthesized NPs exhibit excellent physical stability and good photostability. In addition, they have amine groups on surfaces, which benefit further conjugation for biological applications. Through

  7. Delineation of HER2 Gene Status in Breast Carcinoma by Silver in Situ Hybridization is Reproducible among Laboratories and Pathologists

    PubMed Central

    Carbone, Antonino; Botti, Gerardo; Gloghini, Annunziata; Simone, Gianni; Truini, Mauro; Curcio, Maria Pia; Gasparini, Patrizia; Mangia, Anita; Perin, Tiziana; Salvi, Sandra; Testi, Adele; Verderio, Paolo

    2008-01-01

    An automated enzyme metallographic silver in situ hybridization method (SISH) has been reported to successfully determine human epidermal growth factor receptor 2 (HER2) gene amplification. We evaluated the staining and interpretative reproducibility of the HER2 SISH assay at five laboratories and compared SISH results with other in situ hybridization (ISH) methods. The HER2 gene status of 89 breast carcinomas was analyzed in parallel using manual dual-color fluorescence ISH, manual chromogenic ISH, and bright-field automated SISH. A total of 1098 SISH-stained slides were evaluated. For comparison, all specimens were stained by 4B5 immunohistochemistry for HER2 protein expression. Interpretation was performed by pathologists at five different laboratories using the algorithms provided by the manufacturers and the guidelines of American Society of Clinical Oncology/College of American Pathologists. Staining and interpretative reproducibility were measured through the computation of weighted kappa statistics. Following the optimization of SISH staining, 1077/1098 (98%) of slides were evaluable. Excellent reproducibility and efficacy of HER2 SISH staining, and interobserver interpretation (Kw = 0.91), were observed among five sites. For the 89 invasive breast cancer cases, the overall rate of concordance between consensus 4B5 and consensus SISH, fluorescence ISH, and chromogenic ISH was 96.6% (86/89), 97.8% (87/89), and 96.6% (86/89), respectively. Overall concordance between positive and negative SISH and fluorescence ISH results, as well as between individual and consensus positive and negative SISH results, was excellent (P < 0.001). PMID:18832456

  8. High expression of integrin β6 in association with the Rho-Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers.

    PubMed

    Desai, Krisha; Nair, Madhumathy G; Prabhu, Jyothi S; Vinod, Anupama; Korlimarla, Aruna; Rajarajan, Savitha; Aiyappa, Radhika; Kaluve, Rohini S; Alexander, Annie; Hari, P S; Mukherjee, Geetashree; Kumar, Rekha V; Manjunath, Suraj; Correa, Marjorrie; Srinath, B S; Patil, Shekhar; Prasad, M S N; Gopinath, K S; Rao, Raman N; Violette, Shelia M; Weinreb, Paul H; Sridhar, T S

    2016-08-01

    Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho-Rac pathway including downstream genes (ACTR2, ACTR3) and effector proteinases (MMP9, MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2- and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho-Rac pathway (P-values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease-free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9-8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node-positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho-Rac pathway through increased expression of MMP9 and MMP15. PMID:27184932

  9. Microfluidic processor allows rapid HER2 immunohistochemistry of breast carcinomas and significantly reduces ambiguous (2+) read-outs

    PubMed Central

    Ciftlik, Ata Tuna; Lehr, Hans-Anton; Gijs, Martin A. M.

    2013-01-01

    Biomarker analysis is playing an essential role in cancer diagnosis, prognosis, and prediction. Quantitative assessment of immunohistochemical biomarker expression on tumor tissues is of clinical relevance when deciding targeted treatments for cancer patients. Here, we report a microfluidic tissue processor that permits accurate quantification of the expression of biomarkers on tissue sections, enabled by the ultra-rapid and uniform fluidic exchange of the device. An important clinical biomarker for invasive breast cancer is human epidermal growth factor receptor 2 [(HER2), also known as neu], a transmembrane tyrosine kinase that connotes adverse prognostic information for the patients concerned and serves as a target for personalized treatment using the humanized antibody trastuzumab. Unfortunately, when using state-of-the-art methods, the intensity of an immunohistochemical signal is not proportional to the extent of biomarker expression, causing ambiguous outcomes. Using our device, we performed tests on 76 invasive breast carcinoma cases expressing various levels of HER2. We eliminated more than 90% of the ambiguous results (n = 27), correctly assigning cases to the amplification status as assessed by in situ hybridization controls, whereas the concordance for HER2-negative (n = 31) and -positive (n = 18) cases was 100%. Our results demonstrate the clinical potential of microfluidics for accurate biomarker expression analysis. We anticipate our technique will be a diagnostic tool that will provide better and more reliable data, onto which future treatment regimes can be based. PMID:23479638

  10. Methylsulfonylmethane inhibits HER2 expression through STAT5b in breast cancer cells.

    PubMed

    Kang, Dong Young; Darvin, Pramod; Yoo, Young Beom; Joung, Youn Hee; Sp, Nipin; Byun, Hyo Joo; Yang, Young Mok

    2016-02-01

    Breast cancer is the most common cancer in women globally. The factors that increase risk include: late age at first birth, alcohol, radiation exposure, family history of breast cancer, and postmenopausal hormone therapy. Numerous drugs are being developed to treat breast cancer. Among them, Herceptin is used for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cases and targets HER2 effectively and efficiently, but it is very expensive. Methylsulfonylmethane (MSM) is an organic sulfur-containing natural compound having no reported toxicity. We examined MSM in breast cancer cell lines and found it inhibited the proliferation of estrogen receptor-positive and HER2-positive breast cancer cells in a dose-dependent manner. It also suppressed the activation of STAT5b and expression of HER2 in breast cancer cells. We determined the STAT5b binding site (GAS element) in the HER2 gene. Detailed analysis showed that MSM decreased the ability of STAT5b to bind the promoter of the HER2 gene and a luciferase assay demonstrated reduced activity. We confirmed that MSM can effectively regulate STAT5b, and thereby decrease HER2 expression. Therefore, we recommend the use of MSM as an inhibitor for the management of HER2-positive breast cancers. PMID:26648017

  11. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    SciTech Connect

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-04-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  12. Accuracy and Reproducibility of HER2 Status in Breast Cancer Using Immunohistochemistry: A Quality Control Study in Tuscany Evaluating the Impact of Updated 2013 ASCO/CAP Recommendations.

    PubMed

    Bianchi, S; Caini, S; Paglierani, M; Saieva, C; Vezzosi, V; Baroni, G; Simoni, A; Palli, D

    2015-04-01

    The correct identification of HER2-positive cases is a key point to provide the most appropriate therapy to breast cancer (BC) patients. We aimed at investigating the reproducibility and accuracy of HER2 expression by immunohistochemistry (IHC) in a selected series of 35 invasive BC cases across the pathological anatomy laboratories in Tuscany, Italy. Unstained sections of each BC case were sent to 12 participating laboratories. Pathologists were required to score according to the Food and Drug Administration (FDA) four-tier scoring system (0, 1+, 2+, 3+). Sixteen and nineteen cases were HER2 non-amplified and amplified respectively on fluorescence in situ hybridization. Among 192 readings of the 16 HER2 non-amplified samples, 153 (79.7%) were coded as 0 or 1+, 39 (20.3%) were 2+, and none was 3+ (false positive rate 0%). Among 228 readings of the 19 HER2 amplified samples, 56 (24.6%) were scored 0 or 1+, 79 (34.6%) were 2+, and 93 (40.8%) were 3+. The average sensitivity was 75.4%, ranging between 47% and 100%, and the overall false negative rate was 24.6%. Participation of pathological anatomy laboratories performing HER2 testing by IHC in external quality assurance programs should be made mandatory, as the system is able to identify laboratories with suboptimal performance that may need technical advice. Updated 2013 ASCO/CAP recommendations should be adopted as the widening of IHC 2+ "equivocal" category would improve overall accuracy of HER2 testing, as more cases would be classified in this category and, consequently, tested with an in situ hybridisation method. PMID:25367072

  13. Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK).

    PubMed

    Matter-Walstra, K; Ruhstaller, T; Klingbiel, D; Schwenkglenks, M; Dedes, K J

    2016-07-01

    Endocrine therapy continues to be the optimal systemic treatment for metastatic ER(+)HER2(-) breast cancer. The CDK4/6 inhibitor palbociclib combined with letrozole has recently been shown to significantly improve progression-free survival. Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system. A Markov cohort simulation based on the PALOMA-1 trial (Finn et al. in Lancet Oncol 16:25-35, 2015) was used as the clinical course. Input parameters were based on summary trial data. Costs were assessed from the Swiss healthcare system perspective. Adding palbociclib to letrozole (PALLET) compared to letrozole monotherapy was estimated to cost an additional CHF342,440 and gain 1.14 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio (ICER) of CHF301,227/QALY gained. In univariate sensitivity analyses, no tested variation in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. PALLET had a 0 % probability of being cost-effective in probabilistic sensitivity analyses. Lowering PALLET's price by 75 % resulted in an ICER of CHF73,995/QALY and a 73 % probability of being cost-effective. At current prices, PALLET would cost the Swiss healthcare system an additional CHF155 million/year. Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system. PMID:27277747

  14. Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers.

    PubMed

    Eng, Juliana; Hsu, Meier; Chaft, Jamie E; Kris, Mark G; Arcila, Maria E; Li, Bob T

    2016-09-01

    Human epidermal growth factor receptor 2 (HER2, ERBB2) mutations occur in 3% of lung adenocarcinomas. While case reports and series have shown activity of HER2 targeted agents in these patients, little is known about outcomes of chemotherapies. Patients with stage IV HER2-mutant lung cancers at Memorial Sloan Kettering were reviewed. Patient demographics, types of HER2 mutations, duration of systemic treatments and survival were analyzed. We identified 38 patients with HER2-mutant lung cancers: median age 62; majority were women (n=24), never smokers (n=22), and all had adenocarcinomas. A 12 base pair in-frame insertion YVMA in exon 20 (p.A775_G776insYVMA) was present in 24 (63%, 95% CI 46-78%) patients. In addition, there were four 9 base pair insertions, one 6 base pair insertion, and five 3 base pair insertions in exon 20, and four single bp substitutions (exon 20 L755F, V777L, D769H, exon 8 S310F). The median overall survival from date of diagnosis of stage IV disease was 2.3 years (95% CI 1.2-2.6). The median duration of chemotherapy was 4.3 months (68 treatments, range 0-21 months): 6.2 months for pemetrexed ±platinum/bevacizumab, 4 months for taxane ±platinum/bevacizumab, 2.6 months for gemcitabine, 3.5 months for vinorelbine. The median duration of HER2 tyrosine kinase inhibitors was 2.2 months (28 treatments, range 0.3-16.3 months). As we search for better targeted therapies for patients with HER2-mutant lung cancers, chemotherapy remains an important component of care. PMID:27565914

  15. Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells.

    PubMed

    Mandl, Stefanie J; Rountree, Ryan B; Dalpozzo, Katie; Do, Lisa; Lombardo, John R; Schoonmaker, Peter L; Dirmeier, Ulrike; Steigerwald, Robin; Giffon, Thierry; Laus, Reiner; Delcayre, Alain

    2012-01-01

    MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (T(reg)) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of T(reg) cells in the lung, resulting in a significantly increased ratio of effector T cells to T(reg) cells. In contrast, administration of HER2 protein formulated in Complete Freund's Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of T(reg) cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced T(reg) cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression. PMID:21822917

  16. A gene-protein assay for human epidermal growth factor receptor 2 (HER2): brightfield tricolor visualization of HER2 protein, the HER2 gene, and chromosome 17 centromere (CEN17) in formalin-fixed, paraffin-embedded breast cancer tissue sections

    PubMed Central

    2012-01-01

    Background The eligibility of breast cancer patients for human epidermal growth factor receptor 2 (HER2)-directed therapies is determined by the HER2 gene amplification and/or HER2 protein overexpression status of the breast tumor as determined by in situ hybridization (ISH) or immunohistochemistry (IHC), respectively. Our objective was to combine the US Food and Drug Administration (FDA)-approved HER2 & chromosome 17 centromere (CEN17) brightfield ISH (BISH) and HER2 IHC assays into a single automated HER2 gene-protein assay allowing simultaneous detection of all three targets in a single tissue section. Methods The HER2 gene-protein assay was optimized using formalin-fixed, paraffin-embedded (FFPE) samples of the xenograft tumors MCF7 [HER2 negative (non-amplified gene, protein negative)] and Calu-3 [HER2 positive (amplified gene, protein positive)]. HER2 IHC was performed using a rabbit monoclonal anti-HER2 antibody (clone 4B5) and a conventional 3,3'-diaminobenzidine IHC detection. The HER2 & CEN17 BISH signals were visualized using horseradish peroxidase-based silver and alkaline phosphatase-based red detection systems, respectively with a cocktail of 2,4-dinitrophenyl-labeled HER2 and digoxigenin-labeled CEN17 probes. The performance of the gene-protein assay on tissue microarray slides containing 189 randomly selected FFPE clinical breast cancer tissue cores was compared to that of the separate HER2 IHC and HER2 & CEN17 BISH assays. Results HER2 protein detection was optimal when the HER2 IHC protocol was used before (rather than after) the BISH protocol. The sequential use of HER2 IHC and HER2 & CEN17 BISH detection steps on FFPE xenograft tumor sections appropriately co-localized the HER2 protein, HER2 gene, and CEN17 signals after mitigating the silver background staining by using a naphthol phosphate-containing hybridization buffer for the hybridization step. The HER2 protein and HER2 gene status obtained using the multiplex HER2 gene-protein assay

  17. Clinicopathological characteristics and her-2/neu status in chinese patients with uterine papillary serous carcinoma.

