Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline

PubMed Central

Mates, M.; Fletcher, G.G.; Freedman, O.C.; Eisen, A.; Gandhi, S.; Trudeau, M.E.; Dent, S.F.

2015-01-01

Background This systematic review addresses the question “What is the optimal targeted therapy for female patients with early-stage human epidermal growth factor receptor 2 (her2)–positive breast cancer?” Methods The medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major guideline organizations were also searched. Results Sixty publications relevant to the targeted therapy portion of the systematic review were identified. In four major trials (hera, National Surgical Adjuvant Breast and Bowel Project B-31, North Central Cancer Treatment Group N9831, and Breast Cancer International Research Group 006), adjuvant trastuzumab for 1 year was superior in disease-free survival (dfs) and overall survival (os) to no trastuzumab; trastuzumab showed no benefit in one trial (pacs 04). A shorter duration of trastuzumab (less than 1 year compared with 1 year) was evaluated, with mixed results for dfs: one trial showed superiority (finher), one trial could not demonstrate noninferiority (phare), another trial showed equivalent results (E 2198), and one trial is still ongoing (persephone). Longer trastuzumab duration (hera: 2 years vs. 1 year) showed no improvement in dfs or os and a higher rate of cardiac events. Newer her2-targeted agents (lapatinib, pertuzumab, T-DM1, neratinib) have been or are still being evaluated in both adjuvant and neoadjuvant trials, either by direct comparison with trastuzumab alone or combined with trastuzumab. In the neoadjuvant setting (neoaltto, GeparQuinto, Neosphere), trastuzumab alone or in combination with another anti-her2 agent (lapatinib, pertuzumab) was compared with either lapatinib or pertuzumab alone and showed superior or equivalent rates of pathologic complete response. In the adjuvant setting, lapatinib alone or in combination with trastuzumab, compared with trastuzumab alone (altto) or with placebo (teach

The economic value of innovative treatments over the product life cycle: the case of targeted trastuzumab therapy for breast cancer.

PubMed

Garrison, Louis P; Veenstra, David L

2009-01-01

Pharmacoeconomic analyses typically project the expected cost-effectiveness of a new product for a specific indication. This analysis develops a dynamic life-cycle model to conduct a multi-indication evaluation using the case of trastuzumab licensed in the United States for both early-stage and metastatic (or late-stage) human epidermal growth factor receptor 2 (HER2)-positive breast cancer therapy (early breast cancer [EBC]; metastatic breast cancer [MBC]), approved in 2006 and 1998, respectively. This dynamic model combined information on expected incremental cost-utility ratios for specific indications with an epidemiologically based projection of utilization by indication over the product life cycle-from 1998 to 2016. Net economic value was estimated as the cumulative quality-adjusted life years (QALYs) gained over the life cycle multiplied by a societal valuation of health gains ($/QALY) minus cumulative net direct treatment costs. Sensitivity analyses were performed under a range of assumptions. We projected that the annual number of EBC patients receiving trastuzumab will be more than three times that of MBC by 2016, in part because adjuvant treatment reduces the future incidence of MBC. Over this life cycle, the estimated overall incremental cost-effectiveness ratio (ICER) was $35,590/QALY with a total of 432,547 discounted QALYs gained. Under sensitivity analyses, the overall ICER varied from $21,000 to $53,000/QALY, and the projected net economic value resulting from trastuzumab treatment ranged from $6.2 billion to $49.5 billion. Average ICERs for multi-indication compounds can increase or decrease over the product life cycle. In this example, the projected overall life-cycle ICER for trastuzumab was less than one half of that in the initial indication. This dynamic perspective-versus the usual static one-highlights the interdependence of drug development decisions and investment incentives, raising important reimbursement policy issues.

Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis.

PubMed

Norum, J; Olsen, J A; Wist, E A; Lønning, P E

2007-01-01

Trastuzumab has shown activity in early breast cancer patients that overexpress HER2. Significant resources have to be allocated to finance this therapy, underlining the need for cost-effectiveness analysis. A model was set up, societal costs were calculated and the discount rate was 3%. Life expectancy data were based on the literature and prolonged according to qualified guess (10% and 20% absolute improvement in overall survival (OS)). The comparator was the FEC(100) regimen. The median additional health care cost per patient treated was 33,597 euros. The yielding cost per life year gained (LYG) was 15,341 euros with a 20% improved OS and 35,947 euros with 10% improved OS. The corresponding net health care cost per quality adjusted life year (QALY) was 19,176 euros and 44,934 euros. Including all resource use the figures were 8148 euros and 30,290 euros per LYG. Sensitivity analyses documented survival gain, price of trastuzumab, production gain and discount rate to be the major factors influencing cost-effectiveness ratio. Trastuzumab is indicated cost effective in Norway.

Long-term survival in trastuzumab-treated patients with HER2-positive metastatic breast cancer: real-world outcomes and treatment patterns in a whole-of-population Australian cohort (2001-2016).

PubMed

Daniels, Benjamin; Kiely, Belinda E; Lord, Sarah J; Houssami, Nehmat; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2018-05-07

Patients treated with trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) are living longer, but there is little information on their outcomes and treatment experience beyond the median survival from clinical trials and real-world observational studies. We aim to describe the real-world treatment patterns and overall survival (OS) for women surviving five or more years from initiation of trastuzumab for HER2+MBC. This is a retrospective, whole-of-population cohort study of women initiating trastuzumab for HER2+MBC between 2001 and 2011, followed to 2016. We defined long-term survivors (LTS) as those patients surviving ≥ 5 years from trastuzumab initiation. We used dispensing claims to describe timing of cancer treatments used by LTS and to estimate time on and off HER2-targeted therapies, and OS from trastuzumab initiation for HER2+MBC. Of 4177 women initiating trastuzumab for HER2+MBC, 1082 (26%) survived ≥ 5 years. Median age for LTS was 54 years (IQR 46-63). At a median follow-up of 9.4 years, 36% of LTS died; their conditional probability of surviving an additional 5 years was 55%. Median time on trastuzumab and all HER2-targeted therapy was 58.9 months (27.6-88.1) and 69.1 months (35.6-124.5), respectively. 85% of LTS had a period off HER2 therapy, lasting a median of 30.4 months (8.2-NR). LTS generally receive HER2-targeted therapies for periods of time longer than in clinical trials, but most LTS also had breaks in treatment. More research is needed to understand the effects of long-term treatment and to identify patients who may be able to safely discontinue HER2-targeted therapy.

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer.

PubMed

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

2017-02-01

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

Ablation of breast cancer cells using trastuzumab-functionalized multi-walled carbon nanotubes and trastuzumab-diphtheria toxin conjugate.

PubMed

Oraki Kohshour, Mojtaba; Mirzaie, Sako; Zeinali, Majid; Amin, Mansour; Said Hakhamaneshi, Mohammad; Jalili, Ali; Mosaveri, Nader; Jamalan, Mostafa

2014-03-01

Trastuzumab (Herceptin(®) ) is a monoclonal antibody (mAb) for specific ablation of HER2-overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano-immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2-overexpressing SK-BR-3 and also HER2-negative MCF-7 cancer cell lines were examined. Cells treated with trastuzumab-MWCNT conjugates were irradiated with near-infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab-MWCNT and trastuzumab-DT conjugates were significantly efficient in the specific killing of SK-BR-3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab-DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT-immunoconjugates. In conclusion, our data demonstrated that trastuzumab-MWCNT is a promising nano-immunoconjugate for killing of HER2-overexpressing cancerous cells. © 2013 John Wiley & Sons A/S.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

PubMed

Denduluri, Neelima; Chavez-MacGregor, Mariana; Telli, Melinda L; Eisen, Andrea; Graff, Stephanie L; Hassett, Michael J; Holloway, Jamie N; Hurria, Arti; King, Tari A; Lyman, Gary H; Partridge, Ann H; Somerfield, Mark R; Trudeau, Maureen E; Wolff, Antonio C; Giordano, Sharon H

2018-05-22

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model

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

Jia, Yanhan; Department of Immunology, Institute of Basic Medical Sciences, Beijing 100850; Zhang, Yan

2013-07-12

Highlights: •We established trastuzumab-resistant cell line SKOV3/T. •SKOV3/T enhances proliferation and in vivo carcinogenesis. •IGF-1R and HER3 genes were up-regulated in SKOV3/T based on microarray analysis. •Targeting IGF-1R and/or HER3 inhibited the proliferation of SKOV3/T. •Therapies targeting IGF-1R and HER3 might be effective in ovarian cancer. -- Abstract: Trastuzumab (Herceptin®) has demonstrated clinical potential in several types of HER2-overexpressing human cancers. However, primary and acquired resistance occurs in many HER2-positive patients with regimens. To investigate the possible mechanism of acquired therapeutic resistance to trastuzumab, we have developed a preclinical model of human ovarian cancer cells, SKOV3/T, with the distinctive featuremore » of stronger carcinogenesis. The differences in gene expression between parental and the resistant cells were explored by microarray analysis, of which IGF-1R and HER3 were detected to be key molecules in action. Their correctness was validated by follow-up experiments of RT-PCR, shRNA-mediated knockdown, downstream signal activation, cell cycle distribution and survival. These results suggest that IGF-1R and HER3 differentially regulate trastuzumab resistance and could be promising targets for trastuzumab therapy in ovarian cancer.« less

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

PubMed Central

Nami, Babak; Wang, Zhixiang

2017-01-01

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

Evaluation of Trastuzumab-induced early cardiac dysfunction using two-dimensional Strain Echocardiography.

PubMed

Emren, Sadik Volkan; Tuluce, Selcen Yakar; Levent, Fatih; Tuluce, Kamil; Kalkan, Toygar; Yildiz, Yasar; Alacacioğlu, Ahmet; Kucukzeybek, Yüksel; Akyol, Murat; Salman, Tarık

2015-12-01

Trastuzumab, a chemotherapeutic agent used in the treatment of breast cancer. has been shown to induce subclinical left ventricular (LV) dysfunction during a three to six month period as evidenced by strain echocardiographic examination without any change occurring in the ejection fraction of LV. The present study evaluated the presence of subclinical LV dysfunction using strain echocardiography 1 day and 7 days after the initiation of trastuzumab therapy. The patients with breast cancer receiving adjuvant trastuzumab therapy underwent 2-dimensional, tissue Doppler, and strain echocardiographic examination at baseline and 1 day and 7 days after therapy. LV global longitudinal strain (GLS), global circumferential strain (GCS) values, and other echocardiographic parameters were calculated. A total of 40 females, mean age 50+/-10 years, were evaluated. Of these patients, 97% received anthracycline and 73% received radiotherapy before the initiation of trastuzumab therapy. No change was observed in any of the echocardiographic parameters 1 day after the initiation of trastuzumab therapy (p>0.05). The LV ejection fraction, tissue Doppler parameters, and GCS values did not show any changes 7 days after the initiation of therapy, whereas significant decreases were observed in GLS value (19.2+/-4.0% vs. 17.2+/-3.4, p=0.001) and systolic annular velocity of the lateral LV wall (S' velocity) (10.5+/-3.2 vs. 8.6+/-2.2, p=0.002). Trastuzumab therapy is associated with subclinical LV dysfunction as early as 7 days after initiation of the therapy as evidenced by the decreases in GLS value of LV and systolic annular velocity of the lateral LV wall.

Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

PubMed

Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

2010-01-01

HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

Cardiac dysfunction in the trastuzumab clinical trials experience.

PubMed

Seidman, Andrew; Hudis, Clifford; Pierri, Mary Kathryn; Shak, Steven; Paton, Virginia; Ashby, Mark; Murphy, Maureen; Stewart, Stanford J; Keefe, Deborah

2002-03-01

This study sought to estimate cardiac dysfunction (CD) risk for patients receiving trastuzumab; to characterize observed CD by severity, treatment, and clinical outcome; to assess effects of baseline clinical risk factors on CD; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD. A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed. Predefined criteria were used for the diagnosis, and the New York Heart Association functional classification system was used to document CD severity. Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset. Patients treated with trastuzumab were found to be at an increased risk for CD. The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide (27%). The risk was substantially lower in patients receiving paclitaxel and trastuzumab (13%) or trastuzumab alone (3% to 7%); however, most of these patients had received prior anthracycline therapy. CD was noted in 8% of patients receiving anthracycline plus cyclophosphamide and 1% receiving paclitaxel alone. Most trastuzumab-treated patients developing CD were symptomatic (75%), and most improved with standard treatment for congestive heart failure (79%). Trastuzumab is associated with an increased risk of CD, which is greatest in patients receiving concurrent anthracyclines. In most patients with metastatic breast cancer, the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab.

Advances of Molecular Targeted Therapy in Gastric Cancer.

PubMed

Cetin, Bulent; Gumusay, Ozge; Cengiz, Mustafa; Ozet, Ahmet

2016-06-01

Gastric cancer is the second most common cause of cancer-related death in the world, and its prognosis remains poor with a median overall survival of 12 months for advanced disease. Advances in the understanding of molecular genetics have led to the development of directed molecular targeted therapy in gastric cancer, leading to improve patient outcomes and quality of life. In the treatment of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, the addition of trastuzumab significantly improves survival in the first-line setting of therapy. Ramucirumab, an antibody directed against vascular endothelial growth factor receptor 2, significantly improved progression-free and overall survival and has been approved for second-line treatment of gastric cancer. Anti-mesenchymal-epithelial transition (c-MET), mammalian target of rapamycin inhibitors, and polo-like kinase 1 inhibitors are under investigation as a novel therapeutic option for the treatment of gastric cancer. The novel therapies target the key immune checkpoint interaction between a T cell co-inhibitory receptor called programmed death 1 (PD-1) and one of its immunosuppressive ligands, PD-L1. This article reviews molecular targeted therapies in gastric cancer, in light of recent advances.

Trastuzumab inhibits pituitary tumor growth modulating the TGFB/Smad2/3 pathway.

PubMed

Petiti, Juan Pablo; Sosa, Liliana Del Valle; Picech, Florencia; Moyano Crespo, Gabriela Deisi; Arevalo Rojas, Jean Zander; Pérez, Pablo Anibal; Guido, Carolina Beatriz; Leimgruber, Carolina; Sabatino, María Eugenia; García, Pedro Emilio; Bengió, Verónica; Papalini, Francisco Roque; Estario, Paula; Bernhardt, Maria Celina; Villarreal, Marcos; Gutiérrez, Silvina; De Paul, Ana Lucía; Mukdsi, Jorge Humberto; Torres, Alicia I

2018-06-06

In pituitary adenomas, early recurrences and resistance to conventional pharmacotherapies are common, but the mechanisms involved are still not understood. The high expression of epidermal growth factor receptor 2 (HER2)/extracellular signal-regulated kinase (ERK1/2) signal observed in human pituitary adenomas, together with the low levels of the antimitogenic transforming growth factor beta receptor 2 (TBR2), encouraged us to evaluate the effect of the specific HER2 inhibition with trastuzumab on experimental pituitary tumor cell growth and its effect on the antiproliferative response to TGFB1. Trastuzumab decreased the pituitary tumor growth as well as the expression of ERK1/2 and the cell cycle regulators cyclin D1 and CDK4. The HER2/ERK1/2 pathway is an attractive therapeutic target, but its intricate relations with other signaling modulators still need to be unraveled. Thus, we investigated possible cross-talk with TGFB signaling, which has not yet been studied in pituitary tumors. In tumoral GH3 cells, co-incubation with trastuzumab and TGFB1 significantly decreased cell proliferation, an effect accompanied by a reduction in ERK1/2 phosphorylation, an increase of SMAD2/3 activation. In addition, through immunoprecipitation assays, a diminution of SMAD2/3-ERK1/2 and an increase SMAD2/3-TGFBR1 interactions were observed when cells were co-incubated with Trastuzumab and TGFB1. These findings indicate that blocking HER2 by trastuzumab inhibited pituitary tumor growth and modulated HER2/ERK1/2 signaling and consequently the anti-mitogenic TGFB1/TBRs/SMADs cascade. The imbalance between HER2 and TGFBRs expression observed in human adenomas and the response to trastuzumab on experimental tumor growth, may make the HER2/ERK1/2 pathway an attractive target for future pituitary adenoma therapy.

[Case Report on Treatment of Metastatic Breast Cancer with Trastuzumab during Pregnancy].

PubMed

Rasenack, R; Gaupp, N; Rautenberg, B; Stickeler, E; Prömpeler, H

2016-04-01

The increasing number of pregnant breast cancer patients calls for a therapy that is as efficient as possible. After 10 years of collecting data on pregnant breast cancer patients in the German Breast Group (GBG), proposals for diagnostic measures and therapy regarding this special situation have been developed on the basis of 500 observed cases. Chemotherapy is regarded as safe from the 14(th) week of gestation on, but it is strongly advised not to use trastuzumab. Adverse outcomes for the newborn were predominantly observed in cases of early preterms. In our department, a 29-year-old second gravida with metastatic breast cancer first diagnosed 7 years ago continued to receive trastuzumab treatment at her express request after detailed information and advice. Trastuzumab treatment had been started 1.5 years before the pregnancy after surgical removal of a lymph node metastasis. After 7 intravenous administrations at intervals of 3 weeks, an oligohydramnios occurred in the 24(th) week of pregnancy. For this reason, trastuzumab treatment was interrupted for 7 weeks, during which time the quantity of amniotic fluid returned to a normal level. As the 8(th) administration of trastuzumab led to a renewed oligohydramnios, the trastuzumab treatment was suspended until birth. The quantity of amniotic fluid having recovered to normal, labour was induced after 36 weeks of pregnancy, followed by a Caesarian section because of prolonged labour. The newborn boy showed no sign of respiratory or renal dysfunction and has developed normally, having at present reached the age of 3 years. From the few reported cases of pregnancies with trastuzumab therapy, it seems that an occurring oligohydramnios is the typical complication with the problem of life-threatening RDS after birth. Probably the reduction of amniotic fluid can be reversed by interrupting the trastuzumab therapy, as we observed in our case. © Georg Thieme Verlag KG Stuttgart · New York.

Targeted therapies in gastric cancer and future perspectives.

PubMed

Yazici, Ozan; Sendur, M Ali Nahit; Ozdemir, Nuriye; Aksoy, Sercan

2016-01-14

Advanced gastric cancer (AGC) is associated with a high mortality rate and, despite multiple new chemotherapy options, the survival rates of patients with AGC remains poor. After the discovery of targeted therapies, research has focused on the new treatment options for AGC. In the last two decades, many targeted molecules were developed against AGC. Currently, two targeted therapy molecules have been approved for patients with AGC. In 2010, trastuzumab was the first molecule shown to improve survival in patients with HER2-positive AGC as part of a first-line combination regimen. In 2014, ramucirumab was the second targeted molecule to improve survival rates and was suggested as treatment for patients with AGC who had progressed after first-line platinum plus fluoropyrimidine with or without anthracycline chemotherapy. Ramucirumab was the first targeted therapy acting as a single agent in patients with advanced gastroesophageal cancers. Although these two molecules were introduced into clinical use, many other promising molecules have been tested in phase I-II trials. It is obvious that in the near future many different targeted therapies will be in use for treatment of AGC. In this review, the current status of targeted therapies in the treatment of AGC and gastroesophageal junction tumors, including HER (2-3) inhibitors, epidermal growth factor receptor inhibitors, tyrosine kinase inhibitors, antiangiogenic agents, c-MET inhibitors, mammalian target of rapamycin inhibitors, agents against other molecular pathways fibroblast growth factor, Claudins, insulin-like growth factor, heat shock proteins, and immunotherapy, will be discussed.

Disparities in Use of Human Epidermal Growth Hormone Receptor 2-Targeted Therapy for Early-Stage Breast Cancer.

PubMed

Reeder-Hayes, Katherine; Peacock Hinton, Sharon; Meng, Ke; Carey, Lisa A; Dusetzina, Stacie B

2016-06-10

Trastuzumab is a key component of adjuvant therapy for stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The rates and patterns of trastuzumab use have never been described in a population-based sample. The recent addition of HER2 information to the SEER-Medicare database offers an opportunity to examine patterns of trastuzumab use and to evaluate possible disparities in receipt of trastuzumab. We examined a national cohort of Medicare beneficiaries with incident stage I to III HER2-positive breast cancer diagnosed in 2010 and 2011 (n = 1,362). We used insurance claims data to track any use of trastuzumab in the 12 months after diagnosis as well as to identify chemotherapy drugs used in partnership with trastuzumab. We used modified Poisson regression analysis to evaluate the independent effect of race on likelihood of receiving trastuzumab by controlling for clinical need, comorbidity, and community-level socioeconomic status. Overall, 50% of white women and 40% of black women received some trastuzumab therapy. Among women with stage III disease, 74% of whites and 56% of blacks received trastuzumab. After adjustment for tumor characteristics, poverty, and comorbidity, black women were 25% less likely to receive trastuzumab within 1 year of diagnosis than white women (risk ratio, 0.745; 95% CI, 0.60 to 0.93). Approxemately one half of patients 65 years of age and older with stage I to III breast cancer do not receive trastuzumab-based therapy, which includes many with locally advanced disease. Significant racial disparities exist in the receipt of this highly effective therapy. Further research that identifies barriers to use and increases uptake of trastuzumab could potentially improve recurrence and survival outcomes in this population, particularly among minority women. © 2016 by American Society of Clinical Oncology.

Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine

DOE PAGES

Fitzsimmons, Jonathan; Nayak, Tapan; Cutler, Cathy; ...

2015-12-30

Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab wasmore » concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.« less

Cardiotoxicity in targeted therapy for breast cancer: A study of the FDA adverse event reporting system (FAERS).

PubMed

Wittayanukorn, Saranrat; Qian, Jingjing; Johnson, Brandon S; Hansen, Richard A

2017-03-01

Purpose Cancer chemotherapy-induced cardiotoxicity is concerning. Certain anthracyclines and targeted therapies are known to have potential for cardiotoxicity, but existing trial evidence is inadequate to understand real-world patterns of cardiotoxicity with newer targeted therapies and their common combinations with older agents. This study evaluated chemotherapy-related cardiotoxicity reports for targeted therapies and their combinations in breast cancer patients. Methods The US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2004 through September 2012 was used to summarize characteristics of reported cardiotoxicity events and their health outcomes. Disproportionality analyses with reporting odds ratios (ROR) and 95% confidence intervals (95% CI) were conducted to detect event signals using a case/non-case method for each targeted therapy and combination. Results A total of 59,739 cases of cardiotoxicity reports were identified; 937 cases identified targeted therapy as the suspect drug. Trastuzumab had the highest number of reports followed by bevacizumab and lapatinib. Proportions of reports of death and disability outcomes for each targeted therapy were approximately 20-25% of the total reports of serious events. Trastuzumab had the highest ROR as a single agent (ROR = 5.74; 95% CI = 5.29-6.23) or combination use of cyclophosphamide (ROR = 16.83; 95% CI = 13.32-21.26) or doxorubicin (ROR = 17.84; 95% CI = 13.77-23.11). Relatively low cardiotoxicity reporting rates were found with lapatinib, regardless of use with combination therapy. Conclusions Analysis of FAERS data identified signals for adverse cardiotoxicity events with targeted therapies and their combinations. Practitioners should consider factors that may increase the likelihood of cardiotoxicity when assessing treatment. Findings support continued surveillance, risk factor identification, and comparative studies.

Targeted therapy in advanced gastric carcinoma: the future is beginning.

PubMed

Schinzari, G; Cassano, A; Orlandi, A; Basso, M; Barone, C

2014-01-01

Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patients present in advanced stage and outcome still remains poor with high mortality rate despite decreasing incidence and new diagnostic and therapeutic strategies. Although utility of classical chemotherapy agents has been widely explored, advances have been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12 months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis and deeper knowledge of the cancer cell phenotype, as well on development of rationally designed drugs that would target specific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulating growth and angiogenic factors and other molecules involved in downstream intracellular signaling pathways, including receptor tyrosine kinases. However, therapeutic advances in gastric cancer are not so encouraging when compared to other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted agents in gastric cancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action, current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinical trials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important international meetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinical or phase I studies. Today, in first-line treatment only trastuzumab has shown significantly increased survival in combination with chemotherapy, whereas ramucirumab as single agent resulted effective in progressing patients, but - despite several disappointing results - these are the proof of principle that targeting the proper

Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients.

PubMed

Moilanen, Tiina; Jokimäki, Anna; Tenhunen, Olli; Koivunen, Jussi P

2018-06-05

Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting. Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006-2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records. 32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1 year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to < 10% of the baseline was seen in most cases (62.5%). There was no statistically significant difference in the survival of patients according to EF drop. Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.

Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.

PubMed

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

2018-06-14

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

Adjuvant trastuzumab in HER2-positive breast cancer.

PubMed

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

2011-10-06

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

HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy.

PubMed

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

2016-01-01

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

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

PubMed

Santini, Daniele; Vincenzi, Bruno; Adamo, Vincenzo; Addeo, Raffaele; Fusco, Vittorio; Russo, Antonio; Montemurro, Filippo; Roato, Ilaria; Redana, Stefania; Lanzetta, Gaetano; Satolli, Maria Antonietta; Berruti, Alfredo; Leoni, Valentina; Galluzzo, Sara; Antimi, Mauro; Ferraro, Giuseppa; Rossi, Maura; Del Prete, Salvatore; Valerio, Maria Rosaria; Marra, Monica; Caraglia, Michele; Tonini, Giuseppe

2011-06-01

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Integrating molecular mechanisms and clinical evidence in the management of trastuzumab resistant or refractory HER-2⁺ metastatic breast cancer.

PubMed

Wong, Hilda; Leung, Roland; Kwong, Ava; Chiu, Joanne; Liang, Raymond; Swanton, Charles; Yau, Thomas

2011-01-01

Human epidermal growth factor receptor (HER)-2(+) breast cancer is a distinct molecular and clinical entity, the prognosis of which is improved by trastuzumab. However, primary resistance to trastuzumab is observed in >50% of patients with HER-2(+) advanced breast cancer, and the majority of patients who initially respond to treatment eventually develop disease progression. To facilitate crosstrial comparisons and the understanding of resistance mechanisms, we propose a unifying definition of trastuzumab resistance as progression at first radiological reassessment at 8-12 weeks or within 3 months after first-line trastuzumab in the metastatic setting or new recurrences diagnosed during or within 12 months after adjuvant trastuzumab. In contrast, we define trastuzumab-refractory breast cancer as disease progression after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at first radiological assessment. We review mechanisms of trastuzumab resistance mediated by p95HER-2 overexpression, phosphoinositide 3-kinase pathway activation, and signaling pathway activation driven by HER-3, epidermal growth factor receptor, and insulin-like growth factor 1 receptor. We distinguish in vitro from in vivo evidence, highlighting that most data describing trastuzumab resistance are derived from preclinical studies or small retrospective patient cohorts, and discuss targeted therapeutic approaches to overcome resistance. Prospective analysis through clinical trials with robust tissue collection procedures, prior to and following acquisition of resistance, integrated with next-generation tumor genome sequencing technologies, is identified as a priority area for development. The identification of predictive biomarkers is of paramount importance to optimize health economic costs and enhance stratification of anti-HER-2 targeted therapies.

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer

PubMed Central

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

2013-01-01

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

Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer.

PubMed

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

2013-10-01

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

Liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus infection.

PubMed

Liu, Yu; Li, Zhan-Yi; Li, Xi; Wang, Jia-Ni; Huang, Qun-Ai; Huang, Yong

2017-10-01

Chemotherapy has greatly improved the prognosis of breast cancer patients. However, it may also result in undesirable side effects such as hepatitis virus reactivation. Little information is available on the liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus (HBV/HCV) infection. We performed a retrospective survey of 835 patients diagnosed with breast cancer between January 2010 and December 2015 at our institution. All patients had been screened for HBV/HCV infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicity of chemotherapy and the changes in HBV/HCV load based on a medical record review. 52 patients with positive anti-HBV antibody test and 21 patients with positive anti-HCV antibody tests received chemotherapy. 762 patients without HBV and HCV infection served as the control group. The morbidity of liver toxicity and disruptions in chemotherapy attributable to liver toxicity were not significantly different among control group, HBV group and HCV groups (27.7% vs 34.6% vs 42.9%, P = 0.189 and 5.0% vs 9.6% vs 9.5%, P = 0.173, respectively). No patients presented with HBV/HCV reactivation. Breast cancer patients with HCV can be treated with chemotherapy and targeted therapy with trastuzumab. Breast cancer patients with HBV who accept antiviral therapy can be treated with chemotherapy and targeted therapy with trastuzumab and patients can benefit from prophylactic antiviral therapy before chemotherapy. However, a multidisciplinary cooperation and closely monitoring liver function during the course of chemotherapy may benefit patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

PubMed Central

Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-01-01

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer. PMID:25327561

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression.

PubMed

Li, Guangchao; Zhao, Likun; Li, Wei; Fan, Kexing; Qian, Weizhu; Hou, Sheng; Wang, Hao; Dai, Jianxin; Wei, Huafeng; Guo, Yajun

2014-09-30

Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.

Tyrosine kinase inhibitors as modulators of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity in breast cancer cell lines.

PubMed

Collins, Denis M; Gately, Kathy; Hughes, Clare; Edwards, Connla; Davies, Anthony; Madden, Stephen F; O'Byrne, Kenneth J; O'Donovan, Norma; Crown, John

2017-09-01

Trastuzumab is an anti-HER2 monoclonal antibody (mAb) therapy capable of antibody-dependent cell-mediated cytotoxicity (ADCC) and used in the treatment of HER2+ breast cancer. Through interactions with FcƴR+ immune cell subsets, trastuzumab functions as a passive immunotherapy. The EGFR/HER2-targeting tyrosine kinase inhibitor (TKI) lapatinib and the next generation TKIs afatinib and neratinib, can alter HER2 levels, potentially modulating the ADCC response to trastuzumab. Using LDH-release assays, we investigated the impact of antigen modulation, assay duration and peripheral blood mononuclear cell (PBMC) activity on trastuzumab-mediated ADCC in breast cancer models of maximal (SKBR3) and minimal (MCF-7) target antigen expression to determine if modulating the ADCC response to trastuzumab using TKIs may be a viable approach for enhancing tumor immune reactivity. HER2 levels were determined in lapatinib, afatinib and neratinib-treated SKBR3 and MCF-7 using high content analysis (HCA). Trastuzumab-mediated ADCC was assessed following treatment with TKIs utilising a colorimetric LDH release-based protocol at 4 and 12h timepoints. PBMC activity was assessed against non-MHC-restricted K562 cells. A flow cytometry-based method (CFSE/7-AAD) was also used to measure trastuzumab-mediated ADCC in medium-treated SKBR3 and MCF-7. HER2 antigen levels were significantly altered by the three TKIs in both cell line models. The TKIs significantly reduced LDH levels directly in SKBR3 cells but not MCF-7. Lapatinib and neratinib augment trastuzumab-related ADCC in SKBR3 but the effect was not consistent with antigen expression levels and was dependent on volunteer PBMC activity (vs. K562). A 12h assay timepoint produced more consistent results. Trastuzumab-mediated ADCC (PBMC:target cell ratio of 10:1) was measured at 7.6±4.7% (T12) by LDH assay and 19±3.2 % (T12) using the flow cytometry-based method in the antigen-low model MCF-7. In the presence of effector cells with high

Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy.

PubMed

Rossi, Valentina; Nolè, Franco; Redana, Stefania; Adamoli, Laura; Martinello, Rossella; Aurilio, Gaetano; Verri, Elena; Sapino, Anna; Viale, Giuseppe; Aglietta, Massimo; Montemurro, Filippo

2014-02-01

Five to 10% of women with newly diagnosed breast cancer have synchronous metastases (de novo stage IV). A further 20% will develop metastases during follow-up (recurring stage IV). We compared the clinical outcomes of women with HER2-positive metastatic breast cancer (MBC) receiving first-line trastuzumab-based therapy according to type of metastatic presentation. Retrospective analysis of 331 MBC patients receiving first-line trastuzumab-based treatment. Response rates (RR) were compared by the chi-square test. Time-to progression (TTP) and overall survival (OS) curves were compared by the log-rank test. Cox-proportional hazards models were used to study predictors of PFS and OS, including the type of metastatic presentation. Seventy-seven patients (23%) had de novo stage IV disease. Forty-six of these patients underwent surgery of the primary ("de novo/surgery"). Response rates to first-line trastuzumab-based therapy and median progression-free survival did not differ in patients with "recurring", "de novo/surgery" and "de novo" without surgery ("de novo/no surgery) stage IV breast cancer. However, women with "de novo/surgery" stage IV breast cancer had the longest median OS (60 months), and those with "de novo/no surgery" stage IV breast cancer the shortest (26 months). For women with recurring metastatic breast cancer median OS was 40 months (overall log-rank test, p < 0.01). Multivariate analysis confirmed these findings. Our analysis shows that response rates and PFS to first-line trastuzumab-based therapy do not differ significantly between de novo and recurring stage IV, HER2 positive breast cancer. The observed difference in OS favoring women with de novo stage IV disease submitted to surgery of the primary tumor could be the result of a selection bias. Copyright © 2013 Elsevier Ltd. All rights reserved.

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study.

PubMed

Perez, Edith A; Barrios, Carlos; Eiermann, Wolfgang; Toi, Masakazu; Im, Young-Hyuck; Conte, Pierfranco; Martin, Miguel; Pienkowski, Tadeusz; Pivot, Xavier; Burris, Howard; Petersen, Jennifer A; Stanzel, Sven; Strasak, Alexander; Patre, Monika; Ellis, Paul

2017-01-10

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) -targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31.

PubMed

Gelmon, Karen A; Boyle, Frances M; Kaufman, Bella; Huntsman, David G; Manikhas, Alexey; Di Leo, Angelo; Martin, Miguel; Schwartzberg, Lee S; Lemieux, Julie; Aparicio, Samuel; Shepherd, Lois E; Dent, Susan; Ellard, Susan L; Tonkin, Katia; Pritchard, Kathleen I; Whelan, Timothy J; Nomikos, Dora; Nusch, Arnd; Coleman, Robert E; Mukai, Hirofumi; Tjulandin, Sergei; Khasanov, Rustem; Rizel, Shulamith; Connor, Anne P; Santillana, Sergio L; Chapman, Judith-Anne W; Parulekar, Wendy R

2015-05-10

The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab

A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer.

PubMed

Menyhárt, Otília; Santarpia, Libero; Győrffy, Balázs

2015-01-01

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

Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer.

PubMed

Singh, Prabhsimranjot; Toom, Sudhamshi; Huang, Yiwu

2017-05-12

Targeted therapy and immunotherapy have revolutionized treatment of various cancers in the past decade. Despite targeted therapy with trastuzumab in Her2-positive gastric cancer patients, survival has been dismal, mostly due to disease progression and toxicity related to the treatments. One area of active development is looking for ideal monoclonal antibodies (IMAB) specific to the proteins only on the tumor and hence avoiding unnecessary side effects. Claudin proteins with isoform 2 are one such protein, specific for several cancers, particularly gastric cancer and its metastases, leading to the development of anti-claudin 18.2 specific antibody, claudiximab. This review will highlight the latest development of claudiximab as first in class IMAB for the treatment of gastric cancer.

Adjuvant Trastuzumab in HER2-Positive Breast Cancer

PubMed Central

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

2011-01-01

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

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

Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen.

PubMed

Kong, Anthony; Rea, Daniel; Ahmed, Samreen; Beck, J Thaddeus; López López, Rafael; Biganzoli, Laura; Armstrong, Anne C; Aglietta, Massimo; Alba, Emilio; Campone, Mario; Hsu Schmitz, Shu-Fang; Lefebvre, Caroline; Akimov, Mikhail; Lee, Soo-Chin

2016-06-21

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.

Adding Targeted Therapy to Treatment for Esophageal Cancer

Cancer.gov

In this phase III clinical trial, people with confirmed HER2-positive locally advanced esophageal cancer will be randomly assigned to receive preoperative radiation therapy and chemotherapy, with or without trastuzumab.

First-line trastuzumab plus taxane-based chemotherapy for metastatic breast cancer: cost-minimization analysis.

PubMed

Nerich, Virginie; Chelly, Jennifer; Montcuquet, Philippe; Chaigneau, Loïc; Villanueva, Cristian; Fiteni, Frédéric; Meneveau, Nathalie; Perrin, Sophie; Voidey, Aline; Monnot, Tess; Pivot, Xavier; Limat, Samuel

2014-10-01

To carry out a cost-minimization analysis including a comparison of the costs arising from first-line treatment by trastuzumab plus docetaxel versus trastuzumab plus paclitaxel in patients with metastatic breast cancer. All consecutive patients with human epidermal growth receptor 2-postive metastatic breast cancer who were treated at Besançon University Hospital and Saint Vincent private hospital between 2001 and 2010 by first-line therapy containing trastuzumab plus taxane were retrospectively studied. Economic analysis took into account costs related to drugs, hospitalization, and healthcare travel. Progression-free survival difference between the two treatments was not significant (p = 0.65). First-line treatment by trastuzumab plus taxane was estimated at approximately €68,000 (p = 0.74). The drug costs represented around 70-75% of the total cost, mainly related to the use of trastuzumab. Our economic analysis shows that although the costs of the two trastuzumab plus taxane regimens are similar, they may contribute to the on-going debate about the availability and use of innovative chemotherapy drugs, in particular in human epidermal growth factor receptor 2-positive metastatic breast cancer with new therapies such as trastuzumab-DM1 and pertuzumab. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions.

PubMed

Young, Kate; Chau, Ian

2016-01-01

The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system.

Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2–Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study

PubMed Central

Perez, Edith A.; Barrios, Carlos; Eiermann, Wolfgang; Toi, Masakazu; Im, Young-Hyuck; Conte, Pierfranco; Martin, Miguel; Pienkowski, Tadeusz; Pivot, Xavier; Burris, Howard; Petersen, Jennifer A.; Stanzel, Sven; Strasak, Alexander; Patre, Monika; Ellis, Paul

2017-01-01

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast

Long-term remission of a Her2/neu positive primary breast cancer under double monoclonal antibody therapy with trastuzumab and bevacizumab

PubMed Central

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

2014-01-01

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

Targeted cancer therapy--are the days of systemic chemotherapy numbered?

PubMed

Joo, Won Duk; Visintin, Irene; Mor, Gil

2013-12-01

Targeted therapy or molecular targeted therapy has been defined as a type of treatment that blocks the growth of cancer cells by interfering with specific cell molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells as with traditional chemotherapy. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the growing relevance of this therapeutic approach. Targeted cancer therapies, also referred to as "Personalized Medicine", are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The objective of personalized medicine is the identification of patients that would benefit from a specific treatment based on the expression of molecular markers. Examples of this approach include bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer. Combinations of trastuzumab with pertuzumab, or T-DM1 and mTOR inhibitors added to an aromatase inhibitor are new therapeutic strategies for breast cancer. Although this approach has been seen as a major step in the expansion of personalized medicine, it has substantial limitations including its high cost and the presence of serious adverse effects. The Cancer Genome Atlas is a useful resource to identify novel and more effective targets, which may help to overcome the present limitations. In this review we will discuss the clinical outcome of some of these new therapies with a focus on ovarian and breast cancer. We will also discuss novel concepts in targeted therapy, the target of cancer stem cells. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Trastuzumab and survival of patients with metastatic breast cancer.

PubMed

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Familial breast cancer - targeted therapy in secondary and tertiary prevention.

PubMed

Kast, Karin; Rhiem, Kerstin

2015-02-01

The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer.

PubMed

Diaby, Vakaramoko; Tawk, Rima; Sanogo, Vassiki; Xiao, Hong; Montero, Alberto J

2015-05-01

cancer, evidence about trastuzumab value differed by age. Trastuzumab was cost-effective only in women with HER2-positive breast cancer younger than 65 years and over a life-time horizon. The cost-effectiveness of trastuzumab in HER2-positive metastatic breast cancer yielded conflicting results. The same conclusions were reached in comparisons between vinorelbine and taxanes. In both early stage and advanced/metastatic breast cancer, newer aromatase inhibitors (AIs) have proved cost-effective compared to older treatments. This overview of systematic reviews shows that there is heterogeneity in the evidence concerning the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer. The cost-effectiveness of these treatments depends not only on the comparators but the context, i.e., adjuvant or metastatic setting, subtype of patient population, and perspective adopted. Decisions involving the cost-effectiveness of breast cancer treatments could be made easier and more transparent by better harmonizing the reporting of economic evaluations assessing the value of these treatments.

A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer

PubMed Central

Diaby, Vakaramoko; Xiao, Hong; Montero, Alberto J.

2015-01-01

early-stage breast cancer, evidence about trastuzumab value differed by age. Trastuzumab was cost-effective only in women with HER2-positive breast cancer younger than 65 years and over a life-time horizon. The cost-effectiveness of trastuzumab in HER2-positive metastatic breast cancer yielded conflicting results. The same conclusions were reached in comparisons between vinorelbine and taxanes. In both early stage and advanced/metastatic breast cancer, newer aromatase inhibitors (AIs) have proved cost-effective compared to older treatments. This overview of systematic reviews shows that there is heterogeneity in the evidence concerning the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer. The cost-effectiveness of these treatments depends not only on the comparators but the context, i.e., adjuvant or metastatic setting, subtype of patient population, and perspective adopted. Decisions involving the cost-effectiveness of breast cancer treatments could be made easier and more transparent by better harmonizing the reporting of economic evaluations assessing the value of these treatments. PMID:25893588

Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

PubMed Central

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

2017-01-01

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

Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

PubMed

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

2017-08-05

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

Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells

PubMed Central

2010-01-01

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

p95HER2 Methionine 611 Carboxy-Terminal Fragment Is Predictive of Trastuzumab Adjuvant Treatment Benefit in the FinHer Trial.

PubMed

Sperinde, Jeff; Huang, Weidong; Vehtari, Aki; Chenna, Ahmed; Kellokumpu-Lehtinen, Pirkko-Liisa; Winslow, John; Bono, Petri; Lie, Yolanda S; Petropoulos, Christos J; Weidler, Jodi; Joensuu, Heikki

2018-03-13

Purpose: Expression of p95HER2 (p95), a truncated form of the HER2 receptor, which lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcomes in patients with trastuzumab-treated HER2-positive metastatic breast cancer. The impact of p95 expression on trastuzumab treatment efficacy in early HER2-positive breast cancer is less clear. In the current study, p95 was tested as a predictive marker of trastuzumab treatment benefit in the HER2-positive subset of the FinHer adjuvant phase III trial. Experimental Design: In the FinHer trial, 232 patients with HER2-positive early breast cancer were randomized to receive chemotherapy plus 9 weeks of trastuzumab or no trastuzumab treatment. Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag assay (Monogram Biosciences), specific for the M611 form of p95. Quantitative HER2 protein expression was measured using the HERmark assay (Monogram Biosciences). Distant disease-free survival (DDFS) was used as the primary outcome measure. Results: In the arm receiving chemotherapy only, increasing log 10 (p95) correlated with shorter DDFS (HR, 2.0; P = 0.02). In the arm receiving chemotherapy plus trastuzumab ( N = 95), increasing log 10 (p95) was not correlated with a shorter DDFS. In a combined analysis of both treatment arms, high breast tumor p95 content was significantly correlated with trastuzumab treatment benefit in multivariate models (interaction P = 0.01). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 1-7. ©2018 AACR. ©2018 American Association for Cancer Research.