    PubMed

    Ren, Yulan; Wang, Huaying; Zhou, Xiaoyan; Yang, Wentao; Huang, Xiaowei; Lu, Yongming; Shi, Daren

    2011-01-01

    Objective. To analyze clinico-pathological features of Chinese patients with UPSC, and investigate roles of Her-2/neu protein expression and gene amplification in UPSC prognosis. Methods. Thirty-six patients with UPSC treated in Cancer Hospital of Fudan University from 1996 to 2006 were analysed retrospectively. Chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) were performed to evaluate Her-2/neu gene amplification and protein expression respectively. Results. The median age was 63 years, and 61% (22/36) were late stages (stage III/IV). The 1-year, 3-year, and 5-year overall survival (OS) was 73.1%, 51.9% and 43.9%, respectively. Advanced stages (P = .0006) and deep myometrial invasion (P = .0138) were significantly associtated with a shorter OS. In 36 cases, 27.8% (10/36) showed 2+ staining and 8.3% (3/36) showed 3+ by IHC. Amplification of the Her-2/neu gene was observed in 11.1% (4/36) cases. The 5-year overall survival rate in Her-2/neu IHC 2 + ∼3+ and 0 ~ 1+ cases was 12.9% and 68.6% respectively. Her-2/neu protein expression 2 + ∼3+ was significantly associated with advanced surgical stage and worse overall survival (P = .03 and P = .0023, resp.). Conclusion. Chinese patients with UPSC showed characteristics of deep myometrial invasion, advanced stages and poor overall survival. Her-2/neu protein overexpression is associated with advanced stage and poor survival outcome. PMID:21647234

  18. HER2 testing in gastric cancer: An update

    PubMed Central

    Abrahao-Machado, Lucas Faria; Scapulatempo-Neto, Cristovam

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system. PMID:27217694

  19. HER2 testing in gastric cancer: An update.

    PubMed

    Abrahao-Machado, Lucas Faria; Scapulatempo-Neto, Cristovam

    2016-05-21

    Human epidermal growth factor receptor 2 (HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system. PMID:27217694

  20. Estrogen Receptor and HER2 Status on Disseminated Tumor Cells and Primary Tumor in Patients with Early Breast Cancer

    PubMed Central

    Jäger, Bernadette A.S.; Finkenzeller, Charlotte; Bock, Carolin; Majunke, Leonie; Jueckstock, Julia K.; Andergassen, Ulrich; Neugebauer, Julia K.; Pestka, Aurelia; Friedl, Thomas W.P.; Jeschke, Udo; Janni, Wolfgang; Doisneau-Sixou, Sophie F.; Rack, Brigitte K.

    2015-01-01

    BACKGROUND: We evaluated both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disseminated tumor cells (DTCs) in the bone marrow of 54 patients with early breast cancer and compared these with the corresponding primary tumor (PT). MATERIALS AND METHODS: Bone marrow aspirates were obtained at the time of first surgery, and ER and HER2 status on DTCs was assessed simultaneously by immunocytochemistry using a triple fluorescence staining method. RESULTS: The median number of DTCs was 13 (range 1-95). The concordance rate between ER status on DTC and PT was 74%. Patients with an ER-positive PT were significantly more likely to have at least one ER-positive DTC (34 out of 42) than patients with an ER-negative PT (6 out of 12; P = .031). Thirty-nine (93%) of the 42 patients with ER-positive PT had at least one ER-negative DTC. The concordance rate between HER2 status on DTC and PT was 52%. The probability of having at least one HER2-positive DTC was not related to the HER2 status of the PT (P = 0.56). Twenty-two (46%) of the 48 patients with a HER2-negative PT had at least one HER2-positive DTC. All the six patients with a HER2-positive PT had at least one HER2-negative DTC. CONCLUSION: Taken together, our study confirms that ER and/or HER2 status may differ between DTC and PT. This discordance could be important for patients lacking ER or HER2 expression on the PT but showing ER-positive or HER2-positive DTC because they might benefit from an endocrine and/or HER2-targeted therapy. PMID:26692533

  1. Positive Feedback between Mycorrhizal Fungi and Plants Influences Plant Invasion Success and Resistance to Invasion

    PubMed Central

    Zhang, Qian; Yang, Ruyi; Tang, Jianjun; Yang, Haishui; Hu, Shuijin; Chen, Xin

    2010-01-01

    Negative or positive feedback between arbuscular mycorrhizal fungi (AMF) and host plants can contribute to plant species interactions, but how this feedback affects plant invasion or resistance to invasion is not well known. Here we tested how alterations in AMF community induced by an invasive plant species generate feedback to the invasive plant itself and affect subsequent interactions between the invasive species and its native neighbors. We first examined the effects of the invasive forb Solidago canadensis L. on AMF communities comprising five different AMF species. We then examined the effects of the altered AMF community on mutualisms formed with the native legume forb species Kummerowia striata (Thunb.) Schindl. and on the interaction between the invasive and native plants. The host preferences of the five AMF were also assessed to test whether the AMF form preferred mutualistic relations with the invasive and/or the native species. We found that S. canadensis altered AMF spore composition by increasing one AMF species (Glomus geosporum) while reducing Glomus mosseae, which is the dominant species in the field. The host preference test showed that S. canadensis had promoted the abundance of AMF species (G. geosporum) that most promoted its own growth. As a consequence, the altered AMF community enhanced the competitiveness of invasive S. canadensis at the expense of K. striata. Our results demonstrate that the invasive S. canadensis alters soil AMF community composition because of fungal-host preference. This change in the composition of the AMF community generates positive feedback to the invasive S. canadensis itself and decreases AM associations with native K. striata, thereby making the native K. striata less dominant. PMID:20808770

  2. Giacomo Castelvetro's salads. Anti-HER2 oncogene nutraceuticals since the 17th century?

    PubMed

    Colomer, R; Lupu, R; Papadimitropoulou, A; Vellón, L; Vázquez-Martín, A; Brunet, J; Fernández-Gutiérrez, A; Segura-Carretero, A; Menéndez, J A

    2008-01-01

    We are accumulating evidence to suggest that 17(th) century Renaissance foodways -largely based on the old "Mediterranean dietary traditions"- may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that "The Sacred Law of Salads" (i.e., "raw vegetables... plenty of generous (olive) oil") -originally proposed in 1614 by Giacomo Castelvetro in its book The Fruit, Herbs & Vegetables of Italy- might be considered the first (unintended) example of customised diets for breast cancer prevention based on individual genetic make-up (i.e., nutraceuticals against human breast carcinomas bearing HER2 oncogene amplification/overexpression). First, the so-called salad vegetables dietary pattern (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect mostly confined to the HER2-positive breast cancer subtype, with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid oleic acid and polyphenolic compounds such as the secoiridoid oleuropein or the lignan 1-[+]-acetoxypinoresinol) dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER2- positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats likewise decreasing HER2 expression levels. If early 1600s Castelvetro's salads can be used as dietary protocols capable to protecting women against biologically aggressive HER2-positive breast cancer subtypes is an intriguing prospect that warrants to be evaluated in human pilot studies in the future. Here, at least, we would like to recognise Giacomo Castelvetro as the father of modern nutritional genomics in oncology. PMID:18208790

  3. Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

    PubMed Central

    Blancafort, Adriana; Giró-Perafita, Ariadna; Oliveras, Glòria; Palomeras, Sònia; Turrado, Carlos; Campuzano, Òscar; Carrión-Salip, Dolors; Massaguer, Anna; Brugada, Ramon; Palafox, Marta; Gómez-Miragaya, Jorge; González-Suárez, Eva; Puig, Teresa

    2015-01-01

    Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies. PMID:26107737

  4. PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer.

    PubMed

    Jeong, Jaekwang; VanHouten, Joshua N; Dann, Pamela; Kim, Wonnam; Sullivan, Catherine; Yu, Herbert; Liotta, Lance; Espina, Virginia; Stern, David F; Friedman, Peter A; Wysolmerski, John J

    2016-01-19

    In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer. PMID:26729871

  5. Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted SiRNA Delivery to HER2+ Breast Cancer

    PubMed Central

    Ngamcherdtrakul, Worapol; Morry, Jingga; Gu, Shenda; Castro, David J.; Goodyear, Shaun M.; Sangvanich, Thanapon; Reda, Moataz M.; Lee, Richard; Mihelic, Samuel A.; Beckman, Brandon L.; Hu, Zhi; Gray, Joe W.; Yantasee, Wassana

    2015-01-01

    In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2−) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation. PMID:26097445

  6. Hyperthermia-triggered intracellular delivery of anticancer agent to HER2+ cells by HER2-specific Affibody (ZHER2-GS-Cys)-Conjugated Thermosensitive Liposomes (HER2+ Affisomes)

    PubMed Central

    Smith, Brandon; Lyakhov, Ilya; Loomis, Kristin; Needle, Danielle; Baxa, Ulrich; Yavlovich, Amichai; Capala, Jacek; Blumenthal, Robert; Puri, Anu

    2011-01-01

    We previously reported the formulation and physical properties of HER2 (Human Epidermal Growth Factor Receptor 2)-specific Affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2+ Affisomes). Here we examined localized delivery potential of these Affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine-serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell-surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2+ Affisomes). HER2+ Affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug Doxorubicin (DOX). Fluorescently labeled HER2+ Affisomes showed at least 10 fold increase in binding to HER2+ cells (SK-BR-3) when compared to HER2− cells (MDA-MB-468) at 37°C. A competition experiment using free ZHER2-GS-Cys blocked HER2+ Affisomes-SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2+ Affisomes accumulated in the cytosol of SK-BR-3 cells at 37°C. Hyperthermia-induced intracellular release experiments showed that the treatment of HER2+ Affisome/SK-BR-3 cell complexes with a 45°C (±1°C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20 minutes at 45°C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2+ Affisomes showed at least 2–3 fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2+ Affisomes. Brief exposure of liposome-cell complexes at 45°C prior to the onset of incubations for cell killing assays

  7. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    NASA Astrophysics Data System (ADS)

    Shukla, Rameshwer; Thomas, Thommey P.; Desai, Ankur M.; Kotlyar, Alina; Park, Steve J.; Baker, James R., Jr.

    2008-07-01

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket.

  8. PYK2 integrates growth factor and cytokine receptors signaling and potentiates breast cancer invasion via a positive feedback loop

    PubMed Central

    Selitrennik, Michael; Lev, Sima

    2015-01-01

    The involvement of ErbB family members in breast cancer progression and metastasis has been demonstrated by many studies. However, the downstream effectors that mediate their migratory and invasive responses have not been fully explored. In this study, we show that the non-receptor tyrosine kinase PYK2 is a key effector of EGFR and HER2 signaling in human breast carcinoma. We found that PYK2 is activated by both EGF and heregulin (HRG) in breast cancer cells, and positively regulates EGF/HRG-induced cell spreading, migration and invasion. PYK2 depletion markedly affects ERK1/2 and STAT3 phosphorylation in response to EGF/HRG as well as to IL8 treatment. Importantly, PYK2 depletion also reduced EGF/HRG-induced MMP9 and IL8 transcription, while IL8 inhibition abrogated EGF-induced MMP9 transcription and attenuated cell invasion. IL8, which is transcriptionally regulated by STAT3 and induces PYK2 activation, prolonged EGF-induced PYK2, STAT3 and ERK1/2 phosphorylation suggesting that IL8 acts through an autocrine loop to reinforce EGF-induced signals. Collectively our studies suggest that PYK2 is a common downstream effector of ErbB and IL8 receptors, and that PYK2 integrates their signaling pathways through a positive feedback loop to potentiate breast cancer invasion. Hence, PYK2 could be a potential therapeutic target for a subset of breast cancer patients. PMID:26084289

  9. A FcγRIII-engaging bispecific antibody expands the range of HER2-expressing breast tumors eligible to antibody therapy.