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

PubMed

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

2009-05-01

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

Cost-effectiveness analysis of 1st through 3rd line sequential targeted therapy in HER2-positive metastatic breast cancer in the United States

PubMed Central

Adunlin, Georges; Ali, Askal A.; Zeichner, Simon B.; de Lima Lopes, Gilberto; Kohn, Christine G.; Montero, Alberto J.

2016-01-01

Purpose Based on available phase III trial data, we performed a cost-effectiveness analysis of different treatment strategies that can be used in patients with newly diagnosed HER2-positive metastatic breast cancer (mBC). Patients and Methods We constructed a Markov model to assess the cost-effectiveness of four different HER2 targeted treatment sequences in patients with HER2-positive mBC treated in the U.S. The model followed patients weekly over their remaining life expectancies. Health states considered were progression free survival (PFS) 1st to 3rd lines, and death. Transitional probabilities were based on published phase III trials. Cost data (2015 US dollars) was captured from the U.S. Centers for Medicare and Medicaid Services (CMS) drug payment table and physician fee schedule. Health utility data were extracted from published studies. The outcomes considered were PFS, OS, costs, QALYs, the incremental cost per QALY gained ratio, and the net monetary benefit. Deterministic and probabilistic sensitivity analyses assessed the uncertainty around key model parameters and their joint impact on the base-case results. Results The combination of trastuzumab, pertuzumab, and docetaxel (THP) as first-line therapy, trastuzumab emtansine (T-DM1) as second-line therapy, and lapatinib/capecitabine third-line resulted in 1.81 QALYs, at a cost of $335,231.35. The combination of trastuzumab/docetaxel as first line without subsequent T-DM1 or pertuzumab yielded 1.41 QALYs, at a cost of $175,240.69. The least clinically effective sequence (1.27 QALYs), but most cost-effective at a total cost of $149,250.19, was trastuzumab/docetaxel as first-line therapy, T-DM1 as second-line therapy, and trastuzumab/lapatinib as third line therapy. Conclusion Our results suggest that THP as first-line therapy, followed by T-DM1 as second-line therapy, would require at least a 50% reduction in the total drug acquisition cost for it to be considered a cost-effective strategy. PMID:27654970

Adjuvant trastuzumab with chemotherapy is effective in women with small, node-negative, HER2-positive breast cancer.

PubMed

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

2011-12-15

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

Target cell specific antibody-based photosensitizers for photodynamic therapy

NASA Astrophysics Data System (ADS)

Rosenblum, Lauren T.; Mitsunaga, Makoto; Kakareka, John W.; Morgan, Nicole Y.; Pohida, Thomas J.; Choyke, Peter L.; Kobayashi, Hisataka

2011-03-01

In photodynamic therapy (PDT), localized monochromatic light is used to activate targeted photosensitizers (PS) to induce cellular damage through the generation of cytotoxic species such as singlet oxygen. While first-generation PS passively targeted malignancies, a variety of targeting mechanisms have since been studied, including specifically activatable agents. Antibody internalization has previously been employed as a fluorescence activation system and could potentially enable similar activation of PS. TAMRA, Rhodamine-B and Rhodamine-6G were conjugated to trastuzumab (brand name Herceptin), a humanized monoclonal antibody with specificity for the human epidermal growth factor receptor 2 (HER2), to create quenched PS (Tra-TAM, Tra-RhoB, and Tra-Rho6G). Specific PDT with Tra-TAM and Tra-Rho6G, which formed covalently bound H-dimers, was demonstrated in HER2+ cells: Minimal cell death (<6%) was observed in all treatments of the HER2- cell line (BALB/3T3) and in treatments the HER2+ cell line (3T3/HER2) with light or trastuzumab only. There was significant light-induced cell death in HER2 expressing cells using Tra-TAM (3% dead without light, 20% at 50 J/cm2, 46% at 100 J/cm2) and Tra-Rho6G (5% dead without light, 22% at 50 J/cm2, 46% at 100 J/cm2). No efficacy was observed in treatment with Tra-RhoB, which was also non-specifically taken up by BALB/3T3 cells and which had weaker PS-antibody interactions (as demonstrated by visualization of protein and fluorescence on SDS-PAGE).

Molecular targeted therapy for advanced gastric cancer.

PubMed

Kim, Jong Gwang

2013-03-01

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

De-Escalation Strategies in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer (BC): Final Analysis of the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early BC HER2- and Hormone Receptor-Positive Phase II Randomized Trial-Efficacy, Safety, and Predictive Markers for 12 Weeks of Neoadjuvant Trastuzumab Emtansine With or Without Endocrine Therapy (ET) Versus Trastuzumab Plus ET.

PubMed

Harbeck, Nadia; Gluz, Oleg; Christgen, Matthias; Kates, Ronald Ernest; Braun, Michael; Küemmel, Sherko; Schumacher, Claudia; Potenberg, Jochem; Kraemer, Stefan; Kleine-Tebbe, Anke; Augustin, Doris; Aktas, Bahriye; Forstbauer, Helmut; Tio, Joke; von Schumann, Raquel; Liedtke, Cornelia; Grischke, Eva-Maria; Schumacher, Johannes; Wuerstlein, Rachel; Kreipe, Hans Heinrich; Nitz, Ulrike Anneliese

2017-09-10

Purpose Human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor (HR)-positive breast cancer is a distinct subgroup associated with lower chemotherapy sensitivity and slightly better outcome than HER2-positive/HR-negative disease. Little is known about the efficacy of the combination of endocrine therapy (ET) with trastuzumab or with the potent antibody-cytotoxic, anti-HER2 compound trastuzumab emtansine (T-DM1) with or without ET for this subgroup. The West German Study Group trial, ADAPT (Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer) compares pathologic complete response (pCR) rates of T-DM1 versus trastuzumab with ET in early HER2-positive/HR-positive breast cancer. Patients and Methods In this prospective, neoadjuvant, phase II trial, 375 patients with early breast cancer with HER2-positive and HR-positive status (n = 463 screened) were randomly assigned to 12 weeks of T-DM1 with or without ET or to trastuzumab with ET. The primary end point was pCR (ypT0/is/ypN0). Early response was assessed in 3-week post-therapeutic core biopsies (proliferation decrease ≥ 30% Ki-67 or cellularity response). Secondary end points included safety and predictive impact of early response on pCR. Adjuvant therapy followed national standards. Results Baseline characteristics were well balanced among the arms. More than 90% of patients completed the therapy per protocol. pCR was observed in 41.0% of patients treated with T-DM1, 41.5% of patients treated with T-DM1 and ET, and 15.1% with trastuzumab and ET ( P < .001). Early responders (67% of patients with assessable response) achieved pCR in 35.7% compared with 19.8% in nonresponders (odds ratio, 2.2; 95% CI, 1.24 to 4.19). T-DM1 was associated with a significantly higher prevalence of grade 1 to 2 toxicities, especially thrombocytopenia, nausea, and elevation of liver enzymes. Overall toxicity was low; seventeen

Functional Imaging of HER2-Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab Positron Emission Tomography

PubMed Central

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

2014-01-01

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

Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis.

PubMed

Lewis Phillips, Gail D; Nishimura, Merry C; Lacap, Jennifer Arca; Kharbanda, Samir; Mai, Elaine; Tien, Janet; Malesky, Kimberly; Williams, Simon P; Marik, Jan; Phillips, Heidi S

2017-08-01

The extent to which efficacy of the HER2 antibody Trastuzumab in brain metastases is limited by access of antibody to brain lesions remains a question of significant clinical importance. We investigated the uptake and distribution of trastuzumab in brain and mammary fat pad grafts of HER2-positive breast cancer to evaluate the relationship of these parameters to the anti-tumor activity of trastuzumab and trastuzumab emtansine (T-DM1). Mouse transgenic breast tumor cells expressing human HER2 (Fo2-1282 or Fo5) were used to establish intracranial and orthotopic tumors. Tumor uptake and tissue distribution of systemically administered 89 Zr-trastuzumab or muMAb 4D5 (murine parent of trastuzumab) were measured by PET and ELISA. Efficacy of muMAb 4D5, the PI3K/mTOR inhibitor GNE-317, and T-DM1 was also assessed. 89 Zr-trastuzumab and muMAb 4D5 exhibited robust uptake into Fo2-1282 brain tumors, but not normal brains. Uptake into brain grafts was similar to mammary grafts. Despite this, muMAb 4D5 was less efficacious in brain grafts. Co-administration of muMAb 4D5 and GNE-317, a brain-penetrant PI3K/mTOR inhibitor, provided longer survival in mice with brain lesions than either agent alone. Moreover, T-DM1 increased survival in the Fo5 brain metastasis model. In models of HER2-positive breast cancer brain metastasis, trastuzumab efficacy does not appear to be limited by access to intracranial tumors. Anti-tumor activity improved with the addition of a brain-penetrant PI3K/mTOR inhibitor, suggesting that combining targeted therapies is a more effective strategy for treating HER2-positive breast cancer brain metastases. Survival was also extended in mice with Fo5 brain lesions treated with T-DM1.

Barriers to the Use of Trastuzumab for HER2+ Breast Cancer and the Potential Impact of Biosimilars: A Physician Survey in the United States and Emerging Markets.

PubMed

Lammers, Philip; Criscitiello, Carmen; Curigliano, Giuseppe; Jacobs, Ira

2014-09-17

Trastuzumab in combination with chemotherapy has become a standard of care for patients with HER2+ breast cancer. The cost of therapy, however, can limit patient access to trastuzumab in areas with limited financial resources for treatment reimbursement. This study examined access to trastuzumab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia and Brazil via physician survey. The study also investigated if the availability of a biosimilar to trastuzumab would improve access to and use of HER2 monoclonal antibody therapy. Across all countries, a subset of oncologists reported barriers to the use of trastuzumab in a neoadjuvant, adjuvant or metastatic setting. Common barriers to the use of trastuzumab included issues related to insurance coverage, drug availability and cost to the patient. Overall, nearly half of oncologists reported that they would increase the use of HER2 monoclonal antibody therapy across all treatment settings if a lower cost biosimilar to trastuzumab were available. We conclude that the introduction of a biosimilar to trastuzumab may alleviate cost-related barriers to treatment and could increase patient access to HER2-directed therapy in all countries examined.

Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo

PubMed Central

Huang, Shengshi; Zhang, Shu; Wang, Fengshan; Shi, Yikang

2015-01-01

Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab. PMID:26498681

Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.

PubMed

Li, Wentong; Zhai, Limin; Wang, Hui; Liu, Chuanliang; Zhang, Jinbao; Chen, Weijuan; Wei, Qun

2016-05-10

Therapeutic resistance to trastuzumab caused by dysregulation of long noncoding RNAs (lncRNAs) is a major obstacle to clinical management of HER2-positive breast cancer. To investigate which lncRNAs contribute to trastuzumab resistance, we screened a microarray of lncRNAs involved in the malignant phenotype of trastuzumab-resistant SKBR-3/Tr cells. Expression of the lncRNA GAS5 was decreased in SKBR-3/Tr cells and in breast cancer tissue from trastuzumab-treated patients. Inhibition of GAS5 promoted SKBR-3 cell proliferation, and GAS5 knockdown partially reversed lapatinib-induced inhibition of SKBR-3/Tr cell proliferation. GAS5 suppresses cancer proliferation by acting as a molecular sponge for miR-21, leading to the de-repression of phosphatase and tensin homologs (PTEN), the endogenous target of miR-21. Moreover, mTOR activation associated with reduced GAS5 expression was required to suppress PTEN. This work identifies GAS5 as a novel prognostic marker and candidate drug target for HER2-positive breast cancer.

Preparation and preclinical evaluation of 131 I-trastuzumab for breast cancer.

PubMed

Kameswaran, Mythili; Gota, Vikram; Ambade, Rajwardhan; Gupta, Sudeep; Dash, Ashutosh

2017-01-01

Trastuzumab that targets the human epidermal growth factor receptor type 2 (HER2) is known to benefit patients with HER2+ metastatic breast cancer. The objective was to explore the potential of 131 I-trastuzumab for treatment of breast cancers. Radioiodination of trastuzumab was carried out by chloramine-T method, purified by using PD-10 column, and characterized by size exclusion high-performance liquid chromatography on a gel column. In vitro studies were carried out in HER2+ cells to determine the specificity of the radioimmunoconjugate. Uptake and retention of 131 I-trastuzumab were determined by biodistribution studies in tumor-bearing non-obese diabetic/severe combined immunodeficiency and normal severe combined immunodeficiency mice. The radiochemical purity (RCP) of 131 I-trastuzumab was 98 ± 0.4% with retention time of 17 minutes by high-performance liquid chromatography. In vitro stability studies exhibited RCP of more than 90% in serum at 37°C after 120 hours of radioiodination. In vitro cell binding with 131 I-trastuzumab in HER2+ cells showed binding of 28% to 35% which was inhibited significantly, with unlabeled trastuzumab confirming its specificity. K d value of 131 I-trastuzumab was 0.5 nM, while its immunoreactivity was more than 80%. Uptake of more than 12% and retention were observed in the tumors up to 120 hours p.i. 131 I-trastuzumab prepared in-house-exhibited RCP of more than 98%, excellent immunoreactivity, affinity to HER2+ cell lines and good tumor uptake thereby indicating its potential for further evaluation in HER2+ breast cancers. Copyright © 2016 John Wiley & Sons, Ltd.

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

Policies and Programs to Facilitate Access to Targeted Cancer Therapies in Thailand

PubMed Central

Sruamsiri, Rosarin; Ross-Degnan, Dennis; Lu, Christine Y.; Chaiyakunapruk, Nathorn; Wagner, Anita K.

2015-01-01

Background Increasing access to clinically beneficial targeted cancer medicines is a challenge in every country due to their high cost. We describe the interplay of innovative policies and programs involving multiple stakeholders to facilitate access to these medicines in Thailand, as well as the utilization of selected targeted therapies over time. Methods We selected two medicines on the 2013 Thai national list of essential medicines (NLEM) [letrozole and imatinib] and three unlisted medicines for the same indications [trastuzumab, nilotinib and dasatinib]. We created timelines of access policies and programs for these products based on scientific and grey literature. Using IMS Health sales data, we described the trajectories of sales volumes of the study medicines between January 2001 and December 2012. We compared estimated average numbers of patients treated before and after the implementation of policies and programs for each product. Results Different stakeholders implemented multiple interventions to increase access to the study medicines for different patient populations. During 2007–2009, the Thai Government created a special NLEM category with different coverage requirements for payers and issued compulsory licenses; payers negotiated prices with manufacturers and engaged in pooled procurement; pharmaceutical companies expanded patient assistance programs and lowered prices in different ways. Compared to before the interventions, estimated numbers of patients treated with each medicine increased significantly afterwards: for letrozole from 645 (95% CI 366–923) to 3683 (95% CI 2,748–4,618); for imatinib from 103 (95% CI 72–174) to 350 (95% CI 307–398); and for trastuzumab from 68 (95% CI 45–118) to 412 (95% CI 344–563). Conclusions Government, payers, and manufacturers implemented multi-pronged approaches to facilitate access to targeted cancer therapies for the Thai population, which differed by medicine. Routine monitoring is needed to

Trastuzumab-induced cardiotoxicity.

PubMed

Moss, Lisa Stegall; Starbuck, Mandy Fields; Mayer, Deborah K; Harwood, Elaine Brooks; Glotzer, Jana

2009-11-01

To review trastuzumab-related cardiotoxic effects in the breast cancer adjuvant setting, present a system for pretreatment screening for cardiovascular risk factors, describe monitoring recommendations, provide a tool to facilitate adherence to monitoring guidelines, and discuss implications for patient education. Literature regarding cardiotoxicity and trastuzumab in breast cancer. Trastuzumab was approved in 2006 for use in the adjuvant setting. A small percentage of women (approximately 4%) developed heart failure during or after treatment. However, the trials excluded women with cardiac disease. Current screening for cardiotoxicity relies on sequential left ventricular function measurements with either echocardiography or multigated acquisition scanning at baseline and every three months. Treatment modifications are recommended if changes from baseline are detected. Long-term and late effects have yet to be determined. Although a small number of women experienced cardiotoxicity in the adjuvant setting, an increase may be seen because women with preexisting heart disease receive this treatment. Guidelines and tools will be helpful for appropriate and consistent screening of cardiac risk factors and disease prior to initiation of trastuzumab and for monitoring during and after administration. Nurses are instrumental in assessing, monitoring, and treating women receiving trastuzumab. Implementing guidelines to promote adherence to recommended monitoring is important in the early detection of cardiotoxicity in this population. Educating women about their treatment and side effects is an important aspect of care.

In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

PubMed

Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

2015-08-01

The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile.

Trastuzumab-binding peptide display by Tobacco mosaic virus

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

Frolova, Olga Y.; Petrunia, Igor V.; Komarova, Tatiana V.

2010-11-10

Human epidermal growth factor receptor-2 (HER2/neu) is a target for the humanized monoclonal antibody trastuzumab. Recently, trastuzumab-binding peptides (TBP) of HER2/neu that inhibit proliferation of breast cancer cells were identified. We have now studied conditions of efficient assembly in vivo of Tobacco mosaic virus (TMV)-based particles displaying TBP on its surface. The system is based on an Agrobacterium-mediated co-delivery of binary vectors encoding TMV RNA and coat protein (CP) with TBP in its C-terminal extension into plant leaves. We show how the fusion of amino acid substituted TBP (sTBP) to CP via a flexible peptide linker can improve the manufacturabilitymore » of recombinant TMV (rTMV). We also reveal that rTMV particles with exposed sTBP retained trastuzumab-binding capacity but lost an anti-HER2/neu immunogenic scaffold function. Mouse antibodies against rTMV did not recognize HER2/neu on surface of human SK-BR-3 cells.« less

MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6.

PubMed

Lu, Xiangdong; Ma, Jingjing; Chu, Jiahui; Shao, Qing; Zhang, Yao; Lu, Guangping; Li, Jun; Huang, Xiang; Li, Wei; Li, Yongfei; Ling, Yang; Zhao, Tao

2017-01-01

Trastuzumab is an important treatment used for patients with Her-2-positive breast cancer, but an increasing incidence of trastuzumab resistance has been observed clinically during the past decade. Aberrant microRNA (miR) expression levels are correlated with prognosis and response to trastuzumab in breast cancer. MiR-129-5p is downregulated in trastuzumab-resistant human breast cancer cells (JIMT-1), but its potential function and underlying mechanism remain unclear. Quantitative RT-PCR (qRT-PCR) was used to determine the expression levels of miR-129-5p and its potential target genes. The effects of miR-129-5p on cell responses to trastuzumab were analyzed by CCK-8 and flow cytometry assays in Her-2-positive breast cancer cells (SKBR-3 and JIMT-1). Bio-informatics analyses were performed to predict target genes of miR-129-5p, and luciferase assays were carried out to confirm the binding of miR-129-5p and rpS6. MiR-129-5p, which was downregulated and predicted to target rpS6 in trastuzumab-resistant breast cancer cells, enhanced the sensitivity of breast cancer cells to trastuzumab by reducing the expression of rpS6. Moreover, the overexpression of rpS6 reversed the sensitivity of cells to trastuzumab induced by miR-129-5p. MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. These findings provide novel insights into the common role of rpS6 and its related molecular mechanisms in mediating trastuzumab-resistance in Her-2-positive breast cancers. © 2017 The Author(s). Published by S. Karger AG, Basel.

Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer.

PubMed

Dang, Chau; Guo, Hao; Najita, Julie; Yardley, Denise; Marcom, Kelly; Albain, Kathy; Rugo, Hope; Miller, Kathy; Ellis, Matthew; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Moy, Beverly; Groarke, John; Moslehi, Javid; Krop, Ian; Burstein, Harold J; Hudis, Clifford; Winer, Eric P; Tolaney, Sara M

2016-01-01

Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF

[Primary safety analysis of trastuzumab after adjuvant chemotherapy in 30 Chinese Her2-positive early breast cancer patients].

PubMed

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

2008-12-01

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

A gene expression profile indicative of early stage HER2 targeted therapy response.

PubMed

O'Neill, Fiona; Madden, Stephen F; Clynes, Martin; Crown, John; Doolan, Padraig; Aherne, Sinéad T; O'Connor, Robert

2013-07-01

Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.

Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET.

PubMed

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

2014-01-01

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

Systematic Review of the Side Effects Associated With Anti-HER2-Targeted Therapies Used in the Treatment of Breast Cancer, on Behalf of the EORTC Quality of Life Group.

PubMed

Sodergren, Samantha C; Copson, Ellen; White, Alice; Efficace, Fabio; Sprangers, Mirjam; Fitzsimmons, Deborah; Bottomley, Andrew; Johnson, Colin D

2016-06-01

Targeted therapies (TTs), notably trastuzumab, have improved outcomes for breast cancer characterised by overexpression of human epidermal growth factor receptors including HER2. Compared with chemotherapy treatments, TTs are more specific in their targets and are delivered over longer periods of time, thus presenting different side-effect profiles. The objective of this paper is to systematically review and describe the side effects associated with TTs used in the adjuvant and metastatic settings for HER2+ breast cancer. The MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library databases were searched from January 2007 to March 2015 to identify clinical trials and prospective studies reporting toxicities associated with TTs (mainly trastuzumab and lapatinib) used without other therapies in the treatment of HER2-positive breast cancer. Two independent reviewers selected papers based on their titles and abstracts. All papers selected by either reviewer were included. A third reviewer extracted and tabulated the relevant data using a data extraction form. We identified 5478 papers, of which 299 were reviewed and 18 trials identified involving 6980 patients. A total of 66 side effects were identified, including 46 "patient-based" symptoms and 20 "medically defined" outcomes. Side effects were more common for patients treated with therapies other than trastuzumab or with dual-HER2 regimens and for patients with metastatic disease. Diarrhoea and skin rash were the most prevalent symptoms, experienced by 29 % and 22 % of patients overall, respectively. There were 119 (2 %) cardiac events reported, and these were not exclusive to trastuzumab-treated patients. The majority of side effects (n = 52) were experienced by 1 % or less of patients and were predominantly of grade 1/2 toxicity. This systematic review provides a detailed analysis of side effects of HER2+ therapies in a large number of patients included in trials, enabling an accurate estimate of

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

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer

PubMed Central

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

2014-01-01

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

Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene--amplified breast cancer cells.

PubMed

Milella, Michele; Trisciuoglio, Daniela; Bruno, Tiziana; Ciuffreda, Ludovica; Mottolese, Marcella; Cianciulli, Anna; Cognetti, Francesco; Zangemeister-Wittke, Uwe; Del Bufalo, Donatella; Zupi, Gabriella

2004-11-15

To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members. Bcl-2 and Bcl-XL expression and apoptosis induction were analyzed in HER-2 gene-amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1. In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-XL, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 +/- 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-XL expression, resulting in a 21 +/- 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 +/- 6%, P <0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index=0.58 +/- 0.18), as assessed by isobologram analysis. Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.

PubMed

Smith, John W; Buyse, Marc E; Rastogi, Priya; Geyer, Charles E; Jacobs, Samuel A; Patocskai, Erica J; Robidoux, André; Conlin, Alison K; Ansari, Bilal; Keogh, George P; Stella, Philip J; Gross, Howard M; Lord, Raymond S; Polikoff, Jonathan A; Mauquoi, Celine; Mamounas, Eleftherios P; Swain, Sandra M; Wolmark, Norman

2017-02-01

The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m 2 ) followed by 4 cycles of docetaxel (100 mg/m 2 ). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations. Copyright © 2016 Elsevier Inc. All rights reserved.

Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy.

PubMed

Urruticoechea, Ander; Rizwanullah, Mohammed; Im, Seock-Ah; Ruiz, Antonio Carlos Sánchez; Láng, István; Tomasello, Gianluca; Douthwaite, Hannah; Badovinac Crnjevic, Tanja; Heeson, Sarah; Eng-Wong, Jennifer; Muñoz, Montserrat

2017-09-10

Purpose To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane. Patients and Methods Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m 2 twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m 2 on the same schedule as arm A. The primary end point was independent review facility-assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate. Results Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months' median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B. Conclusion The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.

Metastatic Extramammary Paget's Disease of Scrotum Responds Completely to Single Agent Trastuzumab in a Hemodialysis Patient: Case Report, Molecular Profiling and Brief Review of the Literature

PubMed Central

Barth, Peter; Dulaimi Al-Saleem, Essel; Edwards, Kristin W.; Millis, Sherri Z.; Wong, Yu-Ning; Geynisman, Daniel M.

2015-01-01

Extramammary Paget's disease (EMPD) is a rare cancer. Although EMPD is usually noninvasive and treated with local therapy, once metastatic the prognosis of EMPD is poor and treatment options are limited. We report a case of a complete response to single agent trastuzumab in a hemodialysis patient with metastatic Her2/neu overexpressed EMPD of the scrotum. Molecular profiling of his case as well as 12 other EMPD and 8 mammary Paget disease (MPD) cases was completed and revealed multiple biomarker aberrations. Overexpression of Her2 was frequently noted (30%–40%) in both EMPD and MPD patients and when present can be effectively treated with Her2 targeted agents. Trastuzumab therapy can be safely utilized in a hemodialysis patient. In addition, multiple protein overexpression and loss were seen in EMPD including PD-1, PD-L1, PTEN, and AR as well as PIK3CA mutation. These findings may lead to possible therapeutic interventions targeting these pathways in a disease with few effective treatment options. PMID:25692060

Budget impact analysis of trastuzumab in early breast cancer: a hospital district perspective.

PubMed

Purmonen, Timo T; Auvinen, Päivi K; Martikainen, Janne A

2010-04-01

Adjuvant trastuzumab is widely used in HER2-positive (HER2+) early breast cancer, and despite its cost-effectiveness, it causes substantial costs for health care. The purpose of the study was to develop a tool for estimating the budget impact of new cancer treatments. With this tool, we were able to estimate the budget impact of adjuvant trastuzumab, as well as the probability of staying within a given budget constraint. The created model-based evaluation tool was used to explore the budget impact of trastuzumab in early breast cancer in a single Finnish hospital district with 250,000 inhabitants. The used model took into account the number of patients, HER2+ prevalence, length and cost of treatment, and the effectiveness of the therapy. Probabilistic sensitivity analysis and alternative case scenarios were performed to ensure the robustness of the results. Introduction of adjuvant trastuzumab caused substantial costs for a relatively small hospital district. In base-case analysis the 4-year net budget impact was 1.3 million euro. The trastuzumab acquisition costs were partially offset by the reduction in costs associated with the treatment of cancer recurrence and metastatic disease. Budget impact analyses provide important information about the overall economic impact of new treatments, and thus offer complementary information to cost-effectiveness analyses. Inclusion of treatment outcomes and probabilistic sensitivity analysis provides more realistic estimates of the net budget impact. The length of trastuzumab treatment has a strong effect on the budget impact.

Pilot study of 68Ga-DOTA-F(ab')2-trastuzumab in patients with breast cancer.

PubMed

Beylergil, Volkan; Morris, Patrick G; Smith-Jones, Peter M; Modi, Shanu; Solit, David; Hudis, Clifford A; Lu, Yang; O'Donoghue, Joseph; Lyashchenko, Serge K; Carrasquillo, Jorge A; Larson, Steven M; Akhurst, Timothy J

2013-12-01

68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-F(ab')2-trastuzumab [68Ga-DOTA-F(ab')2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab')2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously. A group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab')2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not. It was determined that 68Ga-DOTA-F(ab')2-trastuzumab was well tolerated, with a T½ of ≈ 3.6 ± 0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease. The reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort

PubMed Central

Daniels, Benjamin; Lord, Sarah J; Kiely, Belinda E; Houssami, Nehmat; Haywood, Philip; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2017-01-01

Background The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia. Methods/design Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research. Ethics and dissemination Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these

Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01).

PubMed

Azim, Hatem A; Metzger-Filho, Otto; de Azambuja, Evandro; Loibl, Sibylle; Focant, Florine; Gresko, Ekaterina; Arfi, Mounir; Piccart-Gebhart, Martine

2012-05-01

Only few case reports describe the pregnancy course and outcome of breast cancer patients, who were under treatment with trastuzumab at the time of conception or who have completed trastuzumab therapy before becoming pregnant. The HERA trial is a large phase III randomized clinical trial in which patients with early HER2-positive breast cancer were randomized to receive 1 or 2 years of trastuzumab or observation following completion of primary chemotherapy. To examine the effect of trastuzumab on pregnancy outcome, we report all pregnancy events that occurred until March 2010 in patients enrolled in the study. For the sake of this analysis, patients were assigned to three groups: (1) pregnancy occurring during and up to 3 months after trastuzumab exposure (group 1); (2) pregnancy occurring >3 months of last trastuzumab dose (group 2); and (3) pregnancy occurring in patients without prior exposure to trastuzumab (group 3). Sixteen, 45 and 9 pregnancies took place in groups 1, 2, and 3, respectively. 25 and 16% of patients in groups 1 and 2 experienced spontaneous abortion, the former being higher than figures reported in the general population. However, short-term fetal outcome appeared normal across the three groups. Only 2 congenital anomalies were reported, one in group 2 and one in group 3. No congenital anomalies were reported in those exposed to trastuzumab in utero. This is the first report from a large randomized trial assessing the effect of trastuzumab on pregnancy course and outcome. Based on our results, trastuzumab does not appear to affect fetal outcome in patients who manage to complete their pregnancy. We are currently initiating a collaboration to collect similar data from the other large adjuvant trastuzumab trials to confirm these findings.

A gene expression profile indicative of early stage HER2 targeted therapy response

PubMed Central

2013-01-01

Background Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Results Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. Conclusions In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor. Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents. PMID:23816254

Trastuzumab Benefits Women with Locally Advanced or Inflammatory

Cancer.gov

Women treated with trastuzumab (Herceptin) and chemotherapy before surgery and trastuzumab again after surgery had a reduced risk of the disease recurring or progressing compared with women who received pre-surgical chemotherapy but no trastuzumab, accord

Targeted Therapy for Breast Cancer Prevention

PubMed Central

den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

2013-01-01

With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

Monitoring therapeutic response of human ovarian cancer to trastuzumab by SPECT imaging with (99m)Tc-peptide-Z(HER2:342).

PubMed

Zhang, Jingmian; Zhao, Xinming; Wang, Shijie; Wang, Na; Han, Jingya; Jia, Lizhuo; Ren, Xiuchun

2015-06-01

group during the treatment, the transplanted tumours in trastuzumab-treated group had a slower growth than those in control group (p < 0.05). Compared with the baseline, the results of in vivo imaging showed that radionuclide accumulation in transplanted tumours reduced significantly in trastuzumab-treated group after treatment (p < 0.05), whereas the tumour accumulation in control group increased after treatment. Biodistribution studies demonstrated that the results corresponded well with in vivo imaging data. Immunohistochemical staining confirmed the significant reduction in tumor HER2 level upon trastuzumab treatment, and there was an obviously positive correlation between T/NT ratios and HER2 level of tumours with correlation coefficient rs = 0.919, p < 0.05. There was no significant significance in cell binding ratios between varying amount of trastuzumab and the absence of trastuzumab (p > 0.05). The early response to trastuzumab in mice bearing SKOV-3 xenografts was successfully monitored by SPECT imaging using (99m)Tc-peptide-Z(HER2:342). This approach may be valuable in monitoring the therapeutic response in HER 2-positive tumours under HER2-targeted therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting {sup 227}Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

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

Heyerdahl, Helen, E-mail: Helen.Heyerdahl@rr-research.no; Røe, Kathrine; Brevik, Ellen Mengshoel

2013-09-01

Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study themore » effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.« less

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

PubMed

Groeneweg, Jolijn W; Hernandez, Silvia F; Byron, Virginia F; DiGloria, Celeste M; Lopez, Hector; Scialabba, Vanessa; Kim, Minji; Zhang, Ling; Borger, Darrell R; Tambouret, Rosemary; Foster, Rosemary; Rueda, Bo R; Growdon, Whitfield B

2014-12-15

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts. Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation. Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation. ©2014 American Association for Cancer Research.

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer.

PubMed

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

2015-01-01

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

Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941.

PubMed

Junttila, Teemu T; Akita, Robert W; Parsons, Kathryn; Fields, Carter; Lewis Phillips, Gail D; Friedman, Lori S; Sampath, Deepak; Sliwkowski, Mark X

2009-05-05

Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.

Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after α-particle-emitting ²²⁷Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts.

PubMed

Heyerdahl, Helen; Røe, Kathrine; Brevik, Ellen Mengshoel; Dahle, Jostein

2013-09-01

The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab. Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts. Copyright © 2013 Elsevier Inc. All rights reserved.

Trastuzumab Injection

MedlinePlus

... with other medications to treat certain types of stomach cancer that have spread to other parts of the ... weeks. When trastuzumab injection is used to treat stomach cancer, it is usually given once every 3 weeks. ...

A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer

PubMed Central

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

2005-01-01

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

Activated d16HER2 homodimers and SRC kinase mediate optimal efficacy for trastuzumab.

PubMed

Castagnoli, Lorenzo; Iezzi, Manuela; Ghedini, Gaia C; Ciravolo, Valentina; Marzano, Giulia; Lamolinara, Alessia; Zappasodi, Roberta; Gasparini, Patrizia; Campiglio, Manuela; Amici, Augusto; Chiodoni, Claudia; Palladini, Arianna; Lollini, Pier Luigi; Triulzi, Tiziana; Menard, Sylvie; Nanni, Patrizia; Tagliabue, Elda; Pupa, Serenella M

2014-11-01

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment. ©2014 American Association for Cancer Research.

Use of adjuvant trastuzumab in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer by race/ethnicity and education within the National Comprehensive Cancer Network.

PubMed

Freedman, Rachel A; Hughes, Melissa E; Ottesen, Rebecca A; Weeks, Jane C; He, Yulei; Wong, Yu-Ning; Theriault, Richard; Keating, Nancy L

2013-02-15

Trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly efficacious yet costly and time-intensive, and few data are available about its use. The authors of this report examined receipt and completion of adjuvant trastuzumab by race/ethnicity and education for women with HER2-positive disease. The National Comprehensive Cancer Network Breast Cancer Outcomes Database was used to identify 1109 women who were diagnosed with stage I through III, HER2-positive breast cancer during September 2005 through December 2008 and were followed for ≥1 year. The authors used multivariable logistic regression to assess the association of race/ethnicity and education with the receipt of trastuzumab and, among those women who initiated trastuzumab, with the completion of > 270 days of therapy. The cohort was 75% white, 8% black, and 9% Hispanic; and 20% of women had attained a high school degree or less. Most women (83%) received trastuzumab, and no significant differences were observed according to race/ethnicity or socioeconomic status. Among the women who initiated trastuzumab, 73% of black women versus 87% of white women (P = .007) and 70% of women with less than a high school education versus 90% of women with a college degree completed > 270 days of therapy (P = .006). In adjusted analyses, black women (vs white women) and women without a high school degree (vs those with a college degree) had lower odds of completing therapy (black women: odds ratio, 0.45; 95% confidence interval, 0.27-074; white women: odds ratio, 0.27, 95% confidence interval, 0.14-0.51). Differences in completing trastuzumab therapy were observed according to race and educational attainment among women who received treatment at National Comprehensive Cancer Network centers. Efforts to assure the appropriate use of trastuzumab and to understand treatment barriers are needed and may lead to improved outcomes. The authors report differences in the rate at which

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

Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.

PubMed

Shak, S

1999-08-01

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

HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

PubMed

Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

2016-08-01

The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.

PubMed

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

2017-11-01

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

Phosphorylated ribosomal S6 (p-rpS6) as a post-treatment indicator of HER2 signalling targeted drug resistance.

PubMed

Yang-Kolodji, Gloria; Mumenthaler, Shannon M; Mehta, Arjun; Ji, Lingyun; Tripathy, Debu

2015-01-01

To identify clinically relevant predictive biomarkers of trastuzumab resistance. MTT, FACS assays, immunoblotting and immunocytochemistry were used to phenotypically characterize drug responses of two cell models BT474R and SKBR3R. Student's t-test and Spearman's correlation were applied for statistic analysis. The activity of a downstream effector of the HER2 pathway phosphorylated ribosomal protein S6 (p-rpS6), was suppressed by trastuzumab in the parental cell lines yet remained unchanged in the resistant cells following treatment. The level of p-rpS6 was inversely correlated to the drug induced growth inhibition of trastuzumab-resistant cells when they are treated with selected HER2 targeting drugs. p-rpS6 is a robust post-treatment indicator of HER2 pathway-targeted therapy resistance.

Catecholamine-Induced β2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression.

PubMed

Shi, Ming; Yang, Zhengyan; Hu, Meiru; Liu, Dan; Hu, Yabin; Qian, Lu; Zhang, Wei; Chen, Hongyu; Guo, Liang; Yu, Ming; Song, Lun; Ma, Yuanfang; Guo, Ning

2013-06-01

Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.

Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study

PubMed Central

North, Richard T; Harvey, Vernon J; Cox, Levonne C; Ryan, Stuart N

2015-01-01

Background In New Zealand, trastuzumab is standard therapy for human epidermal growth factor receptor-2 (HER2)-positive early and metastatic breast cancer. Given the requirement for ongoing adjuvant or maintenance treatment and intravenous (IV) delivery, such a regimen consumes considerable health care resources. The development of a subcutaneous (SC) trastuzumab formulation with a short administration time offers the potential to reduce hospital expenditure. The aim of this study was to determine medical resource utilization associated with administration of trastuzumab SC injection via handheld syringe vs trastuzumab IV infusion in patients with HER2-positive breast cancer in New Zealand. Methods This noninterventional, descriptive study was conducted at the outpatient oncology centers at Auckland City and Tauranga Hospitals. Trained observers recorded times associated with health care professional (HCP) tasks and consumables use associated with preparation and administration of trastuzumab IV or SC in women with early or metastatic breast cancer. The cost for each formulation was calculated as the mean cost of HCP time (based on Pharmaceutical Management Agency hourly rates) plus the mean cost of consumables used. Results Use of trastuzumab SC vs IV reduced mean chair time by 36.95 minutes and total nurse time by 6.12 minutes; there was a 20.45-minute reduction in pharmacist time when the SC formulation was used. After adding consumable costs, the overall estimated saving with trastuzumab SC vs IV was $76.94 (New Zealand dollars) per patient per cycle. Conclusions Compared with trastuzumab IV infusion, administration of trastuzumab via SC injection reduced time spent in the clinic and decreased HCP resources and consumables needed to administer treatment. These reductions could contribute to a decrease in health care costs and an improvement in the efficiency of HER2-positive breast cancer treatment delivery. PMID:26251623

HER2 copy number of circulating tumour DNA functions as a biomarker to predict and monitor trastuzumab efficacy in advanced gastric cancer.

PubMed

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

2018-01-01

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

HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: Implication for further clinical research.

PubMed

Pietrantonio, F; Caporale, M; Morano, F; Scartozzi, M; Gloghini, A; De Vita, F; Giommoni, E; Fornaro, L; Aprile, G; Melisi, D; Berenato, R; Mennitto, A; Volpi, C C; Laterza, M M; Pusceddu, V; Antonuzzo, L; Vasile, E; Ongaro, E; Simionato, F; de Braud, F; Torri, V; Di Bartolomeo, M

2016-12-15

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease. © 2016 UICC.

Ado-trastuzumab Emtansine

MedlinePlus

... and has not improved or has worsened after treatment with other medications. Ado-trastuzumab emtansine is in ... once every 3 weeks. The length of your treatment depends on how well your body responds to ...

Phase II Study of S-1 plus Trastuzumab for HER2-positive Metastatic Breast Cancer (GBCCSG-01).

PubMed

Fujii, Takaaki; Horiguchi, Jun; Yanagita, Yasuhiro; Koibuchi, Yukio; Ikeda, Fumihiro; Uchida, Nobuyuki; Kimura, Morihiko

2018-02-01

Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC. We conducted a single-arm, open-label, multicenter prospective phase II study to evaluate the efficacy of an S-1 plus trastuzumab regimen for HER2-positive MBC. S-1 was administered orally [80-120 mg, based on body surface area (BSA)] twice a day for 14 consecutive days in a 3-week cycle. Patients with BSA of <1.25 m 2 received a total of 80 mg of S-1, those with BSA ≥1.5 m 2 received 120 mg, and the remaining received 100 mg daily in two divided doses. Trastuzumab was administered intravenously at 8 mg/kg on day 1 of the first cycle and at 6 mg/kg on day 1 of subsequent cycles, i.e., every 3 weeks. Between December 2008 and March 2013, 10 patients were enrolled and received a median of 17 (range=3-76) cycles of treatment. Overall response and clinical benefit rates were 60.0% and 90.0%, respectively. Progression-free survival was 15.8 (95% confidence interval=9.4-29.6) months and overall survival was 45.5 (95% confidence interval=37.1-62.2) months. Grade 3/4 adverse events included were neutropenia and hyperglycemia in one patient each (10.0%). There was no clinically significant cardiotoxicity. The combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this study. S-1 plus anti-HER2 therapy is a feasible treatment option for HER2-positive MBC. Copyright© 2018, International Institute of Anticancer Research (Dr. George J

Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy.

PubMed

Stagg, John; Loi, Sherene; Divisekera, Upulie; Ngiow, Shin Foong; Duret, Helene; Yagita, Hideo; Teng, Michele W; Smyth, Mark J

2011-04-26

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells are involved in trastuzumab therapy, the relative contribution of lymphocyte-mediated cellular cytotoxicity and antitumor cytokines remains unknown. We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL. Our study thus challenges the notion that classical antibody-dependent, lymphocyte-mediated cellular cytotoxicity is important for trastuzumab. We demonstrate that anti-ErbB-2 mAb therapy of experimental tumors derived from MMTV-ErbB-2 transgenic mice triggers MyD88-dependent signaling and primes IFN-γ-producing CD8+ T cells. Adoptive cell transfer of purified T cell subsets confirmed the essential role of IFN-γ-producing CD8+ T cells. Notably, anti-ErbB-2 mAb therapy was independent of IL-1R or IL-17Ra signaling. Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.

Correlation Between Quantitative HER-2 Protein Expression and Risk for Brain Metastases in HER-2+ Advanced Breast Cancer Patients Receiving Trastuzumab-Containing Therapy

PubMed Central

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

2012-01-01

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

Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.

PubMed

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

2012-01-01

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

HER2 activating mutations are targets for colorectal cancer treatment.

PubMed

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

2015-08-01

The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. 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 mutants 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) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. 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 PDXs. HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. ©2015 American Association for Cancer Research.