    PubMed

    Turini, Marc; Chames, Patrick; Bruhns, Pierre; Baty, Daniel; Kerfelec, Brigitte

    2014-07-30

    Trastuzumab is established as treatment of HER2high metastatic breast cancers but many limitations impair its efficacy. Here, we report the design of a Fab-like bispecific antibody (HER2bsFab) that displays a moderate affinity for HER2 and a unique, specific and high affinity for FcγRIII. In vitro characterization showed that ADCC was the major mechanism of action of HER2bsFab as no significant HER2-driven effect was observed. HER2bsFab mediated ADCC at picomolar concentration against HER2high, HER2low as well as trastuzumab-refractive cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth by recruitment of mouse FcγRIII and IV-positive resident effector cells and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2low tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of V/F158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Thus, taking advantage of its epitope specificity and affinity for HER2 and FcγRIIIA, HER2bsFab exhibits potent anti-tumor activity against HER2low tumors while evading most of trastuzumab Fc-linked limitations thereby potentially enlarging the number of patients eligible for breast cancer immunotherapy. PMID:24979648

  10. A FcγRIII-engaging bispecific antibody expands the range of HER2-expressing breast tumors eligible to antibody therapy

    PubMed Central

    Turini, Marc; Chames, Patrick; Bruhns, Pierre

    2014-01-01

    Trastuzumab is established as treatment of HER2high metastatic breast cancers but many limitations impair its efficacy. Here, we report the design of a Fab-like bispecific antibody (HER2bsFab) that displays a moderate affinity for HER2 and a unique, specific and high affinity for FcγRIII. In vitro characterization showed that ADCC was the major mechanism of action of HER2bsFab as no significant HER2-driven effect was observed. HER2bsFab mediated ADCC at picomolar concentration against HER2high, HER2low as well as trastuzumab-refractive cell lines. In vivo HER2bsFab potently inhibited HER2high tumor growth by recruitment of mouse FcγRIII and IV-positive resident effector cells and more importantly, exhibited a net superiority over trastuzumab at inhibiting HER2low tumor growth. Moreover, FcγRIIIA-engagement by HER2bsFab was independent of V/F158 polymorphism and induced a stronger NK cells activation in response to target cell recognition. Thus, taking advantage of its epitope specificity and affinity for HER2 and FcγRIIIA, HER2bsFab exhibits potent anti-tumor activity against HER2low tumors while evading most of trastuzumab Fc-linked limitations thereby potentially enlarging the number of patients eligible for breast cancer immunotherapy. PMID:24979648

  11. The case for HER2/neu as a therapeutic target for gynecologic malignancies.

    PubMed

    Goyne, Hannah E; Cannon, Martin J

    2012-08-01

    Evaluation of: Guzzo F, Bellone S, Buza N et al. HER2/neu as a potential target for immunotherapy in gynecological carcinosarcomas. Int. J. Gynecol. Pathol. 31, 211-221 (2012). Trastuzumab (Herceptin(®)) is a human monoclonal antibody that is US FDA-approved for the treatment of HER2/neu-overexpressing breast cancer and metastatic gastric cancer. HER2/neu expression has also been observed in other malignancies, notably in subsets of endometrial and ovarian cancers, raising the possibility that trastuzumab may be a viable treatment option in these settings. The current paper reveals that HER2/neu may also be expressed in gynecologic carcinosarcomas, which are rare but aggressive tumors with a high rate of resistance to chemotherapy. Cell lines derived from ovarian carcinosarcomas expressed HER2/neu and were sensitive to trastuzumab ADCC. By contrast, cell lines derived from uterine carcinosarcomas were HER2/neu-negative and insensitive to trastuzumab ADCC. These observations indicate that at least a subset of gynecologic carcinosarcoma patients may benefit from trastuzumab treatment. However, trastuzumab monotherapy typically has relatively low response rates, which in part may be related to impaired NK cell function in patients with advanced disease. Accordingly, treatments that boost NK cell activity may improve response rates to trastuzumab treatment, not only for gynecologic carcinosarcomas, but also for other HER2/neu-positive malignancies. PMID:22947006

  12. HER2- and EGFR-specific affiprobes: novel recombinant optical probes for cell imaging.

    PubMed

    Lyakhov, Ilya; Zielinski, Rafal; Kuban, Monika; Kramer-Marek, Gabriela; Fisher, Robert; Chertov, Oleg; Bindu, Lakshman; Capala, Jacek

    2010-02-15

    The human epidermal growth factor receptors, EGFR and HER2, are members of the EGFR family of cell-surface receptors/tyrosine kinases. EGFR- and HER2-positive cancers represent a more aggressive disease with greater likelihood of recurrence, poorer prognosis, and decreased survival rate, compared to EGFR- or HER2-negative cancers. The details of HER2 proto-oncogenic functions are not deeply understood, partially because of a restricted availability of tools for EGFR and HER2 detection (A. Sorkin and L. K. Goh, Exp. Cell Res. 2009, 315, 683-696). We have created photostable and relatively simple-to-produce imaging probes for in vitro staining of EGFR and HER2. These new reagents, called affiprobes, consist of a targeting moiety, a HER2- or EGFR-specific Affibody molecule, and a fluorescent moiety, mCherry (red) or EGFP (green). Our flow cytometry and confocal microscopy experiments demonstrated high specificity and signal/background ratio of affiprobes. Affiprobes are able to stain both live cells and frozen tumor xenograph sections. This type of optical probe can easily be extended for targeting other cell-surface antigens/ receptors. PMID:20052708

  13. Positive Effects of Nonnative Invasive Phragmites australis on Larval Bullfrogs

    PubMed Central

    Rogalski, Mary Alta; Skelly, David Kiernan

    2012-01-01

    Background Nonnative Phragmites australis (common reed) is one of the most intensively researched and managed invasive plant species in the United States, yet as with many invasive species, our ability to predict, control or understand the consequences of invasions is limited. Rapid spread of dense Phragmites monocultures has prompted efforts to limit its expansion and remove existing stands. Motivation for large-scale Phragmites eradication programs includes purported negative impacts on native wildlife, a view based primarily on observational results. We took an experimental approach to test this assumption, estimating the effects of nonnative Phragmites australis on a native amphibian. Methodology/Principal Findings Concurrent common garden and reciprocal transplant field experiments revealed consistently strong positive influences of Phragmites on Rana catesbeiana (North American bullfrog) larval performance. Decomposing Phragmites litter appears to contribute to the effect. Conclusions/Significance Positive effects of Phragmites merit further research, particularly in regions where both Phragmites and R. catesbeiana are invasive. More broadly, the findings of this study reinforce the importance of experimental evaluations of the effects of biological invasion to make informed conservation and restoration decisions. PMID:22952976

  14. HER2 testing in breast carcinoma: very low concordance rate between reference and local laboratories in Brazil.

    PubMed

    Wludarski, Sheila Cristina Lordelo; Lopes, Lisandro Ferreira; Berto E Silva, Tácio R; Carvalho, Filomena M; Weiss, Lawrence M; Bacchi, Carlos E

    2011-03-01

    Breast cancer accounts for approximately one quarter of all cancers in females. HER2 gene amplification or HER2 protein overexpression, detected in about 20% of breast carcinomas, predicts a more aggressive clinical course and determines eligibility for targeted therapy with trastuzumab. HER2 testing has become an essential part of the clinical evaluation of all breast carcinoma patients, and accurate HER2 results are critical in identifying patients who may be benefited from targeted therapy. This study investigated the concordance in the results of HER2 immunohistochemistry assays performed in 500 invasive breast carcinomas between a reference laboratory and 149 local laboratories from all geographic regions of Brazil. Our results showed an overall poor concordance (171 of 500 cases, 34.2%) regarding HER2 results between local and reference laboratories, which may be related to the low-volume load of HER2 assays, inexperience with HER2 scoring system, and/or technical issues related to immunohistochemistry in local laboratories. Standardization of HER2 testing with rigorous quality control measures by local laboratories is highly recommended to avoid erroneous treatment of breast cancer patients. PMID:20930616

  15. Quantitative Analysis of HER2-mediated Effects on HER2 and Epidermal Growth Factor Receptor Endocytosis: DISTRIBUTION OF HOMO- AND HETERODIMERS DEPENDS ON RELATIVE HER2 LEVELS

    SciTech Connect

    Hendriks, Bart S.; Opresko, Lee ); Wiley, H Steven ); Lauffenburger, Douglas A.

    2003-05-15

    Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR) family. Many cell types express multiple EGFR family members (including EGFR, HER2, HER3 and/or HER4) that interact to form an array of homo- and hetero-dimers. Differential trafficking of these receptors should strongly affect signaling through this system by changing substrate access and heterodimerization efficiency. Because of the complexity of these dynamic processes we used a quantitative, computational model to understand this system. As a test case, parameters characterizing EGFR and HER2 interactions were derived using experimental data obtained from mammary epithelial cells constructed to express different levels of HER2. With this data we were able to estimate receptor-specific internalization rate constants and dimer uncoupling rate constants. These parameters were not otherwise experimentally accessible due to the complex system interplay. Our models indicated that HER2:EGFR heterodimers traffic as single entities. Direct experiments using EGF and anti-HER2 and anti-EGFR antibodies using independently derived cell lines confirmed many of the predictions of the model. Furthermore, our model could predict the relationship between HER2 expression levels and the transient distribution of EGFR homodimers and heterodimers. Our results suggest that the levels of HER2 found on normal cells are barely at the threshold necessary to drive efficient heterodimerization. Thus, altering local HER2 concentrations in membrane microdomains could serve as an effective mechanism for regulating HER2 heterodimerization and could explain why HER2 overexpression found in some cancers have such a profound effect on cell physiology.

  16. Rapid fluorescence in situ hybridisation (FISH) for HER2 (ERBB2) assessment in breast and gastro-oesophageal cancer.

    PubMed

    Tafe, Laura J; Steinmetz, Heather B; Allen, Samantha F; Dokus, Betty J; Tsongalis, Gregory J

    2015-04-01

    Evaluation of HER2 (ERBB2) gene amplification or protein expression is standard of care in breast (BR) and advanced stage gastro-oesophageal cancers to identify patients eligible for anti-HER2 therapies. Here, we evaluate a rapid fluorescence in situ hybridisation (FISH) technology (HER2 instant quality (IQ) FISH pharmDx Kit) for detection of HER2 in patients with BR and gastro-oesophageal cancer using 30 FFPE samples that had been previously evaluated with the PathVysion HER2 DNA Probe Kit. Cases were scored as positive (HER2:CEN-17 ≥2.0), negative (HER2:CEN-17 <2.0) or equivocal according to the ASCO/CAP 2013 BR cancer guidelines. Ten samples were positive for HER2 amplification while 20 were negative; none were equivocal. The IQ FISH was able to detect low level amplification (HER2:CEN-17 ratio 2.4). The HER2 IQ FISH pharmDx Kit is a FDA approved kit that offers a rapid turnaround time (approximately 3.5 h) and in our laboratory was 100% concordant with prior PathVysion results. PMID:25576545

  17. Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells.

    PubMed

    Diessner, Joachim; Bruttel, Valentin; Becker, Kathrin; Pawlik, Miriam; Stein, Roland; Häusler, Sebastian; Dietl, Johannes; Wischhusen, Jörg; Hönig, Arnd

    2013-01-01

    Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44(high)CD24(low)HER2(low) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells. PMID:23593542

  18. Targeting breast cancer stem cells with HER2-specific antibodies and natural killer cells

    PubMed Central

    Diessner, Joachim; Bruttel, Valentin; Becker, Kathrin; Pawlik, Miriam; Stein, Roland; Häusler, Sebastian; Dietl, Johannes; Wischhusen, Jörg; Hönig, Arnd

    2013-01-01

    Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44highCD24lowHER2low cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells. PMID:23593542

  19. HER2 activating mutations are targets for colorectal cancer treatment

    PubMed Central

    Kavuri, Shyam M.; Jain, Naveen; Galimi, Francesco; Cottino, Francesca; Leto, Simonetta M.; Migliardi, Giorgia; Searleman, Adam C.; Shen, Wei; Monsey, John; Trusolino, Livio; Jacobs, Samuel A.; Bertotti, Andrea; Bose, Ron

    2015-01-01

    The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of colorectal cancer patients. Introduction of the HER2 mutations, S310F, L755S, V777L, V842I, and L866M, into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutations are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors, neratinib and afatinib. HER2 gene sequencing of 48 cetuximab resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) WT colorectal cancer patient-derived xenografts (PDX’s) identified 4 PDX’s with HER2 mutations. HER2 targeted therapies were tested on two PDX’s. Treatment with a single HER2 targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2 targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2 mutated PDX’s. PMID:26243863

  20. MicroRNA and HER2-overexpressing Cancer

    PubMed Central

    Wang, Shizhen Emily; Lin, Ren-Jang

    2013-01-01

    The discovery of microRNAs (miRNAs) has opened up new avenues for studying cancer at the molecular level, featuring a post-genomic era of biomedical research. These non-coding regulatory RNA molecules of ~22 nucleotides have emerged as important cancer biomarkers, effectors, and targets. In this review, we focus on the dysregulated biogenesis and function of miRNAs in cancers with an overexpression of the proto-oncogene HER2. Many of the studies reviewed here were carried out in breast cancer, where HER2 overexpression has been extensively studied and HER2-targeted therapy practiced for more than a decade. MiRNA signatures that can be used to classify tumors with different HER2 status have been reported but little consensus can be established among various studies, emphasizing the needs for additional well-controlled profiling approaches and meta-analyses in large and well-balanced patient cohorts. We further discuss three aspects of microRNA dysregulation in or contribution to HER2-associated malignancies or therapies: (a) miRNAs that are up- or down-regulated by HER2 and mediate the downstream signaling of HER2; (b) miRNAs that suppress the expression of HER2 or a factor in HER2 receptor complexes, such as HER3; and (c) miRNAs that affect responses to anti-HER2 therapies. The regulatory mechanisms are elaborated using mainly examples of miR-205, miR-125, and miR-21. Understanding the regulation and function of miRNAs in HER2-overexpressing tumors shall shed new light on the pathogenic mechanisms of microRNAs and the HER2 proto-oncogene in cancer, as well as on individualized or combinatorial anti-HER2 therapies. PMID:25070783

  1. Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

    PubMed Central

    Nowara, Elżbieta

    2016-01-01

    The HER2/neu (ERBB2) oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed. PMID:27095932

  2. Human Epidermal Growth Factor Receptor 2 (HER-2/neu)-Directed Therapy for Rare Metastatic Epithelial Tumors with HER-2 Amplification

    PubMed Central

    Shin, Daniel Sanghoon; Sherry, Timothy; Kallen, Michael E.; Wong, Steven; Drakaki, Alexandra

    2016-01-01

    Case 1 A 67-year-old Asian female was diagnosed with locally advanced high-grade salivary duct carcinoma in June 2011. Molecular analysis revealed human epidermal growth factor receptor 2 (HER-2) amplification. She received adjuvant therapy with carboplatin/paclitaxel/ trastuzumab and maintenance of trastuzumab. Upon disease progression, trastuzumab could not be continued due to lack of financial coverage. Instead, she was treated with compassionate use of lapatinib from April 2013 and standard 5-fluorouracil. Her disease ultimately progressed and she expired later in 2013. Case 2 A 68-year-old Asian male was diagnosed with extramammary Paget's disease of the scrotum with HER-2 amplification in May 2011. He received 6 cycles of adjuvant trastuzumab/docetaxel/carboplatin followed by maintenance trastuzumab, which was changed to compassionate use of lapatinib as his insurance did not cover further administration of trastuzumab. He showed clinical benefits from single-agent lapatinib and a combination of lapatinib/capecitabine upon progression to the single-agent lapatinib. Ultimately, he was started on ado-trastuzumab emtansine, which was approved at that time by the FDA for HER-2-positive breast cancer progressed on trastuzumab. He is having clinical and radiographic complete response based on current imaging and normalization of his tumor markers. Conclusion HER-2-targeted therapy should be considered for tumors with HER-2 amplification. In our case series, we would like to emphasize this approach in other rare histologies. Specifically, our patient with extramammary Paget's disease of the scrotum represents the first reported case of a non-breast, non-gastric tumor with HER-2 overexpression with complete clinical and radiographic response to HER-2-targeted therapy PMID:27403128

  3. HER2 expression in primary gastric cancers and paired synchronous lymph node and liver metastases. A possible road to target HER2 with radionuclides.