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

PubMed Central

Hoti, Ada; Iovene, Pietro Alessandro; Natalello, Antonino; Avvakumova, Svetlana; Colombo, Miriam

2018-01-01

Background We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading

Baseline Immunoglobulin E Levels as a Marker of Doxorubicin and Trastuzumab-Associated Cardiac Dysfunction

PubMed Central

Beer, Lynn A.; Kossenkov, Andrew V.; Liu, Qin; Luning Prak, Eline; Domchek, Susan; Speicher, David W.; Ky, Bonnie

2016-01-01

Rationale There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). Objective We aimed to discover new biomarkers associated with doxorubicin and trastuzumab-induced CTRCD using high-throughput proteomic profiling. Methods and Results Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from three cases with CTRCD and four age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography- mass spectrometry (LC-MS). From these analyses, 862 proteins were identified from case/control pairs 1 and 2, and 1,360 proteins from case/control pair 3. Proteins with a greater than 1.5-fold change in cases compared to controls with a p<0.05 either at the time of CTRCD diagnosis or across all timepoints were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E (IgE), with higher levels detected at baseline and across all timepoints in controls without CTRCD as compared to matched CTRCD cases (p<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline IgE levels were associated with a significantly lower risk of CTRCD (p=0.018). Conclusions In patients receiving doxorubicin and trastuzumab, high baseline IgE levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin and trastuzumab-induced cardiac dysfunction. PMID:27582370

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging

PubMed Central

Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

2017-01-01

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4. PMID:28915583

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89Zr-Trastuzumab and 18F-FDG PET imaging.

PubMed

Wimana, Zéna; Gebhart, Geraldine; Guiot, Thomas; Vanderlinden, Bruno; Larsimont, Denis; Doumont, Gilles; Van Simaeys, Gaetan; Goldman, Serge; Flamen, Patrick; Ghanem, Ghanem

2017-08-22

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ( 89 Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity ( 89 Zr-Trastuzumab HER2-immunoPET) and glucose metabolism ( 18 F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

Tumor dosimetry for I-131 trastuzumab therapy in a Her2+ NCI N87 xenograft mouse model using the Siemens SYMBIA E gamma camera with a pinhole collimator

NASA Astrophysics Data System (ADS)

Lee, Young Sub; Kim, Jin Su; Deuk Cho, Kyung; Kang, Joo Hyun; Moo Lim, Sang

2015-07-01

We performed imaging and therapy using I-131 trastuzumab and a pinhole collimator attached to a conventional gamma camera for human use in a mouse model. The conventional clinical gamma camera with a 2-mm radius-sized pinhole collimator was used for monitoring the animal model after administration of I-131 trastuzumab The highest and lowest radiation-received organs were osteogenic cells (0.349 mSv/MBq) and skin (0.137 mSv/MBq), respectively. The mean coefficients of variation (%CV) of the effective dose equivalent and effective dose were 0.091 and 0.093 mSv/MBq respectively. We showed the feasibility of the pinholeattached conventional gamma camera for human use for the assessment of dosimetry. Mouse dosimetry and prediction of human dosimetry could be used to provide data for the safety and efficacy of newly developed therapeutic schemes.

Tyrosine kinase inhibitor induced growth factor receptor upregulation enhances the efficacy of near-infrared targeted photodynamic therapy in esophageal adenocarcinoma cell lines.

PubMed

Hartmans, Elmire; Linssen, Matthijs D; Sikkens, Claire; Levens, Afra; Witjes, Max J H; van Dam, Gooitzen M; Nagengast, Wouter B

2017-05-02

Esophageal carcinoma (EC) is a global health problem, with disappointing 5-year survival rates of only 15-25%. Near-infrared targeted photodynamic therapy (NIR-tPDT) is a novel strategy in which cancer-targeted phototoxicity is able to selectively treat malignant cells. In this in vitro report we demonstrate the applicability of antibody-based NIR-tPDT in esophageal adenocarcinoma (EAC), using the phototoxic compounds cetuximab-IRDye700DX and trastuzumab-IRDye700DX, targeting respectively epidermal growth factor receptor 1 (EGFR) and 2 (HER2). Furthermore, we demonstrate that NIR-tPDT can be made more effective by tyrosine kinase inhibitor (TKI) induced growth receptor upregulation. Together, these results unveil a novel strategy for non-invasive EAC treatment, and by pretreatment-induced receptor upregulation its future clinical application may be optimized.

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

PubMed Central

Tezuka, Kenji; Takashima, Tsutomu; Kashiwagi, Shinichiro; Kawajiri, Hidemi; Tokunaga, Shinya; Tei, Seika; Nishimura, Shigehiko; Yamagata, Shigehito; Noda, Satoru; Nishimori, Takeo; Mizuyama, Yoko; Sunami, Takeshi; Ikeda, Katsumi; Ogawa, Yoshinari; Onoda, Naoyoshi; Ishikawa, Tetsuro; Kudoh, Shinzoh; Takada, Minoru; Hirakawa, Kosei

2017-01-01

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.

PubMed

Stebbing, Justin; Baranau, Yauheni; Baryash, Valeriy; Manikhas, Alexey; Moiseyenko, Vladimir; Dzagnidze, Giorgi; Zhavrid, Edvard; Boliukh, Dmytro; Stroyakovskii, Daniil; Pikiel, Joanna; Eniu, Alexandru; Komov, Dmitry; Morar-Bolba, Gabriela; Li, Rubi K; Rusyn, Andriy; Lee, Sang Joon; Lee, Sung Young; Esteva, Francisco J

2017-07-01

ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. Celltrion Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sequential Versus Concurrent Trastuzumab in Adjuvant Chemotherapy for Breast Cancer

PubMed Central

Perez, Edith A.; Suman, Vera J.; Davidson, Nancy E.; Gralow, Julie R.; Kaufman, Peter A.; Visscher, Daniel W.; Chen, Beiyun; Ingle, James N.; Dakhil, Shaker R.; Zujewski, JoAnne; Moreno-Aspitia, Alvaro; Pisansky, Thomas M.; Jenkins, Robert B.

2011-01-01

Purpose NCCTG (North Central Cancer Treatment Group) N9831 is the only randomized phase III trial evaluating trastuzumab added sequentially or used concurrently with chemotherapy in resected stages I to III invasive human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods Patients received doxorubicin and cyclophosphamide every 3 weeks for four cycles, followed by paclitaxel weekly for 12 weeks (arm A), paclitaxel plus sequential trastuzumab weekly for 52 weeks (arm B), or paclitaxel plus concurrent trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (arm C). The primary end point was disease-free survival (DFS). Results Comparison of arm A (n = 1,087) and arm B (n = 1,097), with 6-year median follow-up and 390 events, revealed 5-year DFS rates of 71.8% and 80.1%, respectively. DFS was significantly increased with trastuzumab added sequentially to paclitaxel (log-rank P < .001; arm B/arm A hazard ratio [HR], 0.69; 95% CI, 0.57 to 0.85). Comparison of arm B (n = 954) and arm C (n = 949), with 6-year median follow-up and 313 events, revealed 5-year DFS rates of 80.1% and 84.4%, respectively. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (arm C/arm B HR, 0.77; 99.9% CI, 0.53 to 1.11), but the P value (.02) did not cross the prespecified O'Brien-Fleming boundary (.00116) for the interim analysis. Conclusion DFS was significantly improved with 52 weeks of trastuzumab added to adjuvant chemotherapy. On the basis of a positive risk-benefit ratio, we recommend that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen. PMID:22042958

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

PubMed

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

2018-04-03

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

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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Differential behaviors of trastuzumab-sensitive and -resistant SKBR3 cells treated with menadione reveal the involvement of Notch1/Akt/FOXO1 signaling elements.

PubMed

Sajadimajd, Soraya; Yazdanparast, Razieh

2015-10-01

Given that HER2 serves as a putative target for therapy in HER2-positive breast cancer, intrinsic and/or acquired resistance to trastuzumab (T) has been proposed to be the major obstacle in treatments. In addition, chemoresistance is commonly attributed to increased antioxidant capacity. In that regard, we evaluated the effect of menadione (M) alone and/or its combination with trastuzumab on proliferation, intracellular GSH and ROS contents as well as HER2 and Notch1 signaling pathways in both trastuzumab-resistant (SKBR3(R)) and -sensitive SKBR3 (SKBR3(S)) cells. In spite of increased level of ROS and reduced level of GSH in M-treated SKBR3(S) cells, M-treated SKBR3(R) cells showed a decreased content of ROS and GSH compared to untreated cells. However, M/T co-treatment of SKBR3 cells indicated no effect on ROS content, while decreased the level of GSH compared to untreated control cells. Based on the extent of apoptosis, colony formation and wound healing assays, M alone, and/or in combination with T had a stronger inhibitory effect on proliferation of SKBR3(R) cells relative to SKBR3(S) cells. These effects might be due to the stronger effects of M and/or M/T on downregulation of p-Akt, Hes1, NICD, and upregulation of FOXO1 among SKBR3(R) cells relative to the sensitive SKBR3 cells. These findings would certainly shed light on some of the signaling factors involved in induction of trastuzumab resistance and would be of value in designing more efficient chemosensitization strategies.

Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101--Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI.

PubMed

Pituskin, Edith; Haykowsky, Mark; Mackey, John R; Thompson, Richard B; Ezekowitz, Justin; Koshman, Sheri; Oudit, Gavin; Chow, Kelvin; Pagano, Joseph J; Paterson, Ian

2011-07-27

MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

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

2016-03-01

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

Resistance to therapy in estrogen receptor positive and human epidermal growth factor 2 positive breast cancers: progress with latest therapeutic strategies.

PubMed

Lousberg, Laurence; Collignon, Joëlle; Jerusalem, Guy

2016-11-01

In this article, we focus on the subtype of estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-positive breast cancer (BC). Preclinical and clinical data indicate a complex molecular bidirectional crosstalk between the ER and HER2 pathways. This crosstalk probably constitutes one of the key mechanisms of drug resistance in this subclass of BC. Delaying or even reversing drug resistance seems possible by targeting pathways implicated in this crosstalk. High-risk patients currently receive anti-HER2 therapy, chemotherapy and endocrine therapy in the adjuvant setting. In metastatic cases, most patients receive a combination of anti-HER2 therapy and chemotherapy. Only selected patients presenting more indolent disease are candidates for combinations of anti-HER2 therapy and endocrine therapy. However, relative improvements in progression-free survival by chemotherapy-based regimens are usually lower in ER-positive patients than the ER-negative and HER2-positive subgroup. Consequently, new approaches aiming to overcome endocrine therapy resistance by adding targeted therapies to endocrine therapy based regimens are currently explored. In addition, dual blockade of HER2 or the combination of trastuzumab and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOP) inhibitors targeting the downstream pathway are strategies to overcome resistance to trastuzumab. This may lead in the near future to the less frequent use of chemotherapy-based treatment options in ER-positive, HER2-positive BC.

[A paclitaxel-resistant case of recurrent breast cancer responded to combination therapy of capecitabine and trastuzumab].

PubMed

Marutaka, Masahito; Suguri, Takayasu; Miyake, Mikio; Yoshimura, Kouichi

2005-12-01

The patient was a 72-year-old female. Under the supervision of her former doctor, this patient had an operation and adjuvant chemotherapy for progressive breast cancer. During the following period, local recurrence of breast cancer and pulmonary lymphopathia developed. Although medication with paclitaxel was attempted, the focus was resistant to this treatment, and metastasis to the brain was also observed. Due to the dyscrasia above, the patient had difficulty breathing and became bedridden. Subsequently, combination treatment of capecitabine and trastuzumab was attempted. As a result,metastasis in the brain and pulmonary lymphopathia were improved. The patient recovered enough to be discharged at one time. However, his condition took a turn for the worse after the interruption of the combination treatment by a side effect. In conclusion, the combination treatment of capecitabine and trastuzumab is thought to be effective for non-responders to paclitaxel.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PubMed

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-02-10

The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. © 2014 by American Society of Clinical Oncology.

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

Targeted therapies in gastric cancer treatment: where we are and where we are going.

PubMed

Tomasello, Gianluca; Ghidini, Michele; Liguigli, Wanda; Ratti, Margherita; Toppo, Laura; Passalacqua, Rodolfo

2016-06-01

Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.

[Current Status of Targeted Treatment in Breast Cancer].

PubMed

Seiffert, Katharina; Schmalfeldt, Barbara; Müller, Volkmar

2017-11-01

Within the last years, significant improvements have been achieved in breast cancer treatment, particularly with the development of targeted therapies. Major progress has been made in identifying the drivers malignant growth in oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of the cyclin-dependent kinases CDK4 and CDK6 like palbociclib and inhibitors of mTOR substantially improve progression-free survival. For patients with HER2-positive disease the addition of Pertuzumab to Trastuzumab in combination with chemotherapy has been a significant improvement in anti-HER2 therapy in early as well as metastatic breast cancer. Evidence-based further line therapy options in the metastatic setting include T-DM1 and in later lines Lapatinib. For triple negative disease the angiogenesis inhibitor Bevacizumab is approved, which increases progression free survival. Immune checkpoint inhibitors, PARP-inhibitors or anti-androgens represent promising strategies, all of which are currently being evaluated in clinical trials. The development of predictive biomarkers to guide targeted therapies is still the subject of research. © Georg Thieme Verlag KG Stuttgart · New York.

Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients.

PubMed

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

2009-04-01

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

Estimation of Premature Deaths From Lack of Access to Anti-HER2 Therapy for Advanced Breast Cancer in the Brazilian Public Health System.

PubMed

Debiasi, Márcio; Reinert, Tomás; Kaliks, Rafael; Amorim, Gilberto; Caleffi, Maira; Sampaio, Carlos; Fernandes, Gustavo Dos Santos; Barrios, Carlos H

2017-06-01

Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients. On the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow-up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions. It was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab. Trastuzumab is included in the WHO's list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil.

Estimation of Premature Deaths From Lack of Access to Anti-HER2 Therapy for Advanced Breast Cancer in the Brazilian Public Health System

PubMed Central

Debiasi, Márcio; Reinert, Tomás; Kaliks, Rafael; Amorim, Gilberto; Caleffi, Maira; Sampaio, Carlos; Fernandes, Gustavo dos Santos

2017-01-01

Purpose Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients. Methods On the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow-up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions. Results It was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab. Conclusion Trastuzumab is included in the WHO’s list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil. PMID:28717761

Budget Impact Analysis of Biosimilar Trastuzumab for the Treatment of Breast Cancer in Croatia.

PubMed

Cesarec, August; Likić, Robert

2017-04-01

Breast cancer is the most common cancer in women and has considerable impact on healthcare budgets and patients' quality of life. Trastuzumab (Herceptin ® ) is a monoclonal antibody directed against the human epidermal growth factor receptor (HER2) for the treatment of breast cancer. Several trastuzumab biosimilars are currently in development. In 2015, trastuzumab was the drug with the highest financial consumption among all drugs in Croatia. This model estimates the 1-year budget impact of the introduction of biosimilar trastuzumab in Croatia. A budget impact model, based on approvals for trastuzumab treatment in 2015, was developed for the introduction of biosimilars. Two biosimilar scenarios were developed: biosimilar scenario 1, based on all approvals in 2015, and biosimilar scenario 2, based on approvals after February 2015 and the reimbursement of the subcutaneous formulation of trastuzumab in Croatia. Only trastuzumab-naïve patients and drug-acquisition costs were used in the model. Uptake of biosimilar was assumed at 50 %. Scenarios were calculated with price discounts of 15, 25 and 35 %. The robustness of the model was tested by extensive sensitivity analyses. The projected drug cost savings from the introduction of biosimilar trastuzumab range from €0.26 million (scenario 2, 15 % price discount) to €0.69 million (scenario 1, 35 % price discount). If budget savings were reinvested to treat additional patients with trastuzumab, 14 (scenario 2, 15 % price discount) to 47 (scenario 1, 35 % price discount) additional patients could be treated. Sensitivity analyses showed that the incidence of breast cancer had the highest impact on the model, with a 10 % decrease in incidence leading to an 11.3 % decrease in projected savings. The introduction of biosimilar trastuzumab could lead to significant drug cost savings in Croatia.

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PubMed Central

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-01-01

Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. PMID:25547504

Reorienting the Fab Domains of Trastuzumab Results in Potent HER2 Activators

PubMed Central

Scheer, Justin M.; Sandoval, Wendy; Elliott, J. Michael; Shao, Lily; Luis, Elizabeth; Lewin-Koh, Sock-Cheng; Schaefer, Gabriele; Vandlen, Richard

2012-01-01

The structure of the Fab region of antibodies is critical to their function. By introducing single cysteine substitutions into various positions of the heavy and light chains of the Fab region of trastuzumab, a potent antagonist of HER2, and using thiol chemistry to link the different Fabs together, we produced a variety of monospecific F(ab′)2-like molecules with activities spanning from activation to inhibition of breast tumor cell growth. These isomers (or bis-Fabs) of trastuzumab, with varying relative spatial arrangements between the Fv-regions, were able to either promote or inhibit cell-signaling activities through the PI3K/AKT and MAPK pathways. A quantitative phosphorylation mapping of HER2 indicated that the agonistic isomers produced a distinct phosphorylation pattern associated with activation. This study suggests that antibody geometric isomers, found both in nature and during synthetic antibody development, can have profoundly different biological activities independent of their affinities for their target molecules. PMID:23284778

Targeted Therapy for Cancer

Cancer.gov

Targeted therapy is a type of cancer treatment that targets the changes in cancer cells that help them grow, divide, and spread. Learn how targeted therapy works against cancer and about side effects that may occur.

A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

PubMed

Hudis, Clifford; Swanton, Charles; Janjigian, Yelena Y; Lee, Ray; Sutherland, Stephanie; Lehman, Robert; Chandarlapaty, Sarat; Hamilton, Nicola; Gajria, Devika; Knowles, James; Shah, Jigna; Shannon, Keith; Tetteh, Ernestina; Sullivan, Daniel M; Moreno, Carolina; Yan, Li; Han, Hyo Sook

2013-11-19

Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. ClinicalTrials.gov; identifier: NCT00963547.

Current Molecular Targeted Therapy in Advanced Gastric Cancer: A Comprehensive Review of Therapeutic Mechanism, Clinical Trials, and Practical Application

PubMed Central

Li, Kaichun; Li, Jin

2016-01-01

Despite the great progress in the treatment of gastric cancer, it is still the third leading cause of cancer death worldwide. Patients often miss the opportunity for a surgical cure, because the cancer has already developed into advanced cancer when identified. Compared to best supportive care, chemotherapy can improve quality of life and prolong survival time, but the overall survival is often short. Due to the molecular study of gastric cancer, new molecular targeted drugs have entered the clinical use. Trastuzumab, an antibody targeting human epidermal growth factor receptor 2 (HER2), can significantly improve survival in advanced gastric cancer patients with HER2 overexpression. Second-line treatment of advanced gastric cancer with ramucirumab, an antibody targeting VEGFR-2, alone or in combination with paclitaxel, has been proved to provide a beneficial effect. The VEGFR-2 tyrosine kinase inhibitor, apatinib, can improve the survival of advanced gastric cancer patients after second-line chemotherapy failure. Unfortunately, none of the EGFR targeting antibodies (cetuximab or panitumumab), VEGF targeting monoclonal antibodies (bevacizumab), mTOR inhibitor (everolimus), or HGF/MET pathway targeting drugs has a significant survival benefit. Many other clinical trials based on molecular markers are underway. This review will summarize targeted therapies for advanced gastric cancer. PMID:26880889

The short-term safety of adjuvant paclitaxel plus trastuzumab - A single centre experience.

PubMed

Ates, Ozturk; Sunar, Veli; Aslan, Alma; Karatas, Fatih; Sahin, Suleyman; Altundag, Kadri

2017-01-01

HER2-amplified breast cancer (BC) has a poor prognosis. The combination of trastuzumab with chemotherapy in the adjuvant setting decreases recurrence and improves overall survival in HER2-positive BC. However, the role of adjuvant treatment in patients with HER2-amplified small BC without lymph node involvement is still under debate. The purpose of this study was to investigate the safety of adjuvant paclitaxel and trastuzumab (APT) in this group of patients. A total of 87 operated early BC patients without lymph node involvement (N0) were treated with APT for 12 weeks followed by trastuzumab alone for a total of 9 months. Clinicopathological features and adverse events were analyzed. The median patient age was 50 years (range 28- 82), and 51% of them were postmenopausal. The median tumor diameter was 2.4 cm (range 0.5-6), with 51% of the patients having tumor size between 2 and 3 cm. Eighty-one percent of patients had invasive ductal carcinoma (IDC), and 64% had grade 3 tumors. Adjuvant hormone therapy and adjuvant radiotherapy were administered to 65 and 54% of patients, respectively. At a median follow up of 13 months (range 6-38), one patient (1.1%, 95% CI 0-3.4) experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) and 3 patients (3.4%, 95% CI 0-6.9) experienced grade 3 neuropathy. APT appears to be a safe combination in early-stage, HER2-amplified and node-negative BC.

64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer.

PubMed

Tamura, Kenji; Kurihara, Hiroaki; Yonemori, Kan; Tsuda, Hitoshi; Suzuki, Junko; Kono, Yuzuru; Honda, Natsuki; Kodaira, Makoto; Yamamoto, Harukaze; Yunokawa, Mayu; Shimizu, Chikako; Hasegawa, Koki; Kanayama, Yousuke; Nozaki, Satoshi; Kinoshita, Takayuki; Wada, Yasuhiro; Tazawa, Shusaku; Takahashi, Kazuhiro; Watanabe, Yasuyoshi; Fujiwara, Yasuhiro

2013-11-01

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer.

PubMed

Baselga, José; Lewis Phillips, Gail D; Verma, Sunil; Ro, Jungsil; Huober, Jens; Guardino, Alice E; Samant, Meghna K; Olsen, Steve; de Haas, Sanne L; Pegram, Mark D

2016-08-01

HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with the expression of specific biomarkers in the phase III EMILIA study. Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase PCR; for PTEN protein expression (n = 271) by IHC; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations. Longer progression-free survival (PFS) and overall survival (OS) were observed with T-DM1 compared with capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median PFS (mutant vs. wild type: 4.3 vs. 6.4 months) and OS (17.3 vs. 27.8 months) in capecitabine plus lapatinib-treated patients, but not in T-DM1-treated patients (PFS, 10.9 vs. 9.8 months; OS, not reached in mutant or wild type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations. Although other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors. Clin Cancer Res; 22(15); 3755-63. ©2016 AACR. ©2016 American Association for Cancer Research.

11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.

PubMed

Cameron, David; Piccart-Gebhart, Martine J; Gelber, Richard D; Procter, Marion; Goldhirsch, Aron; de Azambuja, Evandro; Castro, Gilberto; Untch, Michael; Smith, Ian; Gianni, Luca; Baselga, Jose; Al-Sakaff, Nedal; Lauer, Sabine; McFadden, Eleanor; Leyland-Jones, Brian; Bell, Richard; Dowsett, Mitch; Jackisch, Christian

2017-03-25

Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free

Incidence and identification of risk factors for trastuzumab-induced cardiotoxicity in breast cancer patients: an audit of a single "real-world" setting.

PubMed

Tang, Grace H; Acuna, Sergio A; Sevick, Laura; Yan, Andrew T; Brezden-Masley, Christine

2017-09-01

Management of human epidermal growth factor receptor-2-positive (HER2+) breast cancer patients includes the combination of adjuvant chemotherapy and trastuzumab. A meta-analysis reported that <5% of HER2+ breast cancer patients will develop trastuzumab-induced cardiotoxicity (TIC). Observational data suggest that incidence is much higher. We aimed to determine the incidence, time to development, and risk factors associated with TIC among less selected patients. A retrospective cohort study was carried out in 160 HER2+ breast cancer patients who received adjuvant chemotherapy with trastuzumab from January 2006 to June 2014 at St. Michael's Hospital, Toronto, Canada. Patient demographics, cardiovascular history, and TIC were recorded. TIC was defined as symptomatic (heart failure) or asymptomatic [decline in left ventricular ejection fraction (LVEF) by ≥10% or LVEF ≤ 50%]. Of the 160 patients [median age 52 (IQR 45-60), 48.1% on anthracycline-based chemotherapy], 34 patients (21.3%) experienced TIC (median follow-up 55.4 months). The median time to development of TIC was 28.5 weeks during trastuzumab therapy. Those with TIC were more likely to have undergone a mastectomy (52.9 vs. 33.3%, p = 0.04). However, after adjusting for anthracycline-based chemotherapy, and radiotherapy, mastectomy was not independently associated with TIC (HR 2.02; 95% CI 0.88-4.63). The incidence of TIC is higher in our "real-world" population compared to clinical trial data. The median time to development of TIC was 28 weeks after trastuzumab initiation, approximately the 10th treatment of trastuzumab. Timely identification and management of patients is important to avoid irreversible cardiac toxicity and improve breast cancer survival.

Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.

PubMed

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

2015-02-19

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

Intrathecal trastuzumab in the management of HER2+ breast leptomeningeal disease: a single institution experience.

PubMed

Figura, Nicholas B; Long, Wendy; Yu, Michael; Robinson, Timothy J; Mokhtari, Sepideh; Etame, Arnold B; Tran, Nam D; Diaz, Roberto; Soliman, Hatem; Han, Heather S; Sahebjam, Solmaz; Forsyth, Peter A; Ahmed, Kamran A

2018-06-01

Leptomeningeal disease is a rare and devastating presentation of advanced stage metastatic breast cancer with historically poor overall survival. We assessed the safety and feasibility of intrathecal (IT) trastuzumab in HER2+ leptomeningeal disease. A total of 13 patients were treated at our institution with IT trastuzumab beginning November 2012 and followed until November 2017. Outcomes including craniospinal progression as well as overall survival (OS) following initiation of IT trastuzumab were assessed from review of the clinical chart and radiologic examinations. The median age of patients was 48 (range 29-75). Median time from breast cancer diagnosis to development of brain metastases was 87.7 months with a median of 4.6 months from brain metastases diagnosis to the development of leptomeningeal disease. Previous whole brain radiotherapy was received by the majority of patients (92%) and prior surgery for brain metastases was performed in 23%. Median duration of IT trastuzumab treatment was 6.4 months. Median time from IT trastuzumab start to craniospinal progression was 5.7 months with 6- and 12-month Kaplan-Meier rates of 41 and 21%, respectively. Sustained responses > 6 months were achieved in 4 patients. Median survival from the start of IT trastuzumab was 10.6 months with 6- and 12-month OS rates of 68 and 47%, respectively. IT trastuzumab was well tolerated with one patient developing ventriculitis, which resolved with IV antibiotics. IT trastuzumab was well tolerated with prolongation of OS over historical controls. IT trastuzumab should be considered for management of HER2+ leptomeningeal disease patients.

Cardiac monitoring in patients on trastuzumab: correlation of ultrasound and radionuclide ventriculography.

PubMed

Matos, Erika; Jug, Borut; Vidergar Kralj, Barbara; Zakotnik, Branko

2017-06-01

Guidance on cardiac surveillance during adjuvant trastuzumab therapy remains elusive. The recommended methods are two-dimensional echocardiography (2D-ECHO) and electrocardiography gated equilibrium radionuclide ventriculography (RNV). We assessed the correlation and possible specific merits of these two methods. In a prospective cohort study in patients undergoing post-anthracycline adjuvant trastuzumab therapy, clinical assessment, 2D-ECHO and RNV were performed at baseline, 4, 8 and 12 months. The correlation between used methods was estimated with Pearson's correlation coefficient and Bland-Altman analysis. Ninety-two patients (mean age 53.6±9.0 years) were included. The correlation of LVEF measured by ECHO and RNV at each time point was statistically insignificant. Values obtained by ECHO were on average higher (3.7% to 4.5%). A decline in LVEF of ≥10% from baseline was noticed in 19 (24.4%) and 13 (14.9%) patients with ECHO and RNV, respectively, however in only one patient by both methods simultaneously. A decline in LVEF of ≥10% to below 50% was found in three and none patients according to RNV and ECHO measurements, respectively. There is a weak correlation of ECHO and RNV measurements in individual patient, the results obtained by the methods are not interchangeable. LVEF values determined by 2D-ECHO were on average higher compared to RNV determined ones. When in an asymptomatic patient a decline in LVEF requiring treatment interruption is detected by RNV ECHO re-evaluation and referral to a cardiologist is advised.

Impact of α-targeted radiation therapy on gene expression in a pre-clinical model for disseminated peritoneal disease when combined with paclitaxel.

PubMed

Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E; Brechbiel, Martin W

2014-01-01

To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and ²¹²Pb-trastuzumab (Pac/²¹²Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/²¹²Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/²¹²Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that ²¹²Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.

Systemic therapy for HER2-positive early-stage breast cancer.

PubMed

Mathew, Aju; Romond, Edward H

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

3D Culture Represents Apoptosis Induced by Trastuzumab Better than 2D Monolayer Culture.

PubMed

Tatara, Takashi; Mukohara, Toru; Tanaka, Rina; Shimono, Yohei; Funakoshi, Yohei; Imamura, Yoshinori; Toyoda, Masanori; Kiyota, Naomi; Hirai, Midori; Kakeji, Yoshihiro; Minami, Hironobu

2018-05-01

Our hypothesis was that three-dimensional (3D) culture better represents differential in vivo responses to trastuzumab between PIK3CA-wild-type (wt) and mutant (mt) cell lines than does two-dimensional (2D) culture. Apoptosis and cell signaling proteins were evaluated in response to trastuzumab with and without BKM120, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, using western blot analysis of four breast cancer cell lines with human epidermal growth factor receptor 2 (HER2) amplification. Increased expression of cleaved poly (ADP-ribose) polymerase (PARP) was observed only in 3D-cultured PIK3CA-wt lines in response to trastuzumab, but not in 2D-cultured PIK3CA-wt or PIK3CA-mt lines. Decrease in the ratio of phosphorylated (p-)AKT to AKT in response to trastuzumab was more profound in PIK3CA-wt cells than in PIK3CA-mt cells in 3D culture, while the difference between PIK3CA genotypes was less apparent in 2D culture. Treatment with BKM120 and trastuzumab resulted in a stronger increase in cleaved PARP than either treatment alone. 3D Culture appears to better represent trastuzumab-induced apoptosis and resistance to trastuzumab associated with PIK3CA mutation. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment?

PubMed

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-05-01

One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect.Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients' ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits.Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13-82) and the mean number of ZA infusions was 38 (range: 15-56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively).The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab.

Is Administration of Trastuzumab an Independent Risk Factor for Developing Osteonecrosis of the Jaw Among Metastatic Breast Cancer Patients Under Zoledronic Acid Treatment?

PubMed Central

Pilanci, Kezban Nur; Alco, Gul; Ordu, Cetin; Sarsenov, Dauren; Celebi, Filiz; Erdogan, Zeynep; Agacayak, Filiz; Ilgun, Serkan; Tecimer, Coskun; Demir, Gokhan; Eralp, Yesim; Okkan, Sait; Ozmen, Vahit

2015-01-01

Abstract One of the most important adverse effects of zoledronic acid (ZA) is osteonecrosis of the jaw (ONJ). In previous literature, several risk factors have been identified in the development of ONJ. In this study, we aimed to determine the role of trastuzumab, an antiangiogenic agent, as an independent risk factor for the development of this serious side effect. Our study included 97 patients (mean age: 54 ± 10 years) with breast cancer, recorded in the archives of the Istanbul Florence Nightingale Breast Study Group, who received ZA therapy due to bone metastases between March 2006 and December 2013. We recorded the patients’ ages, weights, duration of treatment with ZA, number of ZA infusions, dental procedures, anticancer treatments (chemotherapy, aromatase inhibitor, trastuzumab), the presence of diabetes mellitus or renal dysfunction, and smoking habits. Thirteen patients (13.40%) had developed ONJ. Among the patients with ONJ, the mean time of exposure to ZA was 41 months (range: 13–82) and the mean number of ZA infusions was 38 (range: 15–56). The duration of treatment with ZA and the use of trastuzumab were observed to be 2 factors that influenced the development of ONJ (P = 0.049 and P = 0.028, respectively). The development of ONJ under ZA treatment may be associated solely with the duration of ZA treatment and the concurrent administration of trastuzumab. These findings show that patients who are administered trastuzumab for metastatic breast cancer while undergoing ZA treatment are prone to developing ONJ. Therefore, we recommend intense clinical observation to avoid this particular condition in patients receiving ZA and trastuzumab. PMID:25950681

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study.

PubMed

Safran, Howard; DiPetrillo, Thomas; Nadeem, Ahmed; Steinhoff, Margaret; Tantravahi, Umadevi; Rathore, Ritesh; Wanebo, Harold; Hughes, Marilyn; Maia, Chris; Tsai, James Y; Pasquariello, Terry; Pepperell, John R; Cioffi, William; Kennedy, Teresa; Reeder, Laurie; Ng, Thomas; Adrian, Alyn; Goldstein, Lisa; Chak, Bapsi; Choy, Hak

2004-01-01

To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.

[(64) Cu]-labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice.

PubMed

Schjoeth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren; Højrup, Peter; Hansen, Paul Robert; Gillings, Nic; Kjaer, Andreas

2015-05-30

The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has previously been labelled with copper-64 by conjugation of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the (64) Cu-labelling of DOTA-trastuzumab and as the first to produce and compare with its 1,4,7-triazacyclononane, 1-glutaric acid-5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction temperature and time. Full (64) Cu incorporation could be achieved using a minimum of 10-µg DOTA-trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 µg of DOTA-trastuzumab. In comparison, 80% incorporation was achieved for (64) Cu-labelling of NODAGA-trastuzumab. Both [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both tracers. © 2015 The Authors Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.

Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab.

PubMed

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

2011-06-01

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

The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer.

PubMed

Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

2013-01-01

Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer.

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

PubMed

Mukai, Hirofumi; Saeki, Toshiaki; Aogi, Kenjiro; Naito, Yoichi; Matsubara, Nobuaki; Shigekawa, Takashi; Ueda, Shigeto; Takashima, Seiki; Hara, Fumikata; Yamashita, Tomonari; Ohwada, Shoichi; Sasaki, Yasutsuna

2016-10-01

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Trastuzumab in early stage breast cancer: a cost-effectiveness analysis for Belgium.

PubMed

Neyt, Mattias; Huybrechts, Michel; Hulstaert, Frank; Vrijens, France; Ramaekers, Dirk

2008-08-01

Although trastuzumab is traditionally used in metastatic breast cancer treatment, studies reported on the efficacy and safety of trastuzumab in adjuvant setting for the treatment of early stage breast cancer in HER2+ tumors. We estimated the cost-effectiveness and budget impact of reimbursing trastuzumab in this indication from a payer's perspective. We constructed a health economic model. Long-term consequences of preventing patients to progress to metastatic breast cancer and side effects such as congestive heart failure were taken into account. Uncertainty was handled applying probabilistic modeling and through probabilistic sensitivity analyses. In the HERA scenario, applying an arbitrary threshold of euro30000 per life-year gained, early stage breast cancer treatment with trastuzumab is cost-effective for 9 out of 15 analyzed subgroups (according to age and stage). In contrast, treatment according to the FinHer scenario is cost-effective in 14 subgroups. Furthermore, the FinHer regimen is most of the times cost saving with an average incremental cost of euro668, euro-1045, and euro-6869 for respectively stages I, II and III breast cancer patients whereas the HERA regimen is never cost saving due to the higher initial treatment costs. The model shows better cost-effectiveness for the 9-week initial treatment (FinHer) compared to no trastuzumab treatment than for the 1-year post-chemotherapy treatment (HERA). Both from a medical and an economic point of view, the 9-week initial treatment regimen with trastuzumab shows promising results and justifies the initiation of a large comparative trial with a 1-year regimen.

Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer.

PubMed

Mortimer, Joanne E; Bading, James R; Park, Jinha M; Frankel, Paul H; Carroll, Mary I; Tran, Tri T; Poku, Erasmus K; Rockne, Russell C; Raubitschek, Andrew A; Shively, John E; Colcher, David M

2018-01-01

The goal of this study was to characterize the relationship between tumor uptake of 64 Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Methods: Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, including 18 F-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent 64 Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h after 64 Cu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUV max Average intrapatient SUV max ( pt ) was compared between HER2+ and HER2- patients. Results: Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median pt for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients ( P < 0.005 either day). The distributions of pt overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease ( P < 0.005 and 0.001, respectively, on days 1 and 2). Conclusion: By 1 d after injection, uptake of 64 Cu-DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for 64 Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer.

PubMed

Lu, Dan; Joshi, Amita; Wang, Bei; Olsen, Steve; Yi, Joo-Hee; Krop, Ian E; Burris, Howard A; Girish, Sandhya

2013-08-01

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate recently approved by the US Food and Drug Administration for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer previously treated with trastuzumab and taxane chemotherapy. It comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to the HER2-targeted humanized monoclonal antibody trastuzumab via a stable linker. To characterize the pharmacokinetics of T-DM1 in patients with metastatic breast cancer, concentrations of multiple analytes were quantified, including serum concentrations of T-DM1 conjugate and total trastuzumab (the sum of conjugated and unconjugated trastuzumab), as well as plasma concentrations of DM1. The clearance of T-DM1 conjugate is approximately 2 to 3 times faster than its parent antibody, trastuzumab. However, the clearance pathways accounting for this faster clearance rate are unclear. An integrated population pharmacokinetic model that simultaneously fits the pharmacokinetics of T-DM1 conjugate and total trastuzumab can help to elucidate the clearance pathways of T-DM1. The model can also be used to predict total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data, thereby reducing the frequency of pharmacokinetic sampling. T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab

64Cu-DOTA-trastuzumab PET Imaging in Women with HER2 Overexpressing Breast Cancer

DTIC Science & Technology

2011-10-01

AD_________________ Award Number: W81XWH-10-1-0824 TITLE: 64Cu- DOTA -trastuzumab PET imaging in...September 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 64Cu- DOTA -trastuzumab PET imaging in women with HER2 overexpressing breast cancer 5b...synthesized 64Cu- DOTA -trastuzumab and tested it in model systems. Relative to the 111In-labeled antibody, positron emission tomography (PET) with 64Cu

The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

PubMed Central

Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Corominas-Faja, Bruna; Cuyàs, Elisabet; López-Bonet, Eugeni; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A.

2013-01-01

Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein—a finding that correlates with increased numbers of autophagosomes—and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of “autophagy addiction” because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer. PMID:23965851

Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.

PubMed

Pogue-Geile, Katherine L; Kim, Chungyeul; Jeong, Jong-Hyeon; Tanaka, Noriko; Bandos, Hanna; Gavin, Patrick G; Fumagalli, Debora; Goldstein, Lynn C; Sneige, Nour; Burandt, Eike; Taniyama, Yusuke; Bohn, Olga L; Lee, Ahwon; Kim, Seung-Il; Reilly, Megan L; Remillard, Matthew Y; Blackmon, Nicole L; Kim, Seong-Rim; Horne, Zachary D; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H; Swain, Sandra M; Mamounas, Eleftherios P; Wickerham, D Lawrence; Geyer, Charles E; Costantino, Joseph P; Wolmark, Norman; Paik, Soonmyung

2013-12-04

National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001). We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).

Predicting Degree of Benefit From Adjuvant Trastuzumab in NSABP Trial B-31

PubMed Central

Pogue-Geile, Katherine L.; Kim, Chungyeul; Jeong, Jong-Hyeon; Tanaka, Noriko; Bandos, Hanna; Gavin, Patrick G.; Fumagalli, Debora; Goldstein, Lynn C.; Sneige, Nour; Burandt, Eike; Taniyama, Yusuke; Bohn, Olga L.; Lee, Ahwon; Kim, Seung-Il; Reilly, Megan L.; Remillard, Matthew Y.; Blackmon, Nicole L.; Kim, Seong-Rim; Horne, Zachary D.; Rastogi, Priya; Fehrenbacher, Louis; Romond, Edward H.; Swain, Sandra M.; Mamounas, Eleftherios P.; Wickerham, D. Lawrence; Geyer, Charles E.; Costantino, Joseph P.; Wolmark, Norman

2013-01-01

Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P interaction between the model and trastuzumab < .001). Conclusions We developed a gene expression–based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47). PMID:24262440

Combined SRC inhibitor saracatinib and anti-ErbB2 antibody H2-18 produces a synergistic antitumor effect on trastuzumab-resistant breast cancer

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

Wang, Lingfei; Yu, Xiaojie; Dong, Jian

Despite of the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, trastuzumab resistance emerges as a major and common clinical problem. Thus, circumventing trastuzumab resistance has become an urgent need. Recently, Src inhibitor saracatinib has drawn great attention for its key role in trastuzumab response. As shown in our previous study, H2-18, an anti-ErbB2 antibody, could potently induce programmed cell death (PCD) in trastuzumab-resistant breast cancer cells. Here we combined H2-18 and a Src inhibitor, saracatinib, and studied the antitumor activity of this drug combination in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and saracatinib could synergistically inhibitmore » cell proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cell lines in vitro. H2-18 plus saracatinib could also inhibit the HCC-1954 tumor growth more effectively in vivo than each drug alone. H2-18 plus saracatinib showed a significantly more potent PCD-inducing activity compared with either H2-18 or saracatinib alone. We conclude that enhanced PCD may contribute to the superior antitumor efficacy of this combination therapy. The combination of H2-18 and SRC inhibitor has the potential to be translated into clinic. - Highlights: • Anti-ErbB2 mAb H2-18 induces PCD in ErbB2-overexpresing breast cancer cells. • H2-18 plus saracatinib induce a greater PCD compared with either drug alone. • H2-18 and saracatinib synergistically inhibit in vitro cell proliferation of breast cancer cells. • H2-18 plus saracatinib exert a greater in vivo antitumor activity than either drug alone.« less

Targeted enzyme prodrug therapies.

PubMed

Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

2010-09-01

The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model.

PubMed

Iwata, Tomomi Nakayama; Ishii, Chiaki; Ishida, Saori; Ogitani, Yusuke; Wada, Teiji; Agatsuma, Toshinori

2018-04-27

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only re-challenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd up-regulated CD86 expression on bone marrow-derived DCs in vitro, and that DS-8201a increased tumor-infiltrating DCs and up-regulated their CD86 expression in vivo. DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of re-challenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T cell activity and up-regulated PD-L1 expression induced by DS-8201a. Copyright ©2018, American Association for Cancer Research.

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment.

PubMed

Press, Michael F; Lenz, Heinz-Josef

2007-01-01

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.

CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells

PubMed Central

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

2016-01-01

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

CD147 knockdown improves the antitumor efficacy of trastuzumab in HER2-positive breast cancer cells.

PubMed

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

2016-09-06

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

Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

PubMed

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

2016-12-01

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

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

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

2014-01-01

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

A randomized, single-blind, single-dose study evaluating the pharmacokinetic equivalence of proposed biosimilar ABP 980 and trastuzumab in healthy male subjects.