    PubMed

    Wei, Qichun; Xu, Jing; Shen, Li; Fu, Xianhua; Zhang, Bicheng; Zhou, Xiaofeng; Carlsson, Jorgen

    2014-07-01

    Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention. PMID:24643685

  4. Lack of a pharmacokinetic interaction between trastuzumab and carboplatin in the presence of docetaxel: results from a phase Ib study in patients with HER2-positive metastatic or locally advanced inoperable solid tumors.

    PubMed

    Eppler, Stephen; Gordon, Michael S; Redfern, Charles H; Trudeau, Caroline; Xu, Na; Han, Kelong; Lum, Bert L

    2015-04-01

    The objective of this study was to evaluate the potential for a pharmacokinetic (PK) drug-drug interaction (DDI) between trastuzumab and carboplatin and to evaluate the potential effect of trastuzumab on the electrocardiogram QT interval. Here, we report the results of the PK DDI assessment and an interim safety analysis. Patients with metastatic or locally advanced, inoperable, human epidermal growth factor receptor 2-positive cancer received docetaxel and carboplatin on cycle 1, day 1 and then on day 1 of each subsequent 3-weekly treatment cycle. Trastuzumab was administered by intravenous infusion, with an accelerated loading dose on cycle 1, day 2 and cycle 1, day 8, and then a maintenance dose on day 1 of each subsequent 3-weekly treatment cycle. Blood was collected at various time points to assess free (unbound) plasma carboplatin and serum trastuzumab PK. The study enrolled 59 patients. Carboplatin concentrations in the presence and absence of trastuzumab were similar, as demonstrated by the geometric mean ratios for PK parameters, which were close to 1.0 (no effect). The observed trastuzumab concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, computed using the actual sampling time. In this interim safety analysis, 84.5% of patients had experienced adverse events of grade three or higher, the most common of which were hematologic and as expected. The results suggest that there is no clinically relevant PK DDI between carboplatin and trastuzumab. The safety profile of trastuzumab plus carboplatin and docetaxel was consistent with the known safety profile of this combination. PMID:25643049

  5. HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery

    PubMed Central

    Geng, Lingling; Wang, Zihua; Jia, Xiangqian; Han, Qiuju; Xiang, Zhichu; Li, Dan; Yang, Xiaoliang; Zhang, Di; Bu, Xiangli; Wang, Weizhi; Hu, Zhiyuan; Fang, Qiaojun

    2016-01-01

    Herein, computational-aided one-bead-one-compound (OBOC) peptide library design combined with in situ single-bead sequencing microarray methods were successfully applied in screening peptides targeting at human epidermal growth factor receptor-2 (HER2), a biomarker of human breast cancer. As a result, 72 novel peptides clustered into three sequence motifs which are PYL***NP, YYL***NP and PPL***NP were acquired. Particularly one of the peptides, P51, has nanomolar affinity and high specificity for HER2 in ex vivo and in vivo tests. Moreover, doxorubicin (DOX)-loaded liposome nanoparticles were modified with peptide P51 or P25 and demonstrated to improve the targeted delivery against HER2 positive cells. Our study provides an efficient peptide screening method with a combination of techniques and the novel screened peptides with a clear binding site on HER2 can be used as probes for tumor imaging and targeted drug delivery. PMID:27279916

  6. A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis

    PubMed Central

    Leung, Kin-Mei; Batey, Sarah; Rowlands, Robert; Isaac, Samine J; Jones, Phil; Drewett, Victoria; Carvalho, Joana; Gaspar, Miguel; Weller, Sarah; Medcalf, Melanie; Wydro, Mateusz M; Pegram, Robert; Mudde, Geert C; Bauer, Anton; Moulder, Kevin; Woisetschläger, Max; Tuna, Mihriban; Haurum, John S; Sun, Haijun

    2015-01-01

    FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression. PMID:26234505

  7. Nano-pharmaceutical formulations for targeted drug delivery against HER2 in breast cancer.

    PubMed

    Sadat, Sams M A; Saeidnia, Soodabeh; Nazarali, Adil J; Haddadi, Azita

    2015-01-01

    Nanotechnology has revolutionized fundamental opportunities for higher specific drug delivery with minimum side effects. Since its inception, the goal of nanotechnology has been to advance effective and reliable systems for precise anti-cancer therapy and diagnosis. To accomplish this goal, bio-conjugation strategies of therapeutic agents loaded nanoparticles with monoclonal antibodies or their analogues have demonstrated a targeted approach both in vitro and in vivo. In this review, we primarily focus on the specific recognition of HER2 receptors of HER2 overexpressed tumor cells, and evaluate anti-HER2 monoclonal antibody as an effective tool for active targeting. Currently, a variety of nanoparticle systems are under both preclinical and clinical trials for targeting to HER2 positive breast cancer. Different nanotechnology scaffolds including liposomes, dendrimers, micelles, polymeric and inorganic nanoparticles that have higher flexibility for macromolecular synthesis and versatile functionalizing properties have been reviewed in this study. Continuing advances in anti-HER2 functionalized nanoparticles have good potential to lead to the development of nano-therapy against HER2 positive breast cancer. PMID:25564255

  8. Coexistence of HER2, Ki67, and p53 in Osteosarcoma: A Strong Prognostic Factor

    PubMed Central

    Mardanpour, Keykhosro; Rahbar, Mahtab; Mardanpour, Sourena

    2016-01-01

    Background: Many laboratories are currently evaluating the usefulness of the determination of human epidermal growth factor receptor 2 (HER2), p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in osteosarcoma patients, their clinical usefulness is still controversial. Aims: We proposed to introduce the value of the coexistence of HER2 overexpression, p53 protein accumulation, and Ki67 in osteosarcoma, which could be a prognostic factor in osteosarcoma. Material and Methods: Expression of HER2, p53, and Ki67 was examined by immunohistochemistry in samples of resected bone tumor tissue from 56 patients with osteosarcoma, obtained between 2009 and 2014 (median follow-up period of 48 months), and their significance for prognosis was analyzed. Results: Of the 56 osteogenic sarcoma tissue samples, 80, 89, and 96.5% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. Overexpression of HER2 and accumulation of p53 protein significantly correlated with reduced disease-free (P < 0.01) and overall survival (P < 0.003). HER2 and Ki67 co-overexpression significantly correlated with decreased disease-free (P < 0.03) and overall survival (P < 0.02). HER2, accumulation of p53 protein, and Ki67 co-overexpression significantly correlated with reduced disease-free (P < 0.01) and overall survival (P < 0.005) as did patients with larger tumor size, high grade of tumor, positive lymph node, and metastasis status within the specified period of follow up. Conclusions: We found evidence that coexistence of HER2 and Ki67 overexpression and p53 protein accumulation predict the development of lymph node involvement and metastases in patients with high-grade osteosarcoma and were significantly associated with reduced survival. PMID:27298815

  9. HER2 Status in Ovarian Carcinomas: A Multicenter GINECO Study of 320 Patients

    PubMed Central

    Tuefferd, Marianne; Couturier, Jérôme; Penault-Llorca, Frédérique; Vincent-Salomon, Anne; Broët, Philippe; Guastalla, Jean-Paul; Allouache, Djelila; Combe, Martin; Weber, Béatrice; Pujade-Lauraine, Eric; Camilleri-Broët, Sophie

    2007-01-01

    Background Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy. Methodology/Principal Findings The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases. Conclusions/Significance Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked. PMID:17987122

  10. [Study of Her-2/neu oncogene in relation to prognosis of human breast cancer].

    PubMed

    Chen, R S

    1993-10-01

    A follow-up study of 143 cases of human breast cancer for over 5 years proved that Her-2/neu oncogene overexpression is much more common in the high risk group (patients died within 5 years) in comparison with the low risk group (patients survived over 5 years). The difference between these 2 groups was statistically significant. The Her-2/neu oncogene positive rate in infiltrative ductal carcinoma was 33.3%, the lower the differentiation, the higher the positive rate. Histological typing is also related to the positive rate, comedocarcinoma (intraductal carcinoma) expresses the highest positive rate while lobular carcinoma the lowest. Selection of fixation fluid and the mastering of diagnostic criteria are also important. In the author's opinion, only membrane staining in monoclonal antibody C-erbB-2 can be recognized as truly positive. In conclusion, Her-2/neu oncogene expression can be used as a supplemental marker when considering prognosis in breast cancer. PMID:7909501

  11. Evaluation of the anti-HER2 C6.5 diabody as a PET radiotracer to monitor HER2 status and predict response to trastuzumab treatment

    PubMed Central

    Reddy, Smitha; Shaller, Calvin C.; Doss, Mohan; Shchaveleva, Irina; Marks, James D.; Yu, Jian Q.; Robinson, Matthew K.

    2011-01-01

    Purpose The rapid tumor targeting and pharmacokinetic properties of engineered antibodies make them potentially suitable for use in imaging strategies to predict and monitor response to targeted therapies. This study aims to evaluate C6.5 diabody (C6.5db), a non-covalent anti-HER2 single chain-Fv dimer, as a radiotracer for predicting response to HER2-targeted therapies such as trastuzumab. Experimental Design Immunodeficient mice bearing established HER2-positive tumor xenografts were injected with radioiodinated C6.5db and imaged using PET/CT. Radiotracer biodistribution was quantified using biopsied tumor and normal tissues. Potential competition between trastuzumab and C6.5db was examined in vitro by flow cytometry and co-immunoprecipitations. Results Biodistribution analysis of mice bearing xenografts with varying HER2 density revealed that the tumor uptake of 125I-C6.5db correlates with HER2 tumor density. In vitro competition experiments suggest that the C6.5db targets an epitope on HER2 that is distinct from that bound by trastuzumab. Treatment of SK-OV-3-tumored mice with trastuzumab for 3 d caused a 42% (P=0.002) decrease in tumor uptake of 125I-C6.5db. This is consistent with a dramatic decrease in the tumor PET signal of 124I-C6.5db after trastuzumab treatment. Furthermore, BT-474-tumored mice showed a ∼60% decrease (P=0.0026) in C6.5db uptake after 6 d of trastuzumab treatment. Immunohistochemistry of excised xenograft sections and in vitro flow cytometry revealed that the decreased C6.5db uptake upon trastuzumab treatment is not associated with HER2 downregulation. Conclusions These studies suggest that 124I-C6.5db-based imaging can be used to evaluate HER2 levels as a predictor of respone to HER2-directed therapies. PMID:21177408

  12. Is it necessary to evaluate nuclei in HER2 FISH evaluation?

    PubMed

    López, Carlos; Tomás, Barbara; Korzynska, Anna; Bosch, Ramón; Salvadó, Maria T; Llobera, Montserrat; Garcia-Rojo, Marcial; Alvaro, Tomás; Jaén, Joaquín; Lejeune, Marylène

    2013-01-01

    A new method that simplifies the evaluation of the traditional HER2 fluorescence in situ hybridization (FISH) evaluation in breast cancer was proposed. HER2 status was evaluated in digital images (DIs) captured from 423 invasive breast cancer stained sections. All centromeric/CEP17 and HER2 gene signals obtained from separated stacked DIs were manually counted on the screen. The global ratios were compared with the traditional FISH evaluation and the immunohistochemical status. The 2 FISH scores were convergent in 96.93% of cases, showing an "almost perfect" agreement with a weighted k of 0.956 (95% confidence interval, 0.928-0.985). The new method evaluates at least 3 times more nuclei than traditional methods and also has an almost perfect agreement with the immunohistochemical scores. The proposed enhanced method substantially improves HER2 FISH assessment in breast cancer biopsy specimens because the evaluation of HER2/CEP17 copy numbers is more representative, easier, and faster than the conventional method. PMID:23270898

  13. Adjuvant Medical Therapy for HER2-Positive Breast Cancer

    MedlinePlus

    ... the Licensed Materials from any location via the Internet. b. STANDALONE WORKSTATION: A standalone subscription permits multiple ... computer. A Standalone Workstation license does not include Internet access to the Licensed Materials. c. INSTITUTIONAL SUBSCRIPTION: ...

  14. A bispecific HER2-targeting FynomAb with superior antitumor activity and novel mode of action.

    PubMed

    Brack, Simon; Attinger-Toller, Isabella; Schade, Babette; Mourlane, Frédéric; Klupsch, Kristina; Woods, Richard; Hachemi, Helen; von der Bey, Ulrike; Koenig-Friedrich, Susann; Bertschinger, Julian; Grabulovski, Dragan

    2014-08-01

    Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. PMID:24994770

  15. In vivo photoacoustic imaging of breast cancer tumor with HER2-targeted nanodiamonds

    NASA Astrophysics Data System (ADS)

    Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Jo, Janggun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

    2013-09-01

    Radiation-damaged nanodiamonds (NDs) are ideal optical contrast agents for photoacoustic (PA) imaging in biological tissues due to their good biocompatibility and high optical absorbance in the near-infrared (NIR) range. Acid treated NDs are oxidized to form carboxyl groups on the surface, functionalized with polyethylene glycol (PEG) and human epidermal growth factor receptor 2 (HER2) targeting ligand for breast cancer tumor imaging. Because of the specific binding of the ligand conjugated NDs to the HER2-overexpressing murine breast cancer cells (4T1.2 neu), the tumor tissues are significantly delineated from the surrounding normal tissue at wavelength of 820 nm under the PA imaging modality. Moreover, HER2 targeted NDs (HER2-PEG-NDs) result in higher accumulation in HER2 positive breast tumors as compared to non-targeted NDs after intravenous injection (i.v.). Longer retention time of HER-PEG-NDs is observed in HER2 overexpressing tumor model than that in negative tumor model (4T1.2). This demonstrates that targeting moiety conjugated NDs have great potential for the sensitive detection of cancer tumors and provide an attractive delivery strategy for anti-cancer drugs.