PubMed

Hanes, Vladimir; Chow, Vincent; Zhang, Nan; Markus, Richard

2017-05-01

This study compared the pharmacokinetic (PK) profiles of the proposed biosimilar ABP 980 and trastuzumab in healthy males. In this single-blind study, 157 healthy males were randomized 1:1:1 to a single 6 mg/kg intravenous infusion of ABP 980, FDA-licensed trastuzumab [trastuzumab (US)], or EU-authorized trastuzumab [trastuzumab (EU)]. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUC inf ) and maximum observed serum concentration (C max ). To establish equivalence, the geometric mean ratio (GMR) and 90% confidence interval (CI) for C max and AUC inf had to be within the equivalence criteria of 0.80-1.25. The GMRs and 90% CIs for C max and AUC inf , respectively, were: 1.04 (0.99-1.08) and 1.06 (1.00-1.12) for ABP 980 versus trastuzumab (US); 0.99 (0.95-1.03) and 1.00 (0.95-1.06) for ABP 980 versus trastuzumab (EU); and 0.96 (0.92-1.00) and 0.95 (0.90-1.01) for trastuzumab (US) versus trastuzumab (EU). All comparisons were within the equivalence criteria of 0.80-1.25. Treatment-emergent adverse events (TEAEs) were reported in 84.0, 75.0, and 78.2 of subjects in the ABP 980, trastuzumab (US), and trastuzumab (EU) groups, respectively. There were no deaths or TEAEs leading to study discontinuation and no binding or neutralizing anti-drug anti-bodies were detected. This study demonstrated the PK similarity of ABP 980 to both trastuzumab (US) and trastuzumab (EU), and of trastuzumab (US) to trastuzumab (EU). No differences in safety and tolerability between treatments were noted; no subject tested positive for binding anti-bodies.

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

PubMed

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

2016-08-01

-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine.

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

Trastuzumab for metastatic breast cancer: Real world outcomes from an Australian whole-of-population cohort (2001-2016).

PubMed

Daniels, Benjamin; Kiely, Belinda E; Lord, Sarah J; Houssami, Nehmat; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

2018-04-01

Outcomes for patients treated in clinical trials may not reflect the experience in routine clinical care. We aim to describe the real-world treatment patterns and overall survival (OS) for women receiving trastuzumab for metastatic breast cancer (MBC). Retrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for women in the Herceptin Program for HER2+MBC. We estimated time on trastuzumab and OS from first dispensing of trastuzumab for MBC and rates of cardiac monitoring prior to and during treatment. We stratified outcomes by two groups based on year of initiation: 2001-2008 and 2009-2015. We benchmarked outcomes to two key trastuzumab clinical trials: H0648g (median OS 25 months) and CLEOPATRA (control group median OS 41 months). Median age of the 5899 women at first trastuzumab dispensing was 57 years (interquartile range [IQR]: 48-66). Median time on trastuzumab increased from 15 months (7-33) in Group One to 18 months (8-42) in Group Two. Median OS increased from 27 months (12-57) in Group One to 38 months (16-83) in Group Two. Rates of cardiac monitoring increased at baseline (52%-76%), and on-treatment (47%-67%), in Group One and Two, respectively. OS, duration of trastuzumab, and frequency of cardiac monitoring increased over the study period. Outcomes for trastuzumab in this heterogeneous real world population were reassuringly comparable to those from clinical trials, with the median OS > 3 years in Group Two and 25% of patients living 7 years or longer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trastuzumab Alters the Expression of Genes Essential for Cardiac Function and Induces Ultrastructural Changes of Cardiomyocytes in Mice

PubMed Central

ElZarrad, M. Khair; Mukhopadhyay, Partha; Mohan, Nishant; Hao, Enkui; Dokmanovic, Milos; Hirsch, Dianne S.; Shen, Yi; Pacher, Pal; Wu, Wen Jin

2013-01-01

Treatment with trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of Human Epidermal Growth Factor Receptor 2 (HER2), very successfully improves outcomes for women with HER2-positive breast cancer. However, trastuzumab treatment was recently linked to potentially irreversible serious cardiotoxicity, the mechanisms of which are largely elusive. This study reports that trastuzumab significantly alters the expression of myocardial genes essential for DNA repair, cardiac and mitochondrial functions, which is associated with impaired left ventricular performance in mice coupled with significant ultrastructural alterations in cardiomyocytes revealed by electron microscopy. Furthermore, trastuzumab treatment also promotes oxidative stress and apoptosis in myocardium of mice, and elevates serum levels of cardiac troponin-I (cTnI) and cardiac myosin light chain-1 (cMLC1). The elevated serum levels of cMLC1 in mice treated with trastuzumab highlights the potential that cMLC1 could be a useful biomarker for trastuzumab-induced cardiotoxicity. PMID:24255707

Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

PubMed

Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

2016-01-10

Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Alterations in mRNA profiles of trastuzumab‑resistant Her‑2‑positive breast cancer.

PubMed

Zhao, Bin; Zhao, Yang; Sun, Yan; Niu, Haitao; Sheng, Long; Huang, Dongfang; Li, Li

2018-05-07

Breast cancer is one of the most common malignancies in women. Neoadjuvant trastuzumab therapy improves the prognosis of certain Her‑2‑positive breast cancer patients, however around two‑thirds of patients with Her‑2‑positive breast cancer do not benefit from Her‑2‑targeted therapy. To investigate the key mechanisms in trastuzumab resistance, potential biomarkers for neoadjuvant trastuzumab sensitivity were investigated using the gene expression omnibus (GEO) database for mRNA microarray data of Her‑2‑positive breast cancer patients who received neoadjuvant trastuzumab therapy. GEO profiles of 22 patients with a complete response and 48 patients with a partial response were identified in the GSE22358, GSE62327 and GSE66305 datasets. A total of 2,376, 1,000 and 1,152 differentially expressed genes in GSE22358, GSE62327 and GSE66305 datasets were demonstrated, respectively, utilizing GEO2R software. Furthermore, enriched gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed using the Database for Annotation, Visualization and Integrated Discovery software. Subsequently, a protein‑protein interaction network was established using STRING software. The results demonstrated that low sex‑determining region Y‑box 11 and high Bcl‑2 expression may be employed as markers for neoadjuvant trastuzumab therapy for Her‑2‑positive breast cancer. More importantly, phosphoinositide 3‑kinase/Akt and angiogenesis pathways, which are known to be the key targets of trastuzumab, were activated at a lower level in the partial response patients, while the Wnt and estrogen receptor signaling pathways were activated in these patients. Therefore, combination therapy of trastuzumab and anti‑Wnt or hormone therapy may be a promising treatment modality and should be tested in further studies.

The ALTTO Breast Cancer Trial

Cancer.gov

A collection of material about the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation, or ALTTO, study that will compare the targeted agents lapatinib and trastuzumab alone, in sequence, or in combination as adjuvant therapy for HER2-positive br

The efficacy of adjuvant trastuzumab in HER-2 positive breast cancer with axillary lymph node metastases according to the treatment duration.

PubMed

Sendur, Mehmet A N; Aksoy, Sercan; Ozdemir, Nuriye Y; Yazici, Ozan; Zengin, Nurullah; Altundag, Kadri

2014-12-01

Trastuzumab is the first anti-HER-2 humanized monoclonal antibody. The benefit of adjuvant trastuzumab has been shown in randomized phase III trials. Despite trastuzumab being recommended for 52 weeks in the adjuvant treatment of HER-2 positive breast cancer according to the current breast cancer guidelines, there is still no consensus on the optimal duration of adjuvant trastuzumab. The aim of our study is to investigate the efficacy and safety of adjuvant trastuzumab for 9 weeks and 52 weeks in axillary lymph node positive HER-2 positive breast cancer patients. A total of 271 HER-2 and axillary node positive breast cancer patients who received trastuzumab in adjuvant treatment between the years 2005 and 2013 were retrospectively analyzed. Patients with axillary node positive HER-2 positive breast cancer who were non-metastatic were enrolled to the study. Patients were allocated to the 9 week trastuzumab group (n = 155) or the 52 week trastuzumab group (n = 116). Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). Two-sided p values of <0.05 were considered statistically significant. The most important limitation of our manuscript is the retrospective design. The median follow-up time for this analysis was 34 (4-95) months. Patients' clinical and pathological characteristics were well balanced between the two treatment arms. In the 9 week trastuzumab treatment group, the DFS rate was 96.7%, 84.8% and 74.9% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 94.3%, 80.0% and 80.0% (P = 0.76). In the 9 week trastuzumab treatment group, the OS rate was 99.3%, 92.2% and 88.3% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 99.0%, 94.7% and 78.6% (P = 0.99). In both groups, symptomatic heart failure was not reported but asymptomatic left ventricular ejection fraction (LVEF) decline was observed 3 (1

Trastuzumab use during pregnancy: long-term survival after locally advanced breast cancer and long-term infant follow-up.

PubMed

Andrade, Jurandyr M de; Brito, Luiz G O; Moises, Elaine C D; Amorim, Andréa C; Rapatoni, Liane; Carrara, Hélio H A; Tiezzi, Daniel G

2016-04-01

Here, we describe the case of a patient diagnosed with locally advanced breast cancer 8 years ago. Her treatment course was neoadjuvant chemotherapy, followed by mastectomy and then adjuvant radiotherapy and trastuzumab (TTZ). During the use of adjuvant targeted therapy, an incidental pregnancy was diagnosed. Four years later, she developed bone and cerebral metastases, and since then, she has received courses of TTZ, capecitabine, lapatinib, and radiotherapy with intermittent control of the disease. Her 7-year-old son presents a normal physical and long-term neurological developmental curve according to specialized evaluation. This case is unique for several reasons: the patient received the highest dose of TTZ yet described during pregnancy (4400 mg); there has been a long period of disease-free survival after treatment for locally advanced breast cancer and long overall survival despite successive disease progressions during the metastatic phase of the disease (97 months), and there was a monitored pediatric follow-up period (7 years).

Targeted therapy in esophageal cancer.

PubMed

Zhang, Lei; Ma, Jiaojiao; Han, Yu; Liu, Jinqiang; Zhou, Wei; Hong, Liu; Fan, Daiming

2016-01-01

An increasing number of patients are diagnosed with esophageal cancer at an advanced stages, and only a small group of them can benefit from the traditional chemotherapy and radiotherapy. So far, multiple monoclonal antibodies and tyrosine kinase inhibitors have been developed, alone or in combination with traditional therapy, to improve the prognosis of patients with advanced esophageal cancer. This review summarizes the recent advances of targeted therapies against EGFR, HER2, VEGFR and c-MET in esophageal cancer. More clinical trials should be performed to evaluate the efficacy and safety of various targeted therapy regimens. Future basic research should focus on investigating the molecular mechanisms of therapeutic targets in esophageal cancer.

Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer.

PubMed

Garrison, Louis P; Lubeck, Deborah; Lalla, Deepa; Paton, Virginia; Dueck, Amylou; Perez, Edith A

2007-08-01

Adding trastuzumab to adjuvant chemotherapy provides significant clinical benefit in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A cost-effectiveness analysis was performed to assess clinical and economic implications of adding trastuzumab to adjuvant chemotherapy, based upon joint analysis of NSABP B-31 and NCCTG N9831 trials. A Markov model with 4 health states was used to estimate the cost utility for a 50-year-old woman on the basis of trial results through 4 years and estimates of long-term recurrence and death based on a meta-analysis of trials. From 6 years onward, rates of recurrence and death were assumed to be the same in both trastuzumab and chemotherapy-only arms. Incremental costs were estimated for diagnostic and treatment-related costs. Analyses were from payer and societal perspectives, and these analyses were projected to lifetime and 20-year horizons. Over a lifetime, the projected cost of trastuzumab per quality-adjusted life year (QALY; discount rate 3%) gained was 26,417 dollars (range 9,104 dollars-69,340 dollars under multiway sensitivity analysis). Discounted incremental lifetime cost was 44,923 dollars, and projected life expectancy was 3 years longer for patients who received trastuzumab (19.4 years vs 16.4 years). During a 20-year horizon, the projected cost of adding trastuzumab to chemotherapy was 34,201 dollars per QALY gained. Key cost-effectiveness drivers were discount rate, trastuzumab price, and probability of metastasis. The cost-effectiveness result was robust to sensitivity analysis. Trastuzumab for adjuvant treatment of early stage breast cancer was projected to be cost effective over a lifetime horizon, achieving a cost-effectiveness ratio below that of many widely accepted oncology treatments. (c) 2007 American Cancer Society.

Trastuzumab Emtansine for HER2-Positive Breast Cancer

Cancer.gov

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

Prolonged Response to Trastuzumab in a Patient With HER2-Nonamplified Breast Cancer With Elevated HER2 Dimerization Harboring an ERBB2 S310F Mutation.

PubMed

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

2015-09-01

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

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

PubMed Central

Serie, Daniel J.; Crook, Julia E.; Necela, Brian M.; Axenfeld, Bianca C.; Dockter, Travis J.; Colon-Otero, Gerardo; Perez, Edith A.; Thompson, E. Aubrey; Norton, Nadine

2017-01-01

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy. PMID:29367538

Targeted therapies: a nursing perspective.

PubMed

Kay, Polly

2006-02-01

To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. Research articles. Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Are life-saving anticancer drugs reaching all patients? Patterns and discrepancies of trastuzumab use in the European Union and the USA.

PubMed

Ades, Felipe; Senterre, Christelle; Zardavas, Dimitrios; de Azambuja, Evandro; Popescu, Razvan; Piccart, Martine

2017-01-01

The development of trastuzumab is considered to be one of the greatest improvements in breast cancer treatment in recent years. This study aims to evaluate changes in the uptake of trastuzumab over the last 12 years and to determine whether its use is proportional to patient needs in the European Union and the USA. Using national registry data, the number of new cases of HER2-positive breast cancer patients per year was estimated. The number of likely trastuzumab treatments per year was estimated using trastuzumab procurement data for each country. Western Europe and the USA show increasing procurement level of trastuzumab over the years studied, reaching proportional of use of trastuzumab few years after its marketing authorization in the early 2000's. After the approval in the adjuvant setting, in the year 2006, it was observed underuse of trastuzumab given the increase of the number of patients in need of treatment. Proportional use was shortly met after a couple of years. Few countries in Eastern Europe acquired the needed quantity of trastuzumab, with procurement levels starting to increase only after approval in the adjuvant setting in 2006. Significant differences in trastuzumab procurement are observed between Western Europe, the USA and Eastern Europe, with the latter geographic region acquiring insufficient amounts of the drug required to treat all patients in need.

Cancer-adipose tissue interaction and fluid flow synergistically modulate cell kinetics, HER2 expression, and trastuzumab efficacy in gastric cancer.

PubMed

Akutagawa, Takashi; Aoki, Shigehisa; Yamamoto-Rikitake, Mihoko; Iwakiri, Ryuichi; Fujimoto, Kazuma; Toda, Shuji

2018-04-25

Early local tumor invasion in gastric cancer results in likely encounters between cancer cells and submucosal and subserosal adipose tissue, but these interactions remain to be clarified. Microenvironmental mechanical forces, such as fluid flow, are known to modulate normal cell kinetics, but the effects of fluid flow on gastric cancer cells are poorly understood. We analyzed the cell kinetics and chemosensitivity in gastric cancer using a simple in vitro model that simultaneously replicated the cancer-adipocyte interaction and physical microenvironment. Gastric cancer cells (MKN7 and MKN74) were seeded on rat adipose tissue fragment-embedded discs or collagen discs alone. To generate fluid flow, samples were placed on a rotatory shaker in a CO 2 incubator. Proliferation, apoptosis, invasion, and motility-related molecules were analyzed by morphometry and immunostaining. Proteins were evaluated by western blot analysis. Chemosensitivity was investigated by trastuzumab treatment. Adipose tissue and fluid flow had a positive synergistic effect on the proliferative potential and invasive capacity of gastric cancer cells, and adipose tissue inhibited apoptosis in these cells. Adipose tissue upregulated ERK1/2 signaling in gastric cancer cells, but downregulated p38 signaling. Notably, adipose tissue and fluid flow promoted membranous and cytoplasmic HER2 expression and modulated chemosensitivity to trastuzumab in gastric cancer cells. We have demonstrated that cancer-adipocyte interaction and physical microenvironment mutually modulate gastric cancer cell kinetics. Further elucidation of the microenvironmental regulation in gastric cancer will be very important for the development of strategies involving molecular targeted therapy.

Cardio-oncology: cardiovascular complications of cancer therapy.

PubMed

Henning, Robert J; Harbison, Raymond D

2017-07-01

This paper focuses on three classes of commonly used anticancer drugs, which can cause cardiotoxicity: anthracyclines, monoclonal antibodies exemplified by trastuzumab and tyrosine kinase inhibitors. Anthracyclines can induce cardiomyocyte necrosis and fibrosis. Trastuzumab can cause cardiac stunning. The tyrosine kinase inhibitors can increase systemic arterial pressure and impair myocyte contractility. In addition, radiation therapy to the mediastinum or left chest can exacerbate the cardiotoxicity of these anticancer drugs and can also cause accelerated atherosclerosis, myocardial infarction, heart failure and arrhythmias. Left ventricular ejection fraction measurements are most commonly used to assess cardiac function in patients who receive chemo- or radiation-therapy. However, echocardiographic determinations of global longitudinal strain are more sensitive for detection of early left ventricular systolic dysfunction. Information on patient-risk stratification and monitoring is presented and guidelines for the medical treatment of cardiac dysfunction due to cancer therapies are summarized.

(64)Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients.

PubMed

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

2015-01-01

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

Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial

PubMed Central

Holmes, Eileen; Baselga, José; de Azambuja, Evandro; Dueck, Amylou C.; Viale, Giuseppe; Zujewski, Jo Anne; Goldhirsch, Aron; Armour, Alison; Pritchard, Kathleen I.; McCullough, Ann E.; Dolci, Stella; McFadden, Eleanor; Holmes, Andrew P.; Tonghua, Liu; Eidtmann, Holger; Dinh, Phuong; Di Cosimo, Serena; Harbeck, Nadia; Tjulandin, Sergei; Im, Young-Hyuck; Huang, Chiun-Sheng; Diéras, Véronique; Hillman, David W.; Wolff, Antonio C.; Jackisch, Christian; Lang, Istvan; Untch, Michael; Smith, Ian; Boyle, Frances; Xu, Binghe; Gomez, Henry; Suter, Thomas; Gelber, Richard D.; Perez, Edith A.

2016-01-01

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care. PMID:26598744

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent; Delaloge, Suzette; Moy, Beverly; Iwata, Hiroji; von Minckwitz, Gunter; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Tomašević, Zorica; Denduluri, Neelima; Šeparović, Robert; Gokmen, Erhan; Bashford, Anna; Ruiz Borrego, Manuel; Kim, Sung-Bae; Jakobsen, Erik Hugger; Ciceniene, Audrone; Inoue, Kenichi; Overkamp, Friedrich; Heijns, Joan B; Armstrong, Anne C; Link, John S; Joy, Anil Abraham; Bryce, Richard; Wong, Alvin; Moran, Susan; Yao, Bin; Xu, Feng; Auerbach, Alan; Buyse, Marc; Chan, Arlene

2017-12-01

ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib

HER2-positive male breast cancer: an update

PubMed Central

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

2010-01-01

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

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

the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. Conclusions This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine. PMID:27504960

Targeted therapies for cancer

MedlinePlus

Targeted therapies are promising new treatments, but they have limitations. Cancer cells can become resistant to these drugs. The target sometimes changes, so the treatment no longer works. The cancer may find a different way to grow and survive that ...

Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

PubMed Central

Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

2016-01-01

Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma.

PubMed

Liu, Y J; Shen, D; Yin, X; Gavine, P; Zhang, T; Su, X; Zhan, P; Xu, Y; Lv, J; Qian, J; Liu, C; Sun, Y; Qian, Z; Zhang, J; Gu, Y; Ni, X

2014-03-04

Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs. Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors. Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074. Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients

Improved survival of HER2+ breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain

PubMed Central

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

2016-01-01

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

Economic evaluations of trastuzumab in HER2-positive metastatic breast cancer: a systematic review and critique.

PubMed

Parkinson, Bonny; Pearson, Sallie-Anne; Viney, Rosalie

2014-01-01

Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs). This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions. A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator. Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective. There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting.

Anticancer activity of celastrol in combination with ErbB2-targeted therapeutics for treatment of ErbB2-overexpressing breast cancers

PubMed Central

Clubb, Robert J; Ortega-Cava, Cesar; Williams, Stetson H; Bailey, Tameka A; Duan, Lei; Zhao, Xiangshan; Reddi, Alagarasamy L; Nyong, Abijah M; Natarajan, Amarnath; Band, Vimla

2011-01-01

The receptor tyrosine kinase ErbB2 is overexpressed in up to a third of breast cancers, allowing targeted therapy with ErbB2-directed humanized antibodies such as Trastuzumab. Concurrent targeting of ErbB2 stability with HSP90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP90 and several pathways relevant to ErbB2-dependent oncogenesis including the NFκB pathway and the proteasome, and has shown promising activity in other cancer models. Here, we demonstrate that Celastrol exhibits in vitro antitumor activity against a panel of human breast cancer cell lines with selectivity towards those overexpressing ErbB2. Celastrol strongly synergized with ErbB2-targeted therapeutics Trastuzumab and Lapatinib, producing higher cytotoxicity with substantially lower doses of Celastrol. Celastrol significantly retarded the rate of growth of ErbB2-overexpressing human breast cancer cells in a mouse xenograft model with only minor systemic toxicity. Mechanistically, Celastrol not only induced the expected ubiquitinylation and degradation of ErbB2 and other HSP90 client proteins, but it also increased the levels of reactive oxygen species (ROS). Our studies show that the Michael Acceptor functionality in Celastrol is important for its ability to destabilize ErbB2 and exert its bioactivity against ErbB2-overexpressing breast cancer cells. These studies suggest the potential use of Michael acceptor-containing molecules as novel therapeutic modalities against ErbB2-driven breast cancer by targeting multiple biological attributes of the driver oncogene. PMID:21088503

New targeted therapies in pancreatic cancer.