  16. Testing for her2 in breast cancer: current pathology challenges faced in Canada.

    PubMed

    Hanna, W; Barnes, P; Berendt, R; Chang, M; Magliocco, A; Mulligan, A M; Rees, H; Miller, N; Elavathil, L; Gilks, B; Pettigrew, N; Pilavdzic, D; Sengupta, S

    2012-12-01

    This review is designed to highlight several key challenges in the diagnosis of human epidermal growth factor receptor 2 (her2)-positive breast cancer currently faced by pathologists in Canada: Pre-analysis issues affecting the accuracy of her2 testing in non-excision sample types: core-needle biopsies, effusion samples, fine-needle aspirates, and bone metastasesher2 testing of core-needle biopsies compared with surgical specimensCriteria for retesting her2 status upon disease recurrenceLiterature searches for each topic were carried out using the medline, Embase, International Pharmaceutical Abstracts, and biosis databases. In addition, the congress databases of the American Society of Clinical Oncology (2005-2011) and the San Antonio Breast Cancer Symposium (2007-2011) were searched for relevant abstracts.All authors are expert breast pathologists with extensive experience of her2 testing, and several participated in the development of Canadian her2 testing guidelines. For each topic, the authors present an evaluation of the current data available for the guidance of pathology practice, with recommendations for the optimization or improvement of her2 testing practice. PMID:23300357

  17. HER2-mediated anticancer drug delivery: strategies to prepare targeting ligands highly specific for the receptor.

    PubMed

    Calce, Enrica; Monfregola, Luca; Saviano, Michele; De Luca, Stefania

    2015-01-01

    HER2 receptor, for its involvement in tumorigenesis, has been largely studied as topic in cancer research. In particular, the employment of trastuzumab (Herceptin), a humanized anti-HER2 antibody, showed several clinical benefits in the therapy against the breast cancer. Moreover, for its accessible extracellular domain, this receptor is considered an ideal target to deliver anticancer drugs for the receptormediated anticancer therapy. By now, monoclonal antibody and its fragments, affibody, and some peptides have been employed as targeting agents in order to deliver various drugs to HER2 positive tumor cells. In particular, the ability to perform a fast and reliable screening of a large number of peptide molecules would make possible the selection of highly specific compounds to the receptor target. In this regard, the availability of preparing a simplified synthetic model which is a good mimetic of the receptor target and can be used in a reliable screening method of ligands would be of a strategic importance for the development of selective HER2-targeting peptide molecules. Herein, we illustrate the importance of HER2-targeted anticancer therapies. We also report on a synthetic and effective mimetic of the receptor, which revealed to be a useful tool for the selection of specific HER2 ligands. PMID:25994863

  18. PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

    PubMed Central

    2014-01-01

    Background HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Results Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Conclusions Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies. PMID:24958351

  19. A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors.

    PubMed

    Limentani, Steven A; Campone, Mario; Dorval, Thierry; Curigliano, Giuseppe; de Boer, Richard; Vogel, Charles; White, Shane; Bachelot, Thomas; Canon, Jean-Luc; Disis, Mary; Awada, Ahmad; Berlière, Martine; Amant, Frédéric; Levine, Ellis; Burny, Wivine; Callegaro, Andrea; de Sousa Alves, Pedro Miguel; Louahed, Jamila; Brichard, Vincent; Lehmann, Frédéric F

    2016-04-01

    This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations. PMID:26993131

  20. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor.

    PubMed

    Blackwell, Kimberly; Burris, Howard; Gomez, Patricia; Lynn Henry, N; Isakoff, Steven; Campana, Frank; Gao, Lei; Jiang, Jason; Macé, Sandrine; Tolaney, Sara M

    2015-11-01

    This phase I/II dose-escalation study evaluated the efficacy, safety, and pharmacokinetics of pilaralisib (SAR245408), a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, or voxtalisib (SAR245409), a PI3K and mammalian target of rapamycin inhibitor, in combination with letrozole in hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, non-steroidal aromatase inhibitor-refractory, recurrent or metastatic breast cancer. Maximum tolerated doses (MTDs) were determined using a 3 + 3 design in phase I. Efficacy was evaluated at the MTDs in phase II. Twenty-one patients were enrolled in phase I; MTDs were determined to be pilaralisib tablets 400 mg once daily (QD) or voxtalisib capsules 50 mg twice daily in combination with letrozole tablets 2.5 mg QD. Fifty-one patients were enrolled in phase II; one patient had a partial response in the pilaralisib arm. Rates of progression-free survival at 6 months were 17 and 8 % in the pilaralisib and voxtalisib arms, respectively. The most frequently reported treatment-related grade ≥ 3 adverse events were aspartate aminotransferase increased (5 %) and rash (5 %) in the pilaralisib arm, and alanine aminotransferase increased (11 %) and rash (9 %) in the voxtalisib arm. Pilaralisib and voxtalisib did not interact pharmacokinetically with letrozole. Pilaralisib had a greater pharmacodynamic impact than voxtalisib, as demonstrated by its impact on glucose homeostasis. There was no association between molecular alterations in the PI3K pathway and efficacy. In summary, pilaralisib or voxtalisib, in combination with letrozole, was associated with an acceptable safety profile and limited efficacy in endocrine therapy-resistant HR+ , HER2-negative metastatic breast cancer. PMID:26497877

  1. Anti-HER-2 DNA vaccine protects Syrian hamsters against squamous cell carcinomas

    PubMed Central

    Berta, G N; Mognetti, B; Spadaro, M; Trione, E; Amici, A; Forni, G; Di Carlo, F; Cavallo, F

    2005-01-01

    This paper illustrates the efficacy of DNA vaccination through electroporation in the prevention of oral transplantable carcinoma in Syrian hamsters. At 21 and 7 days before tumour challenge, 19 hamsters were vaccinated with plasmids coding for the extracellular and transmembrane domains of rat HER-2 receptor (EC-TM plasmids), whereas 19 control hamsters were injected intramuscularly with the empty plasmid. Immediately following plasmid injection, hamsters of both groups received two square-wave 25 ms, 375 V cm−1 electric pulses via two electrodes placed on the skin of the injection area. At day 0, all hamsters were challenged in the submucosa of the right cheek pouch with HER-2-positive HCPC I cells established in vitro from an 7,12-dimethylbenz[a]anthracene-induced oral carcinoma. This challenge gave rise to HER-2-positive buccal neoplastic lesions in 14 controls (73.37%), compared with only seven (36.8%, P<0.0027) vaccinated hamsters. In addition, the vaccinated hamsters displayed both a stronger proliferative and cytotoxic response than the controls and a significant anti-HER-2 antibody response. Most of the hamsters that rejected the challenge displayed the highest antibody titres. These findings suggest that DNA vaccination may have a future in the prevention of HER-2-positive human oral cancer. PMID:16265350

  2. HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity.

    PubMed

    Peipp, Matthias; Derer, Stefanie; Lohse, Stefan; Staudinger, Matthias; Klausz, Katja; Valerius, Thomas; Gramatzki, Martin; Kellner, Christian

    2015-10-13

    NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy. PMID:26392331

  3. HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity

    PubMed Central

    Peipp, Matthias; Derer, Stefanie; Lohse, Stefan; Staudinger, Matthias; Klausz, Katja; Valerius, Thomas; Gramatzki, Martin; Kellner, Christian

    2015-01-01

    NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy. PMID:26392331

  4. Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer

    PubMed Central

    Kanematsu, Masako; Futamura, Manabu; Takata, Masafumi; Gaowa, Siqin; Yamada, Atsuko; Morimitsu, Kasumi; Morikawa, Akemi; Mori, Ryutaro; Hara, Hideaki; Yoshida, Kazuhiro

    2015-01-01

    Glycoprotein nonmetastatic B (GPNMB) is a potential oncogene that is particularly expressed in melanoma and breast cancer (BC). To clarify its clinical significance in BC, we measured serum GPNMB in vivo and investigated its cross talk with human epidermal growth factor 2 (HER2). GPNMB was expressed in four of six breast cell lines (SK-BR-3, BT-474, MDA-MD-231, and MDA-MD-157), two of six colorectal cell lines, and two of four gastric cancer (GC) cell lines. We established a GPNMB quantification system using enzyme-linked immunosorbent assay (ELISA) for these cell lines. We measured serum GPNMB in vivo in 162 consecutive BC patients and in 88 controls (50 colorectal cancer [CC] and 38 GC patients). The GPNMB concentration in BC, CC and GC was 8.163, 5.751 and 6.55 ng/mL, respectively. The GPNMB level was significantly higher in BC patients than in CC patients (P = 0.021). The HER2-rich subtype of BC patients had significantly higher GPNMB levels than other subtypes (vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195). These high GPNMB levels decreased after treatment (surgery/chemotherapy). Next, we examined the relationship between GPNMB and HER2 in vitro using SK-BR3 and BT-474 (HER2-positive/GPNMB-positive) cells. GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation. Trastuzumab (Tra) in combination with docetaxel promoted cell growth inhibition, and treatment with Tra or an Extracellular signal-related kinase (ERK) inhibitor enhanced GPNMB expression. These results indicate that GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. GPNMB may therefore emerge as an important player in anti-HER2 therapy. PMID:26077887

  5. Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-07-22

    BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  6. 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. PMID:27220749

  7. Identifying HER2 Inhibitors from Natural Products Database

    PubMed Central

    Yang, Shun-Chieh; Chang, Su-Sen; Chen, Calvin Yu-Chian

    2011-01-01

    The relationship between abnormal HER2 expression and cancer is important in cancer therapeutics. Formation and spread of cancer cells may be restricted by inhibiting HER2. We conducted ligand-based and structure-based studies to assess the potency of natural compounds as potential HER2 inhibitors. Multiple linear regression (MLR) and support vector machine (SVM) models were constructed to predict biological activities of natural compounds, and molecular dynamics (MD) was used to assess their stability with HER2 under a dynamic environment. Predicted bioactivities of the natural compounds ranged from 6.014–9.077 using MLR (r2 = 0.7954) and 5.122–6.950 using SVM (r2 = 0.8620). Both models were in agreement and suggest bioactivity based on candidate structure. Conformation changes caused by MD favored the formation of stabilizing H-bonds. All candidates had higher stability than Lapinatib, which may be due to the number and spatial distribution of additional H-bonds and hydrophobic interactions. Amino acids Lys724 and Lys736 are critical for binding in HER2, and Thr798, Cys805, and Asp808 are also important for increased stability. Candidates may block the entrance to the ATP binding site located within the inner regions and prevent downstream activation of HER2. Our multidirectional approach indicates that the natural compounds have good ligand efficacy in addition to stable binding affinities to HER2, and should be potent candidates of HER2 inhibitors. With regard to drug design, designing HER2 inhibitors with carboxyl or carbonyl groups available for H-bond formation with Lys724 and Lys736, and benzene groups for hydrophobic contact with Cys805 may improve protein-ligand stability. PMID:22174899

  8. Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer

    ClinicalTrials.gov

    2016-09-15

    Ductal Breast Carcinoma In Situ; Estrogen Receptor and/or Progesterone Receptor Positive; HER2/Neu Negative; Invasive Breast Carcinoma; Multicentric Breast Carcinoma; Multifocal Breast Carcinoma; Synchronous Bilateral Breast Carcinoma

  9. Current HER2 Testing Recommendations and Clinical Relevance as a Predictor of Response to Targeted Therapy.

    PubMed

    Ballinger, Tarah J; Sanders, Melinda E; Abramson, Vandana G

    2015-06-01

    Clinical decision-making in the treatment of breast cancer depends on an accurate determination and understanding of human epidermal growth factor receptor 2 (HER2) status. The guidelines for HER2 testing were recently updated in late 2013, but limitations continue to exist in the interpretation and clinical application of results when the tumor specimens do not fall neatly into positive or negative categories with immunohistochemistry and fluorescence in situ hybridization testing. The issues, including discordance between pathologists or laboratories, polysomy, and genetic heterogeneity, present challenging situations that are difficult to translate into clinical significance. The present review discussed the changes in the updated American Society of Clinical Oncology/College of American Pathologists guidelines, the clinical relevance of complex issues in HER2 testing, and the implications of the results on the response to HER2-targeted therapies. Great advances have been made in the treatment of HER2-positive breast cancer; however, the challenge remains to determine the best testing analysis that will identify patients who will benefit the most from these therapies. PMID:25516402

  10. [Immunochemistry evaluation of HER2 status in infiltration breast cancer: technical protocol and interpretation guidelines].

    PubMed

    Penault-Llorca, Frédérique; Balaton, André; Sabourin, Jean-Christophe; Le Doussal, Viviane

    2002-04-01

    In Europe, patients who may benefit from Herceptin((R)) (an HER2 targeted drug) are currently selected by immunohistochemistry (IHC). Reliable detection of HER2 status is essential to the appropriate usage of Herceptin(R), because its specificity is limited to tumours overexpressing HER2. It is essential that the IHC evaluation of the HER2 status of a mammary carcinoma be optimized and reliable. This technical paper reviews the different steps of the IHC technique, the controls and, the rules for interpretation. The sensitivity of the IHC technique must be adjusted so as not to produce false negatives or false positives. As opposed to other methods, it can be carried out whatever the fixation conditions of the tissues. The interpretation of the immunostains also requires training; it is fraught with problems for intermediate positivities. The ideal score to evaluate HER2 status has not yet been defined. It will thus be necessary to report the percentage of stained cells, the intensity of the staining, and, in respect to Herceptin((R)) treatment, the HercepTest scoring system (recommended in the package insert). Once acquired, this knowledge must be perpetuated by the observation of rules of good technical practice (internal and external controls, quality assurance programs). FISH should be used for complementary assessment of 2+ cases (on condition that they have not been fixed in Bouin's liquid) and for the calibration of the IHC technique. PMID:12124503

  11. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT

    PubMed Central

    Sörensen, Jens; Velikyan, Irina; Sandberg, Dan; Wennborg, Anders; Feldwisch, Joachim; Tolmachev, Vladimir; Orlova, Anna; Sandström, Mattias; Lubberink, Mark; Olofsson, Helena; Carlsson, Jörgen; Lindman, Henrik

    2016-01-01

    Purpose: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with 68Ga-gallium ([68Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology. Experimental design: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [68Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [68Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [68Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization. Results: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [68Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients. Conclusion: [68Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer. PMID:26877784

  12. Her2+ and b-HCG Producing Undifferentiated Gastric Adenocarcinoma

    PubMed Central

    Eivaz-Mohammadi, Sahar; Tarar, Omer; Malik, Khurram; Syed, Amer K.

    2014-01-01

    A 25-year-old Hispanic female with a history of anemia, schizoaffective disorder, and psychosis was admitted for anemia associated with fatigue, weakness, shortness of breath, night sweats, weight loss, and abdominal and lower back pain for the past two months. On routine management, she was found to have a positive serum b-HCG of 80.4 (0–5 mIU/mL) but the patient denied any sexual activity in her life. During her admission, U/S of the pelvis was noncontributory. CT angiogram of the chest was significant for prominent mediastinal and hilar lymph nodes, diffusely thickened stomach suggesting gastric malignancy with multiple hypoenhancing lesions in the liver and diffuse lytic lesions in the spine and sacrum suspicious for metastatic disease. The MRI of the abdomen confirmed the CT angiogram findings. After these findings, EGD was performed which showed lesions in the antrum, body of the stomach, fundus, and cardia on the lesser curvature of the stomach body correlating with carcinoma. The biopsy was positive for Her2, b-HCG producing poorly differentiated gastric adenocarcinoma. Patient underwent one successful round of chemotherapy with Taxotene, Cisplatin, and 5-FU for Stage IV gastric adenocarcinoma. PMID:25349615

  13. HER-2/neu and E-cadherin Expression and Microsatellite Instability in Gastric Dysplasia

    PubMed Central

    Ahmadi, L; Kamkari, S; Mokarram, P; Lankarani, K Bagheri; Tabibi, N; Ashktorab, H; Vasei, M

    2011-01-01

    BACKGROUND Gastric dysplasia (GD) is a precursor lesion of gastric adenocarcinoma. Intestinal type gastric carcinoma commonly shows microsatellite instability (MSI) and the diffuse type is associated with down regulation of E-cadherin. HER-2/neu is over-expressed in some cases of gastric cancer. In this study, MSI and expression rates of HER-2/neu and E-cadherin in GD were evaluated. METHODS Paraffin blocks of 21 cases of low grade dysplasia (LD), 11 cases of high grade dysplasia (HD) and 25 cases of indefinite for dysplasia (ID) were collected. After deparaffinization and antigen retrieval, the sections were incubated with antibodies against E-cadherin, hMLH1, hMSH2 and HER-2/neu. The streptavidin-biotin complex method was used followed by peroxidase enzyme development with diaminobenzidine. RESULTS HER-2/neu was positive in six cases of HD (50%), four LD (21%) and two ID (9%). E-cadherin was absent in two cases of LD and showed normal expression in all HD and ID cases. hMLH1 expression was absent or markedly decreased only in the zones of dysplasia in HD (3/11), LD (3/21) and ID (4/25). Absence or diminished expression of hMSH2 was seen in HD (3/11), LD (2/21) and ID (3/25) cases. HER-2/neu expression showed close association with diminished expression of hMLH1 or hMSH2 (p < 0.05). CONCLUSION Stepwise increase in the expression rate of HER-2/neu was seen in ID, LD and HD cases implying its role in cancer evolution. The absence of hMLH1 and hMSH2 in GD may predispose individuals to over-expression of other oncogenes such as HER-2/neu. Abnormal expression of E-cadherin is not a frequent finding in GD. PMID:25197528

  14. A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis▿ †

    PubMed Central

    Pedersen, Kim; Angelini, Pier-Davide; Laos, Sirle; Bach-Faig, Alba; Cunningham, Matthew P.; Ferrer-Ramón, Cristina; Luque-García, Antonio; García-Castillo, Jesús; Parra-Palau, Josep Lluis; Scaltriti, Maurizio; y Cajal, Santiago Ramón; Baselga, José; Arribas, Joaquín

    2009-01-01

    HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis. PMID:19364815

  15. Droplet digital PCR measurement of HER2 in patients with gastric cancer

    PubMed Central

    Kinugasa, H; Nouso, K; Tanaka, T; Miyahara, K; Morimoto, Y; Dohi, C; Matsubara, T; Okada, H; Yamamoto, K

    2015-01-01

    Background: Although there are some new criteria for human epidermal growth factor receptor 2 (HER2) expression with immunohistochemistry/fluorescence in situ hybridisation (IHC/FISH) in gastric cancer, the method is still ambiguous and is somewhat dependent on the subjective qualities of the evaluator. Methods: We used droplet digital polymerase chain reaction (ddPCR) to evaluate HER2 amplification in formalin-fixed and paraffin-embedded (FFPE) samples and cell-free serum circulating tumour DNA (ctDNA) in 25 patients with gastric cancer. Results: The concordance rate of HER2 amplification examined in FFPE samples with ddPCR and IHC/FISH was 92% (23 out of 25). The concordance rate of FFPE with ctDNA was not high (62.5%); however, patients who were HER2-positive by ctDNA had significantly shorter survival compared with HER2-negative patients. Conclusions: Our results demonstrated that this ddPCR method was as effective as IHC/FISH and therefore might become a standard method for analysing not only FFPE but also ctDNA. PMID:25897674

  16. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    PubMed

    Jones, J; Takeda, A; Picot, J; von Keyserlingk, C; Clegg, A

    2009-10-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of lapatinib for the treatment of advanced or metastatic HER2-overexpressing breast cancer based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The scope included women with advanced, metastatic or recurrent HER2-overexpressing breast cancer who have had previous therapy that includes trastuzumab. Outcomes were time to progression, progression-free survival, response rates, overall survival, health-related quality of life and adverse effects. The submission's evidence came from one randomised controlled trial (RCT) of reasonable methodological quality, although it was not powered to detect a statistically significant difference in mean overall survival. Median time to progression was longer in the lapatinib plus capecitabine arm than in the capecitabine monotherapy arm {27.1 [95% confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% CI 0.43 to 0.77; p = 0.00013]}. Median overall survival was very similar between the groups [67.7 (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 to 1.12; p = 0.177)]. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer's economic model to estimate progression-free and overall survival for patients with HER2-positive advanced/metastatic breast cancer who had relapsed following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease area. The base-case incremental cost-effectiveness ratios (ICERs) for lapatinib plus

  17. SU-E-I-81: Targeting of HER2-Expressing Tumors with Dual PET-MR Imaging Probes

    SciTech Connect

    Xu, P; Peng, Y; Sun, M; Yang, X

    2015-06-15

    Purpose: The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Trastuzumab, effective in about 15 % of women with breast cancer, downregulates signalling through the Akt/PI3K and MAPK pathways.These pathways modulate metabolism which can be monitored by positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: The relationship between response of HER2 overexpressing tumours and changes in imaging PET or SPECT and MRI will be examined by a integrated bimodal imaging probe.Small (7 kDa) high-affinity anti-HER2 Affibody molecules and KCCYSL targeting peptide may be suitable tracers for visualization of HER2-expressing tumors. Peptide-conjugated iron oxide nanoparticles (Fe3O4 NPs) as MRI imaging and CB-TE2A as PET imaging are integrated into a single synthetic molecule in the HER2 positive cancer. Results: One of targeted contrast bimodal imaging probe agents was synthesized and evaluated to target HER2-expressing tumors in a HER2 positive rat model. We will report the newest results regarding the development of bimodal imaging probes. Conclusion: The preliminary results of the bimodal imaging probe presents high correlation of MRI signal and PET imaging intensity in vivo. This unique feature can hardly be obtained by single model contrast agents. It is envisioned that this bimodal agents can hold great potential for accurate detection of HER2-expressing tumors which are critical for clinical management of the disease.

  18. HER-2 expression in biopsy and surgical specimen on prognosis of osteosarcoma

    PubMed Central

    Zhang, Qingyu; Liu, Fanxiao; Wang, Bomin; Li, Zhenfeng; Zhou, Dongsheng; Yang, Qiang; Dong, Jinlei; Li, Jianmin

    2016-01-01

    Abstract Numerous original clinical studies have attempted to investigate the prognostic value of HER-2 overexpression in osteosarcoma, but the results of these studies are not consistent. This meta-analysis and systematic review was performed to further assess the correlation between HER-2 expression and prognosis in patients with osteosarcoma. A detailed search of relevant publications was conducted using 7 electronic databases: PubMed, Embase, the Cochrane library, the Wanfang database, the China National Knowledge Internet (CNKI) database, the Chinese VIP database, and the Chinese Biological Medical (CBM) Database for publications through August 1, 2015, using the following keywords (HER-2 OR ErbB-2 OR C-erbB-2 OR neu) AND (osteosarcoma OR osteogenic tumor). The bibliographies of potentially relevant articles and identified articles were then searched by hand. Eligible studies were those that enrolled participants with osteosarcoma and provided survival outcome in HER-2 positive and negative groups. The hazard ratio (HR) and 95% confidence interval (CI) for each individual study was calculated and pooled to obtain integrated estimates, using random effects modeling. Sixteen studies involving 934 participants with osteosarcoma met our inclusion criteria. HER-2 overexpression was documented in 42.2% of patients with osteosarcoma. Compared with patients without HER-2 overexpression, those overexpressing HER-2 had decreased overall survival (HR = 2.03, 95% CI: 1.36–3.03, P < 0.001). Statistical associations between HER-2 overexpression and unfavorable overall survival (OS) were observed for both biopsy and surgical removal specimens (HR = 2.07, 95%CI: 1.16–3.72, P = 0.014; and HR = 2.02, 95%CI: 1.10–3.71, P = 0.024). Results for disease-free survival (DFS) were similar. Overexpression of HER-2 is significantly associated with poor outcome for patients with osteosarcoma and should be assessed at diagnosis and after surgery as a prognostic factor. However

  19. ATM: An unexpected tumor-promoting factor in HER2-expressing tumors

    PubMed Central

    Stagni, Venturina; Oropallo, Veronica; Barilà, Daniela

    2016-01-01

    ABSTRACT ATM kinase is a gatekeeper of genome stability. However, its role in several other signaling pathways suggests that it might not always act as a tumor suppressor. Here, we discuss recent data that unveil a function of ATM as a tumor promoter in HER2-positive breast cancer. PMID:27308589

  20. Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy

    PubMed Central

    Peckys, Diana B.; Korf, Ulrike; de Jonge, Niels

    2015-01-01

    The formation of HER2 homodimers plays an important role in breast cancer aggressiveness and progression; however, little is known about its localization. We have studied the intra- and intercellular variation of HER2 at the single-molecule level in intact SKBR3 breast cancer cells. Whole cells were visualized in hydrated state with correlative fluorescence microscopy and environmental scanning electron microscopy (ESEM). The locations of individual HER2 receptors were detected using an anti-HER2 affibody in combination with a quantum dot (QD), a fluorescent nanoparticle. Fluorescence microscopy revealed considerable differences of HER2 membrane expression between individual cells and between different membrane regions of the same cell (that is, membrane ruffles and flat areas). Subsequent ESEM of the corresponding cellular regions provided images of individually labeled HER2 receptors. The high spatial resolution of 3 nm and the close proximity between the QD and the receptor allowed quantifying the stoichiometry of HER2 complexes, distinguishing between monomers, dimers, and higher-order clusters. Downstream data analysis based on calculating the pair correlation function from receptor positions showed that cellular regions exhibiting membrane ruffles contained a substantial fraction of HER2 in homodimeric state. Larger-order clusters were also present. Membrane areas with homogeneous membrane topography, on the contrary, displayed HER2 in random distribution. Second, HER2 homodimers appeared to be absent from a small subpopulation of cells exhibiting a flat membrane topography, possibly resting cells. Local differences in homodimer presence may point toward functional differences with possible relevance for studying metastasis and drug response. PMID:26601217

  1. Antitumor Activity of a Monoclonal Antibody Targeting Major Histocompatibility Complex Class I–Her2 Peptide Complexes

    PubMed Central

    2013-01-01

    Background Applications of trastuzumab are limited to breast cancer patients with high Her2-expressing tumors. We developed a T-cell receptor mimic (TCRm) monoclonal antibody (hereafter called RL1B) that targets the Her2-E75 peptide (residues 369–377)–HLA-A2 complex and examined its effects in Her2-expressing cancer cells. Methods RL1B binding affinity was determined by surface plasmon resonance and specificity was demonstrated using Her2 antigen-positive and negative tumor cell lines. Immunohistochemistry was used to assess binding to frozen sections of human carcinomas (n = 3). Antitumor activity mediated by RL1B and trastuzumab against Her2+ tumor cell lines was evaluated using the WST-1 cell viability assay and caspase-3 and poly(ADP-ribose) polymerase cleavage assays. A xenograft mouse model (n = 6 per group) was used to assess RL1B antitumor activity. Mechanisms of RL1B-mediated cytotoxicity were evaluated with confocal microscopy, flow cytometry, and histology. All statistical tests were two-sided. Results RL1B bound with high specificity and affinity to the E75 peptide–HLA-A2 complex in all Her2+ and HLA-A2+ cancer cell lines and human carcinomas. Compared with control antibody, RL1B suppressed growth of low Her2–expressing breast tumors in mice (mean volume, RL1B vs control = 241mm3 vs 1531mm3; P = .0109) and statistically significantly increased mouse survival (P = .0098). It reduced viability compared to control monoclonal antibody–treated cells and statistically significantly increased caspase 3 activation of all Her2+ carcinoma cell lines tested, whereas trastuzumab induced apoptosis only in high Her2–expressing cancer cells. Mechanisms of RL1B cytotoxicity were associated with antibody internalization and intracellular signaling. Conclusion The TCRm RL1B could be a new approach to immunotherapy of Her2-expressing malignancies. PMID:23300219

  2. 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

  3. Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy.

    PubMed

    Peckys, Diana B; Korf, Ulrike; de Jonge, Niels

    2015-07-01

    The formation of HER2 homodimers plays an important role in breast cancer aggressiveness and progression; however, little is known about its localization. We have studied the intra- and intercellular variation of HER2 at the single-molecule level in intact SKBR3 breast cancer cells. Whole cells were visualized in hydrated state with correlative fluorescence microscopy and environmental scanning electron microscopy (ESEM). The locations of individual HER2 receptors were detected using an anti-HER2 affibody in combination with a quantum dot (QD), a fluorescent nanoparticle. Fluorescence microscopy revealed considerable differences of HER2 membrane expression between individual cells and between different membrane regions of the same cell (that is, membrane ruffles and flat areas). Subsequent ESEM of the corresponding cellular regions provided images of individually labeled HER2 receptors. The high spatial resolution of 3 nm and the close proximity between the QD and the receptor allowed quantifying the stoichiometry of HER2 complexes, distinguishing between monomers, dimers, and higher-order clusters. Downstream data analysis based on calculating the pair correlation function from receptor positions showed that cellular regions exhibiting membrane ruffles contained a substantial fraction of HER2 in homodimeric state. Larger-order clusters were also present. Membrane areas with homogeneous membrane topography, on the contrary, displayed HER2 in random distribution. Second, HER2 homodimers appeared to be absent from a small subpopulation of cells exhibiting a flat membrane topography, possibly resting cells. Local differences in homodimer presence may point toward functional differences with possible relevance for studying metastasis and drug response. PMID:26601217

  4. 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

  5. HER2-targeted immunotoxins with low nonspecific toxicity and immunogenicity.

    PubMed

    Guo, Rui; Cao, Li; Guo, Wenjun; Liu, Hui; Xu, Hua; Fang, Qi; Hong, Zhangyong

    2016-06-17

    Immunotoxins have efficient anti-tumor activity due to their extreme potency. However, dose-limiting off-target toxicity and immunogenicity are the critical barriers for these immunotoxins to be used in a clinical setting. In this study, we designed a Pseudomonas exotoxin A (PE)-based human epidermal growth factor receptor-2 (HER2)-specific immunotoxin HER2-PE25-X7 by deleting most of domain II and introducing seven point mutations into domain III of the PE38 toxin. The anti-cancer activity, off-target toxicity and immunogenicity of this immunotoxin were carefully evaluated in vitro and in vivo. This new construct maintained the therapeutic potency of the original PE38-based immunotoxin HER2-PE38, with a greatly reduced off-target toxicity and immunogenicity. To compare with HER2-PE38, which resulted in the death of most of the mice after a single dose of 1.0 mg/kg, the new construct was completely tolerated at a dose of 10 mg/kg by the mice and almost completely depleted the tumor after treatment with five doses of 5 mg/kg of the immunotoxin. This work demonstrates a potentially attractive therapeutic modality for HER2-specific cancer treatment. PMID:27178207

  6. EGFR, HER-2 and KRAS in canine gastric epithelial tumors: a potential human model?

    PubMed

    Terragni, Rossella; Casadei Gardini, Andrea; Sabattini, Silvia; Bettini, Giuliano; Amadori, Dino; Talamonti, Chiara; Vignoli, Massimo; Capelli, Laura; Saunders, Jimmy H; Ricci, Marianna; Ricci, Marianna; Ulivi, Paola; Ulivi, Paola

    2014-01-01

    Epidermal growth factor receptor (EGFR or HER-1) and its analog c-erbB-2 (HER-2) are protein tyrosine kinases correlated with prognosis and response to therapy in a variety of human cancers. KRAS mediates the transduction of signals between EGFR and the nucleus, and its mutation has been identified as a predictor of resistance to anti-EGFR drugs. In human oncology, the importance of the EGFR/HER-2/KRAS signalling pathway in gastric cancer is well established, and HER-2 testing is required before initiating therapy. Conversely, this pathway has never been investigated in canine gastric tumours. A total of 19 canine gastric epithelial neoplasms (5 adenomas and 14 carcinomas) were retrospectively evaluated for EGFR/HER-2 immunohistochemical expression and KRAS mutational status. Five (35.7%) carcinomas were classified as intestinal-type and 9 (64.3%) as diffuse-type. EGFR was overexpressed (≥ 1+) in 8 (42.1%) cases and HER-2 (3+) in 11 (57.9%) cases, regardless of tumour location or biological behaviour. The percentage of EGFR-positive tumours was significantly higher in the intestinal-type (80%) than in the diffuse-type (11.1%, p = 0.023). KRAS gene was wild type in 18 cases, whereas one mucinous carcinoma harboured a point mutation at codon 12 (G12R). EGFR and HER-2 may be promising prognostic and therapeutic targets in canine gastric epithelial neoplasms. The potential presence of KRAS mutation should be taken into account as a possible mechanism of drug resistance. Further studies are necessary to evaluate the role of dog as a model for human gastric cancer. PMID:24454858

  7. EGFR, HER-2 and KRAS in Canine Gastric Epithelial Tumors: A Potential Human Model?

    PubMed Central

    Bettini, Giuliano; Amadori, Dino; Talamonti, Chiara; Vignoli, Massimo; Capelli, Laura; Saunders, Jimmy H.; Ricci, Marianna; Ulivi, Paola

    2014-01-01

    Epidermal growth factor receptor (EGFR or HER-1) and its analog c-erbB-2 (HER-2) are protein tyrosine kinases correlated with prognosis and response to therapy in a variety of human cancers. KRAS mediates the transduction of signals between EGFR and the nucleus, and its mutation has been identified as a predictor of resistance to anti-EGFR drugs. In human oncology, the importance of the EGFR/HER-2/KRAS signalling pathway in gastric cancer is well established, and HER-2 testing is required before initiating therapy. Conversely, this pathway has never been investigated in canine gastric tumours. A total of 19 canine gastric epithelial neoplasms (5 adenomas and 14 carcinomas) were retrospectively evaluated for EGFR/HER-2 immunohistochemical expression and KRAS mutational status. Five (35.7%) carcinomas were classified as intestinal-type and 9 (64.3%) as diffuse-type. EGFR was overexpressed (≥1+) in 8 (42.1%) cases and HER-2 (3+) in 11 (57.9%) cases, regardless of tumour location or biological behaviour. The percentage of EGFR-positive tumours was significantly higher in the intestinal-type (80%) than in the diffuse-type (11.1%, p = 0.023). KRAS gene was wild type in 18 cases, whereas one mucinous carcinoma harboured a point mutation at codon 12 (G12R). EGFR and HER-2 may be promising prognostic and therapeutic targets in canine gastric epithelial neoplasms. The potential presence of KRAS mutation should be taken into account as a possible mechanism of drug resistance. Further studies are necessary to evaluate the role of dog as a model for human gastric cancer. PMID:24454858

  8. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry.

    PubMed

    Peña, L; Gama, A; Goldschmidt, M H; Abadie, J; Benazzi, C; Castagnaro, M; Díez, L; Gärtner, F; Hellmén, E; Kiupel, M; Millán, Y; Miller, M A; Nguyen, F; Poli, A; Sarli, G; Zappulli, V; de las Mulas, J Martín

    2014-01-01

    Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms. PMID:24227007

  9. Pomolic acid inhibits metastasis of HER2 overexpressing breast cancer cells through inactivation of the ERK pathway.

    PubMed

    Kim, Buyun; Kim, Yu Chul; Park, Byoungduck

    2016-08-01

    Expression of the CXC chemokine receptor-4 (CXCR4), a G protein-coupled receptor, and HER2, a receptor tyrosine kinase, strongly correlates with tumor progression and metastatic potential of breast cancer cells. We report the identification of pomolic acid (PA) as a novel regulator of HER2 and CXCR4 expression. We found that PA downregulated the expression of HER2 and CXCR4 in SKBR3 cells in a dose- and time-dependent manner. When investigated for the molecular mechanism(s), it was found that the downregulation of HER2 and CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation as indicated by downregulation of mRNA expression. Moreover, we show that PA inhibits phosphorylation of ERK and reduces NF-κB activation. Suppression of CXCR4 expression by PA correlated with the inhibition of CXCL12-induced invasion of HER2-overexpressing breast cancer cells. Overall, our results demonstrate for the first time that PA is a novel inhibitor of HER2 and CXCR4 expression via kinase pathways and may play a critical role in determining the metastatic potential of breast cancer cells. PMID:27277173

  10. PiggyBac-mediated Cancer Immunotherapy Using EBV-specific Cytotoxic T-cells Expressing HER2-specific Chimeric Antigen Receptor

    PubMed Central

    Nakazawa, Yozo; Huye, Leslie E; Salsman, Vita S; Leen, Ann M; Ahmed, Nabil; Rollins, Lisa; Dotti, Gianpietro; Gottschalk, Stephen M; Wilson, Matthew H; Rooney, Cliona M

    2011-01-01

    Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can be modified to function as heterologous tumor directed effector cells that survive longer in vivo than tumor directed T cells without virus specificity, due to chronic stimulation by viral antigens expressed during persistent infection in seropositive individuals. We evaluated the nonviral piggyBac (PB) transposon system as a platform for modifying EBV-CTLs to express a functional human epidermal growth factor receptor 2-specific chimeric antigen receptor (HER2-CAR) thereby directing virus-specific, gene modified CTLs towards HER2-positive cancer cells. Peripheral blood mononuclear cells (PBMCs) were nucleofected with transposons encoding a HER2-CAR and a truncated CD19 molecule for selection followed by specific activation and expansion of EBV-CTLs. HER2-CAR was expressed in ~40% of T cells after CD19 selection with retention of immunophenotype, polyclonality, and function. HER2-CAR-modified EBV-CTLs (HER2-CTLs) killed HER2-positive brain tumor cell lines in vitro, exhibited transient and reversible increases in HER2-CAR expression following antigen-specific stimulation, and stably expressed HER2-CAR beyond 120 days. Adoptive transfer of PB-modified HER2-CTLs resulted in tumor regression in a murine xenograft model. Our results demonstrate that PB can be used to redirect virus-specific CTLs to tumor targets, which should prolong tumor-specific T cell survival in vivo producing more efficacious immunotherapy. PMID:21772253

  11. Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

    PubMed Central

    Datta, Jashodeep; Rosemblit, Cinthia; Berk, Erik; Showalter, Lori; Namjoshi, Prachi; Mick, Rosemarie; Lee, Kathreen P; Brod, Andrew M; Yang, Rachel L; Kelz, Rachel R; Fitzpatrick, Elizabeth; Hoyt, Clifford; Feldman, Michael D; Zhang, Paul J; Xu, Shuwen; Koski, Gary K; Czerniecki, Brian J

    2015-01-01

    Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4+ T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2pos-DCIS, and ultimately to early stage HER2pos-invasive BC patients was detected by IFNγ ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (Treg/MDSCs), but rather associated with a functional shift in IFNγ:IL-10-producing phenotypes. HER2high, but not HER2low, BC cells expressing IFNγ/TNF-α receptors were susceptible to Th1 cytokine-mediated apoptosis in vitro, which could be significantly rescued by neutralizing IFNγ and TNF-α, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2pos-BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not “fixed” and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4+ Th1 immunity may decrease the risk of recurrence and

  12. tabAnti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO)

    PubMed Central

    Menendez, Javier A; Vazquez-Martin, Alejandro; Garcia-Villalba, Rocio; Carrasco-Pancorbo, Alegria; Oliveras-Ferraros, Cristina; Fernandez-Gutierrez, Alberto; Segura-Carretero, Antonio

    2008-01-01

    Background The effects of the olive oil-rich Mediterranean diet on breast cancer risk might be underestimated when HER2 (ERBB2) oncogene-positive and HER2-negative breast carcinomas are considered together. We here investigated the anti-HER2 effects of phenolic fractions directly extracted from Extra Virgin Olive Oil (EVOO) in cultured human breast cancer cell lines. Methods Solid phase extraction followed by semi-preparative high-performance liquid chromatography (HPLC) was used to isolate phenolic fractions from commercial EVOO. Analytical capillary electrophoresis coupled to mass spectrometry was performed to check for the composition and to confirm the identity of the isolated fractions. EVOO polyphenolic fractions were tested on their tumoricidal ability against HER2-negative and HER2-positive breast cancer in vitro models using MTT, crystal violet staining, and Cell Death ELISA assays. The effects of EVOO polyphenolic fractions on the expression and activation status of HER2 oncoprotein were evaluated using HER2-specific ELISAs and immunoblotting procedures, respectively. Results Among the fractions mainly containing the single phenols hydroxytyrosol and tyrosol, the polyphenol acid elenolic acid, the lignans (+)-pinoresinol and 1-(+)-acetoxypinoresinol, and the secoiridoids deacetoxy oleuropein aglycone, ligstroside aglycone, and oleuropein aglycone, all the major EVOO polyphenols (i.e. secoiridoids and lignans) were found to induce strong tumoricidal effects within a micromolar range by selectively triggering high levels of apoptotic cell death in HER2-overexpressors. Small interfering RNA-induced depletion of HER2 protein and lapatinib-induced blockade of HER2 tyrosine kinase activity both significantly prevented EVOO polyphenols-induced cytotoxicity. EVOO polyphenols drastically depleted HER2 protein and reduced HER2 tyrosine autophosphorylation in a dose- and time-dependent manner. EVOO polyphenols-induced HER2 downregulation occurred regardless the

  13. Quantitative assays for the measurement of HER1-HER2 heterodimerization and phosphorylation in cell lines and breast tumors: applications for diagnostics and targeted drug mechanism of action

    PubMed Central

    2011-01-01

    Introduction Ligand-bound and phosphorylated ErbB/HER heterodimers are potent signaling forms of this receptor family, and quantitative measurements of these active receptors may be predictive of patient response to targeted therapies. Using VeraTag™ technology, we developed and characterized quantitative assays measuring epidermal growth factor (EGF)-dependent increases in activated HER receptors in tumor cell line lysates and formalin-fixed, paraffin-embedded (FFPE) tumor sections. We demonstrated the ability of the assays to quantitatively measure changes in activated HER1 and HER2 receptor levels in cell lines following treatment with 2C4, erlotinib, and lapatinib. We utilized these assays to determine the prevalence and distribution of activated HER1, HER2, and HER1-HER2 heterodimers in 43 HER2-positive breast tumors. Methods Assays for activated HER1 and HER2 receptors in FFPE and cell lysate formats were developed using VeraTag™ technology, which requires the proximity of an antibody pair for light-dependent release of a fluorescently labeled tag, followed by capillary electrophoresis-based quantitation. Results Ligand-dependent and independent HER1-HER2 heterodimer levels measured by lysate and FFPE VeraTag™ assays trended with HER1 and HER2 expression levels in tumor cell lines, which was confirmed by co-immunoprecipitation. The formation of EGF-dependent HER1-HER2 heterodimers were inhibited by the HER2-targeted monoclonal antibody 2C4 and stabilized by the HER1 tyrosine kinase inhibitor (TKI) erlotinib. EGF-dependent HER1 and HER2 phosphorylation was inhibited by lapatinib and erlotinib. Further, we observed that dominant receptor signaling patterns may switch between HER1-HER1 and HER1-HER2, depending on drug mechanism of action and relative levels of HER receptors. In FFPE breast tumors that expressed both HER1 and HER2, HER1-HER2 heterodimers were detected in 25 to 50% of tumors, depending on detection method. The levels of activated phospho

  14. Efficacy of TCH/TEC neoadjuvant chemotherapy for the treatment of HER-2-overexpressing breast cancer

    PubMed Central

    CHEN, WEICAI; HE, JINSONG; SONG, SHUFEN; WANG, MIN; WU, HUISHENG; WANG, XIANMING

    2015-01-01

    The aim of the present study was to observe the efficacy of neoadjuvant trastuzumab combined with docetaxel and carboplatin (TCH), and docetaxel, epirubicin and cyclophosphamide (TEC) chemotherapy in human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer. The total cohort of 64 cases of HER-2-overexpressing breast cancer patients was divided into two groups according to their treatment preferences: The TCH group, consisting of 39 patients, and the TEC group, consisting of 25 patients. The neoadjuvant chemotherapy was continued for six cycles prior to comparison of the treatment efficacy. The TCG and TEC groups exhibited an overall response rate of 94.9 and 72.0% (37/39 and 18/25 cases; P<0.05), respectively, and a pathological complete response (pCR; defined as the presence of no invasive or in situ residual tumors in the breast) rate of 69.2 and 32.0% (27/39 and 8/25 cases; P<0.05), respectively. Furthermore, no significant differences were identified between the two groups of patients in terms of adverse reactions, such as cardiac dysfunction, bone marrow suppression and liver function impairment. In the present study, the treatment of HER-2-overexpressing breast cancer patients with TCH neoadjuvant chemotherapy demonstrated more favorable efficacy and a higher pCR rate when compared with the TEC-treated group. PMID:25789069

  15. Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy

    PubMed Central

    Creedon, Helen; Gómez-Cuadrado, Laura; Tarnauskaitė, Žygimantė; Balla, Jozef; Canel, Marta; MacLeod, Kenneth G.; Serrels, Bryan; Fraser, Craig; Unciti-Broceta, Asier; Tracey, Natasha; Le Bihan, Thierry; Klinowska, Teresa; Sims, Andrew H.; Byron, Adam; Brunton, Valerie G.

    2016-01-01

    Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies in the treatment of HER2-positive breast cancer is a major clinical problem. To identify pathways linked to resistance, we generated HER2-positive breast cancer cell lines which are resistant to either lapatinib or AZD8931, two pan-HER family kinase inhibitors. Resistance was HER2 independent and was associated with epithelial-to-mesenchymal transition (EMT), resulting in increased proliferation and migration of the resistant cells. Using a global proteomics approach, we identified a novel set of EMT-associated proteins linked to HER2-independent resistance. We demonstrate that a subset of these EMT-associated genes is predictive of prognosis within the ERBB2 subtype of human breast cancers. Furthermore, targeting the EMT-associated kinases Src and Axl potently inhibited proliferation of the resistant cells, and inhibitors to these kinases may provide additional options for the treatment of HER2-independent resistance in tumors. PMID:26883193

  16. HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

    PubMed Central

    2013-01-01

    Introduction Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, P <0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, P <0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (P = 0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group. Introduction The human epidermal growth factor receptor 2 (HER2) is the prototype of a predictive biomarker for targeted treatment [1-8]. International initiatives have established the

  17. Renal toxicity of anticancer agents targeting HER2 and EGFR.

    PubMed

    Cosmai, Laura; Gallieni, Maurizio; Porta, Camillo

    2015-12-01

    EGFR and HER2 are found overexpressed and/or activated in many different human malignancies (e.g. breast and colon cancer), and a number of drugs specifically targeting these two tyrosine kinases have been developed over the years as anticancer agents. In the present review, the renal safety profile of presently available agents targeting either HER2 or EGFR will be discussed, together with the peculiarities related to their clinical use in patients with impaired renal function, or even in dialysis. Indeed, even though renal toxicity is not so common with these agents, it may nevertheless happen, especially when these agents are combined with traditional chemotherapeutic agents. As a whole, kidney impairment or dialysis should not be regarded per se as reasons not to administer or to stop an active anti-HER or anti-EGFR anticancer treatment, especially given the possibility of significantly improving the life expectancy of many cancer patients with the use of these agents. PMID:26341657

  18. Prognostic Value of KIF2A and HER2-Neu Overexpression in Patients With Epithelial Ovarian Cancer

    PubMed Central

    Wang, Di; Zhu, Huijun; Ye, Qing; Wang, Chenyi; Xu, Yunzhao

    2016-01-01

    Abstract Kinesin family member 2A (KIF2A) is a member of Kinesin-13 family and involved in cell migration and cell signaling. Human epidermal growth factor receptor 2 (HER2-neu) is implicated in the development of many cancers. Both of these 2 proteins are upstream inducer of PI3K/AKT signaling pathway that plays an important role in the regulation of many cellular events including proliferation, survival, and invasion. We hypothesized that aberrant KIF2A and HER2-neu expression might be associated with aggressive behavior of epithelial ovarian cancer (EOC). To address the prognostic implications of KIF2A and HER2-neu in EOC, we assessed protein levels of KIF2A and HER2-neu in 159 ovarian and fallopian tube tissues (111 carcinomas and 48 normal ovary or fallopian tube tissues) by immunohistochemistry (IHC) analysis on tissue microarray and KIF2A mRNA levels in 35 ovarian and fallopian tube tissues (15 carcinomas and 20 normal ovary or fallopian tube tissues) by real-time PCR. We found that significantly higher KIF2A mRNA expression in EOC tumors than that in normal ovary or fallopian tube tissues. The IHC results showed that protein of KIF2A and HER2-neu was overexpressed in EOC tissues compared with normal ovary or fallopian tube tissues, and KIF2A expression level was significantly associated with lymph nodes, metastasis, ascites cells, and FIGO stage. No correlation between KIF2A and HER2-neu expression was observed. Survival analysis showed that patients with KIF2A and HER2-neu overexpression had a worse overall survival (OS) as compared to patients with low or none expression of the 2 proteins. Multivariate analysis of variance revealed that overexpression of KIF2A was an independent prognostic factor for OS. These findings indicate the important role of KIF2A in predicting EOC prognosis. PMID:26937910

  19. Positive association of long telomeres with the invasive capacity of hepatocellular carcinoma cells.

    PubMed

    Ko, Eunkyong; Jung, Guhung

    2014-05-01

    Invasion, the representative feature of malignant tumors, leads to an increase in mortality. The malignant liver tumor - hepatocellular carcinoma (HCC) - has an enhanced invasive capacity that results in increased patient mortality. Moreover, this enhanced invasive capacity is due to the up-regulation of invasion promoters such as zinc finger protein SNAI1 (Snail) and matrix metalloproteinases (MMPs), and the down-regulation of invasion suppressor molecules such as E-cadherin. Telomerase reverse transcriptase (TERT), which encodes the catalytic subunit of telomerase, is highly expressed in a variety of invasive cancers, including HCC. Telomerase activation induces telomere elongation, thereby leading to cell immortalization during malignant tumor progression. However, the relationship between telomere length and invasion is yet to be experimentally corroborated. In this paper, we revealed that invasive HCC cells passing through the Matrigel display significantly longer telomeres than non-invasive HCC cells. Moreover, we established a method that can distinguish and sort cells containing long telomeres and short telomeres. Using this system, we observed that the HCC cells containing long telomeres had a high-level expression of invasion-promoting genes and a low-level expression of invasion-suppressing E-cadherin. Furthermore, HCC cells containing long telomeres exhibited a higher invasive capacity than HCC cells containing short telomeres. Taken together, our findings suggest that long telomeres are positively associated with the invasive capacity of HCC cells and may be a potent target for malignant liver cancer treatment. PMID:24732358

  20. Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens

    PubMed Central

    Matsusaka, Keisuke; Ishikawa, Shumpei; Nakayama, Atsuhito; Ushiku, Tetsuo; Nishimoto, Aiko; Urabe, Masayuki; Kaneko, Nobuyuki; Kunita, Akiko; Kaneda, Atsushi; Aburatani, Hiroyuki; Fujishiro, Mitsuhiro; Seto, Yasuyuki; Fukayama, Masashi

    2016-01-01

    Evaluating HER2 gene amplification is an essential component of therapeutic decision-making for advanced or metastatic gastric cancer. A simple method that is applicable to small, formalin-fixed, paraffin-embedded biopsy specimens is desirable as an adjunct to or as a substitute for currently used HER2 immunohistochemistry and in situ hybridization protocols. In this study, we developed a microfluidics-based digital PCR method for determining HER2 and chromosome 17 centromere (CEP17) copy numbers and estimating tumor content ratio (TCR). The HER2/CEP17 ratio is determined by three variables—TCR and absolute copy numbers of HER2 and CEP17—by examining tumor cells; only the ratio of the latter two can be obtained by digital PCR using the whole specimen without purifying tumor cells. TCR was determined by semi-automatic image analysis. We developed a Tumor Content chart, which is a plane of rectangular coordinates consisting of HER2/CEP17 digital PCR data and TCR that delineates amplified, non-amplified, and equivocal areas. By applying this method, 44 clinical gastric cancer biopsy samples were classified as amplified (n = 13), non-amplified (n = 25), or equivocal (n = 6). By comparison, 11 samples were positive, 11 were negative, and 22 were equivocally immunohistochemistry. Thus, our novel method reduced the number of equivocal samples from 22 to 6, thereby obviating the need for confirmation by fluorescence or dual-probe in situ hybridization to < 30% of cases. Tumor content chart-assisted digital PCR analysis is also applicable to multiple sites in surgically resected tissues. These results indicate that this analysis is a useful alternative to HER2 immunohistochemistry in gastric cancers that can serve as a basis for the automated evaluation of HER2 status. PMID:27119558

  1. Coregulation of Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2 (HER2) Levels and Locations: Quantitative Analysis of HER2 Overexpression Effects

    SciTech Connect

    Hendriks, Bart S.; Opresko, Lee; Wiley, H. S.; Lauffenburger, Douglas A.

    2003-03-01

    Elevated expression of human epidermal growth factor receptor 2 (HER2) is know to alter cell signalilng and behavioral responses implicated in tumor progression. However, multiple diverse mechanisms may be involved in these overall effects, including signaling by HER2 itself, modulation of signalilng by epidermal growth factor receptor (EGFR) and modification of trafficking dynamics for both EGFR and HER2. Continued....

  2. 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

  3. 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. PMID:26358790

  4. MicroRNA-7 Inhibits Multiple Oncogenic Pathways to Suppress HER2Δ16 Mediated Breast Tumorigenesis and Reverse Trastuzumab Resistance

    PubMed Central

    Huynh, Felicia C.; Jones, Frank E.

    2014-01-01

    The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Δ16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that expression of HER2Δ16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2Δ16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2Δ16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Δ16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2Δ16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Δ16 induced cell proliferation and migration while sensitizing HER2Δ16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated

  5. Continuous quantification of HER2 expression by microfluidic precision immunofluorescence estimates HER2 gene amplification in breast cancer

    PubMed Central

    Dupouy, Diego G.; Ciftlik, Ata Tuna; Fiche, Maryse; Heintze, Déborah; Bisig, Bettina; de Leval, Laurence; Gijs, Martin A. M.

    2016-01-01

    Chromogenic