PubMed

Seicean, Andrada; Petrusel, Livia; Seicean, Radu

2015-05-28

Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer.

PubMed

Tanaka, Satoru; Iwamoto, Mitsuhiko; Kimura, Kosei; Matsunami, Nobuki; Morishima, Hirotaka; Yoshidome, Katsuhide; Nomura, Takashi; Morimoto, Takashi; Yamamoto, Daigo; Tsubota, Yu; Kobayashi, Toshihiro; Uchiyama, Kazuhisa

2015-06-01

We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab. Of the 44 patients, 49% achieved a pathologic complete response (pCR). The pCR rate was 36% and 71% in the patients with estrogen receptor-positive and -negative cancer, respectively. Neoadjuvant therapy using this combination appears to be effective and safe. Introduction: Neoadjuvant chemotherapy plus trastuzumab. Neoadjuvant chemotherapy plus trastuzumab results in a 30% to 50% pathologic complete response (pCR) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes. Thus, the pCR rate can be useful in evaluating novel agents in this patient population. Nanoparticle albumin-bound (nab)-paclitaxel (PTX) can reduce the toxicity of PTX while maintaining its efficacy. The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+) breast cancer. We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide (EC) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks (q3w) for 4 cycles, followed by nab-PTX (260 mg/m(2)) plus trastuzumab q3w for 4 cycles. The primary endpoint was the pCR rate. The secondary endpoints included the clinical response rate, disease-free survival, pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery rate, and safety. Forty-six patients were enrolled. One patient met the exclusion criteria because of the coexistence of another malignant disease; therefore, we evaluated 45 patients in the entire study. One patient experienced rapid disease progression during EC therapy, leaving 44 patients evaluable for nab-PTX treatment. Of the 45 patients, 49% achieved a pCR. The pCR rate was 36% and 71% in those with

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.

PubMed

Loi, Sherene; Dafni, Urania; Karlis, Dimitris; Polydoropoulou, Varvara; Young, Brandon M; Willis, Scooter; Long, Bradley; de Azambuja, Evandro; Sotiriou, Christos; Viale, Giuseppe; Rüschoff, Josef; Piccart, Martine J; Dowsett, Mitch; Michiels, Stefan; Leyland-Jones, Brian

2016-08-01

A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, butreferred to asHER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. The HERA trial was an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. Disease-free survival (DFS) and overall survival (OS) were the primary and secondary end points in the intent-to-treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT Pvalue for interaction = .07; censored = .02; IPW = .03

The EGF receptor family as targets for cancer therapy.

PubMed

Mendelsohn, J; Baselga, J

2000-12-27

Human carcinomas frequently express high levels of receptors in the EGF receptor family, and overexpression of at least two of these receptors, the EGF receptor (EGFr) and closely related ErbB2, has been associated with a more aggressive clinical behavior. Further, transfection or activation of high levels of these two receptors in nonmalignant cell lines can lead to a transformed phenotype. For these reasons therapies directed at preventing the function of these receptors have the potential to be useful anti-cancer treatments. In the last two decades monoclonal antibodies (MAbs) which block activation of the EGFr and ErbB2 have been developed. These MAbs have shown promising preclinical activity and 'chimeric' and 'humanized' MAbs have been produced in order to obviate the problem of host immune reactions. Clinical activity with these antibodies has been documented: trastuzumab, a humanized anti-ErbB2 MAb, is active and was recently approved in combination with paclitaxel for the therapy of patients with metastatic ErbB2-overexpressing breast cancer; IMC-C225, a chimeric anti-EGFr MAb, has shown impressive activity when combined with radiation therapy and reverses resistance to chemotherapy. In addition to antibodies, compounds that directly inhibit receptor tyrosine kinases have shown preclinical activity and early clinical activity has been reported. A series of phase III studies with these antibodies and direct tyrosine kinase inhibitors are ongoing or planned, and will further address the role of these active anti-receptor agents in the treatment of patients with cancer.

Exosomal pMHC-I complex targets T cell-based vaccine to directly stimulate CTL responses leading to antitumor immunity in transgenic FVBneuN and HLA-A2/HER2 mice and eradicating trastuzumab-resistant tumor in athymic nude mice.

PubMed

Wang, Lu; Xie, Yufeng; Ahmed, Khawaja Ashfaque; Ahmed, Shahid; Sami, Amer; Chibbar, Rajni; Xu, Qingyong; Kane, Susan E; Hao, Siguo; Mulligan, Sean J; Xiang, Jim

2013-07-01

One of the major obstacles in human epidermal growth factor receptor 2 (HER2)-specific trastuzumab antibody immunotherapy of HER2-positive breast cancer is the development of trastuzumab resistance, warranting the search for other therapeutic strategies. Using mouse models, we previously demonstrated that ovalbumin (OVA)-specific dendritic cell (DC)-released exosome (EXOOVA)-targeted CD4(+) T cell-based (OVA-TEXO) vaccine stimulates efficient cytotoxic T lymphocyte (CTL) responses via exosomal peptide/major histocompatibility complex (pMHC)-I, exosomal CD80 and endogenous IL-2 signaling; and long-term CTL memory by means of via endogenous CD40L signaling. In this study, using two-photon microscopy, we provide the first visual evidence on targeting OVA-TEXO to cognate CD8(+) T cells in vivo via exosomal pMHC-I complex. We prepared HER2/neu-specific Neu-TEXO and HER2-TEXO vaccines using adenoviral vector (AdVneu and AdVHER2)-transfected DC (DCneu and DCHER2)-released EXOs (EXOneu and EXOHER2), and assessed their stimulatory effects on HER2/neu-specific CTL responses and antitumor immunity. We demonstrate that Neu-TEXO vaccine is capable of stimulating efficient neu-specific CTL responses, leading to protective immunity against neu-expressing Tg1-1 breast cancer in all 6/6 transgenic (Tg) FVBneuN mice with neu-specific self-immune tolerance. We also demonstrate that HER2-TEXO vaccine is capable of inducing HER2-specific CTL responses and protective immunity against transgene HLA-A2(+)HER2(+) BL6-10A2/HER2 B16 melanoma in 2/8 double Tg HLA-A2/HER2 mice with HER2-specific self-immune tolerance. The remaining 6/8 mice had significantly prolonged survival. Furthermore, we demonstrate that HER2-TEXO vaccine stimulates responses of CD8(+) T cells capable of not only inducing killing activity to HLA-A2(+)HER2(+) BL6-10A2/HER2 melanoma and trastuzumab-resistant BT474A2 breast cancer cells in vitro but also eradicating 6-day palpable HER2(+) BT474A2 breast cancer (3-4 mm in

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

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study.

PubMed

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus; Maass, Nicolai; Cufer, Tanja; de Jongh, Felix E; Maartense, Eduard; Zielinski, Christoph; Kaufmann, Manfred; Bauer, Wolfgang; Baumann, Klaus H; Clemens, Michael R; Duerr, Ralph; Uleer, Christoph; Andersson, Michael; Stein, Robert C; Nekljudova, Valentina; Loibl, Sibylle

2009-04-20

Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

PubMed Central

Kanzaki, Hirotaka; Mukhopadhya, Nishit K.; Cui, Xiaojiang; Ramanujan, V. Krishnan

2016-01-01

A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer.(1) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-κB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-κB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-κB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-κB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-κB is constitutively activated; this notion is consistent with the recently proposed “progression through grade” or “evolution of resistance” hypothesis. Furthermore, we identified IKK-α/IKK-β and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-κB activation. PMID:26871511

Targeted therapy in lung cancer: IPASS and beyond, keeping abreast of the explosion of targeted therapies for lung cancer

PubMed Central

Savas, Peter; Hughes, Brett

2013-01-01

Advances in the treatment of non-small cell lung cancer (NSCLC) over the last decade have predominantly involved the development of therapies directed at molecular targets such as mutations in the epidermal growth factor receptor (EGFR) or rearrangements in the anaplastic lymphoma kinase (ALK) gene. Other targets have been discovered at low frequency, with multiple agents approved or in development for treatment of these rare molecular subtypes. The tumour microenvironment has also provided opportunities for therapies targeting angiogenesis and the host immune response. This review will provide an overview of current targeted therapies in NSCLC and promising treatment approaches on the horizon. PMID:24163750

Seven-Year Follow-Up Assessment of Cardiac Function in NSABP B-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab As Adjuvant Therapy for Patients With Node-Positive, Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PubMed Central

Romond, Edward H.; Jeong, Jong-Hyeon; Rastogi, Priya; Swain, Sandra M.; Geyer, Charles E.; Ewer, Michael S.; Rathi, Vikas; Fehrenbacher, Louis; Brufsky, Adam; Azar, Catherine A.; Flynn, Patrick J.; Zapas, John L.; Polikoff, Jonathan; Gross, Howard M.; Biggs, David D.; Atkins, James N.; Tan-Chiu, Elizabeth; Zheng, Ping; Yothers, Greg; Mamounas, Eleftherios P.; Wolmark, Norman

2012-01-01

Purpose Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. Patients and Methods In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. Results At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. Conclusion The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab. PMID:22987084

Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial.

PubMed

Shi, W; Jiang, T; Nuciforo, P; Hatzis, C; Holmes, E; Harbeck, N; Sotiriou, C; Peña, L; Loi, S; Rosa, D D; Chia, S; Wardley, A; Ueno, T; Rossari, J; Eidtmann, H; Armour, A; Piccart-Gebhart, M; Rimm, D L; Baselga, J; Pusztai, L

2017-01-01

We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression. There were no recurrent single gene mutations significantly associated with pathologic complete response (pCR), except PIK3CA [odds ratio (OR) = 0.42, P = 0.0185]. Mutations in 33 of 714 pathways were significantly associated with response, but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a ‘trastuzumab resistance-network’ of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared with cases with no mutations (9/16, 56%), OR = 0.035; P < 0.001. Mutations in the ‘Regulation of RhoA activity’ pathway were associated with higher pCR rate to lapatinib (OR = 14.8, adjusted P = 0.001), lapatinib + trastuzumab (OR = 3.0, adjusted P = 0.09), and all arms combined (OR = 3.77, adjusted P = 0.02). Patients (n = 124) with mutations in the trastuzumab resistance network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR = 0.026, P = 0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR = 1.68, P = 0.3). Patients (n = 46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone. Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA-related network are associated with resistance to trastuzumab. The combined mutation status of these two

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.

PubMed

Stemmler, Hans-Joachim; Mengele, Karin; Schmitt, Manfred; Harbeck, Nadia; Laessig, Dorit; Herrmann, Karin A; Schaffer, Pamela; Heinemann, Volker

2008-09-01

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.

Targeted Nanoparticles for Kidney Cancer Therapy

DTIC Science & Technology

2013-10-01

AD_________________ Award Number: W81XWH-10-1-0434 TITLE: Targeted Nanoparticles for Kidney Cancer Therapy PRINCIPAL...Targeted Nanoparticles for Kidney Cancer Therapy 5b. GRANT NUMBER W81XWH-10-1-0434 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...lines following treatment with D5 nanotubes. Tthermoablation will be studied initially. Human kidney cancer cells will be injected into the kidney

Targeted nanosystems: Advances in targeted dendrimers for cancer therapy.

PubMed

Yang, Hu

2016-02-01

Dendrimers possess discrete highly compact nanostructures constituted of successive branched layers. Soon after the inception of dendrimers, recognition of their tunable structures and biologically favorable properties provoked a great enthusiasm in delving deeply into the utility of dendrimers for biomedical and pharmaceutical applications. One of the most important nanotechnology applications is the development of nanomedicines for targeted cancer therapies. Tremendous success in targeted therapies has been achieved with the use of dendrimer-based nanomedicines. This article provides a concise review on latest advances in the utility of dendrimers in immunotherapies and hormone therapies. Much basic and clinical research has been done since the invention of dendrimers, which are highly branched nano-sized molecules with the ability to act as carriers in nanomedicine. In this concise review article, the authors highlighted the current use of dendrimers in immunotherapies and hormone therapies in the fight against cancers. Copyright © 2015 Elsevier Inc. All rights reserved.

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas.

PubMed

Black, Jonathan D; Lopez, Salvatore; Cocco, Emiliano; Bellone, Stefania; Altwerger, Gary; Schwab, Carlton L; English, Diana P; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

2015-09-29

We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.

Novel targets for HIV therapy.

PubMed

Greene, Warner C; Debyser, Zeger; Ikeda, Yasuhiro; Freed, Eric O; Stephens, Edward; Yonemoto, Wes; Buckheit, Robert W; Esté, José A; Cihlar, Tomas

2008-12-01

There are currently 25 drugs belonging to 6 different inhibitor classes approved for the treatment of human immunodeficiency virus (HIV) infection. However, new anti-HIV agents are still needed to confront the emergence of drug resistance and various adverse effects associated with long-term use of antiretroviral therapy. The 21st International Conference on Antiviral Research, held in April 2008 in Montreal, Canada, therefore featured a special session focused on novel targets for HIV therapy. The session included presentations by world-renowned experts in HIV virology and covered a diverse array of potential targets for the development of new classes of HIV therapies. This review contains concise summaries of discussed topics that included Vif-APOBEC3G, LEDGF/p75, TRIM 5alpha, virus assembly and maturation, and Vpu. The described viral and host factors represent some of the most noted examples of recent scientific breakthroughs that are opening unexplored avenues to novel anti-HIV target discovery and validation, and should feed the antiretroviral drug development pipeline in the near future.

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors.

PubMed

Lee, Carol M; Tannock, Ian F

2010-06-03

Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity. Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with ERBB2 (231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2. The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly. Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors.

Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects.

PubMed

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

2018-05-24

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

Genomic Alterations in Advanced Esophageal Cancer May Lead to Subtype-Specific Therapies

PubMed Central

Forde, Patrick M.

2013-01-01

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8–12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease. PMID:23853247

Gene Therapy and Targeted Toxins for Glioma

PubMed Central

Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

2011-01-01

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

Targeted polymeric nanoparticles for cancer gene therapy

PubMed Central

Kim, Jayoung; Wilson, David R.; Zamboni, Camila G.; Green, Jordan J.

2015-01-01

In this article, advances in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed. Characterization and evaluation of biomaterials, targeting ligands, and transcriptional elements are each discussed. Advances in biomaterials have driven improvements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific cancer cells, and the design of transcriptional elements has enabled selective DNA expression specific to the cancer cells. Together, these features have improved the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors to treat cancer. As polymeric nanoparticles can be designed to be biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral platforms, they have significant potential for clinical use. Results of polymeric gene therapy in clinical trials and future directions for the engineering of nanoparticle systems for targeted cancer gene therapy are also presented. PMID:26061296

Heart failure—potential new targets for therapy

PubMed Central

Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

2016-01-01

Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2‑positive breast cancer: an NSABP Foundation Research Program phase I study.

PubMed

Jankowitz, Rachel C; Abraham, Jame; Tan, Antoinette R; Limentani, Steven A; Tierno, Marni B; Adamson, Laura M; Buyse, Marc; Wolmark, Norman; Jacobs, Samuel A

2013-12-01

Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

Evaluation of Left Ventricular Ejection Fractions in Breast Cancer Patients Undergoing Long-Term Trastuzumab Treatment.

PubMed

Sun, Yong; Li, Tao; Zhang, Yuanpeng; Zhang, Qiwen

2016-12-21

BACKGROUND The aim of this study was to assess the long-term clinical tolerance and cardiac safety during trastuzumab treatment for patients diagnosed as having breast cancer with human epidermal growth factor receptor 2 (HER2) overexpression. MATERIAL AND METHODS A total 105 female cases diagnosed as having breast cancer with high expression of Her2, were treated with trastuzumab (T). All of them underwent electrocardiography monitoring in the process of T treatment. Left ventricular ejection fractions (LVEFs) were estimated using echocardiography before the T treatment and every 3 months. General clinical data and above parameters were collected and reviewed as analysis. RESULTS The mean value of LVEFs with baseline was higher than those at other time points. All LVEFs were more than 50% during the course of trastuzumab treatment. The decline scope ≥15% of LVEFs ranged from 2 months to 16 months, and the ratios were counted for 3.1% at 2 months, 4.3% at 6 months, 3.8% at 10 months, and 5.4% at 16 months. Furthermore, a larger decrease of LVEF during the course occurred mainly in the patients with cumulative dose of A >300 mg/m², without CPD and 16-month duration of T treatment. There was a strong correlation between cumulative dose of A, cyto/cardio-protection drugs (CPD), duration of T, and the change of LVEF (P=0.82, P=0.744, and P=0.717, respectively), which indicated that 3 factors may be associated with the change in LVEF (P<0.05). CONCLUSIONS The LVEF in patients with trastuzumab treatment was significantly decreased, which may be seen as a favorable benefit-risk ratio for patients undergoing long-term trastuzumab treatment.

Targeted Therapy for Melanoma

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

Quinn, Thomas; Moore, Herbert

The research project, entitled ”Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg 11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg 11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particularmore » note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.« less

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

PubMed

von Minckwitz, Gunter; Colleoni, Marco; Kolberg, Hans-Christian; Morales, Serafin; Santi, Patricia; Tomasevic, Zorica; Zhang, Nan; Hanes, Vladimir

2018-06-04

ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer. We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m 2 every 3 weeks in 30 min intravenous infusions (or 80 mg/m 2 paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast

Molecular dynamic simulation of Trastuzumab F(ab’)2 structure in corporation with HER2 as a theranostic agent of breast cancer

NASA Astrophysics Data System (ADS)

Hermanto, S.; Yusuf, M.; Mutalib, A.; Hudiyono, S.

2017-05-01

Trastuzumab as intact IgG are well researched for theranostic agent in HER2 overexpressed breast cancer. However, due to the relatively large of molecules it is slowly moved and weak penetration of the target cells. Fragmentation of trastzumab has been developed by pepsin cleavages to get the F(ab’)2 fragments. To observe the stability and accessibility of F(ab’)2 structure in corporation with HER2 (human epidermal growth factor receptor-2), the structure of antibody modeling had been developed with 1IGT as a template. Molecular dynamics (MD) of the F(ab’)2 structure simulation has been done in the aqueous phase with AMBER trajectories for 20 ns. Computational visualization by VMD (Visual Molecular Dynamics) were applied to identify binding site interaction details between trastuzumab F(ab’)2 and HER2 receptor. The results of MD simulations indicated that the fragmentation of trastuzumab F(ab’)2 did not change the structure and conformation of F(ab’)2 as a whole, especially in the CDR (Complementarity Determining Region) area. SASA (solvent accessibility surface area) analysis on lysine residues showed that formation of conjugate DOTA-F(ab’)2 predicted occur on outside of the CDR regions so its not interfered with binding affinity for the HER2 receptor. The molecular dynamic simulation of DOTA-F(ab’)2 with HER2 receptor in aqueous system generated ΔGbinding more highly (15.5066 kkal/mol) than positive control HER2-Fab (-45.1446 kkal/mol).

Prostate Cancer Clinical Consortium Clinical Research Site:Targeted Therapies

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-2-0159 TITLE: Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies PRINCIPAL INVESTIGATOR...Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies 5b. GRANT NUMBER... therapy resistance/sensitivity, identification of new therapeutic targets through high quality genomic analyses, providing access to the highest quality

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas

PubMed Central

Black, Jonathan D; Lopez, Salvatore; Cocco, Emiliano; Bellone, Stefania; Altwerger, Gary; Schwab, Carlton L; English, Diana P; Bonazzoli, Elena; Predolini, Federica; Ferrari, Francesca; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Santin, Alessandro D

2015-01-01

Objectives: We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. Methods: Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. Results: Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. Conclusions: Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment. PMID:26325104

Cost-effectiveness of trastuzumab in metastatic breast cancer: mainly a matter of price in the EU?

PubMed

Garattini, Livio; van de Vooren, Katelijne; Curto, Alessandro

2015-02-01

Trastuzumab (TR), a monoclonal antibody approved by EMA in 2000 and one of the first examples of "targeted therapy", is indicated to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. TR, whose patent will expire in 2015 in Europe, has been judged positively for reimbursement by most public authorities in the EU. Here we critically review the existing evidence on TR in metastatic breast cancer (MBC), in line with the multidisciplinary health technology assessment (HTA) approach, to assess whether the existing evidence supports TR positive reimbursement decisions taken in MBC by EU health authorities. We did a literature search for the main HTA topics (efficacy, quality of life and ethics) on the PubMed international database (2000-2013). Then, we did a specific literature search to select the full economic evaluations (FEEs) conducted in EU countries focused on TR as first-line innovative therapy in MBC. We retrieved scant evidence in the literature to support TR reimbursement in MBC. We found only two clinical trials and their results were unclear because of the large proportion of patients who crossed over. Moreover, the quality of methods was poor in all four European FEEs selected. This example of HTA exercise on a mature monoclonal antibody in a specific indication casts doubts on how often the reimbursement decisions taken by EU health authorities in emotional pathologies like cancer are rational. These decisions should at least be reconsidered periodically on the basis of the latest evidence. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Will nanotechnology influence targeted cancer therapy?

PubMed Central

Grimm, Jan; Scheinberg, David A.

2011-01-01

The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale, as well as the development of new nano-materials, will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy (“theranostics”), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review we will not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we will present properties specific to nanoparticles, and examples of their uses, which demonstrate their importance for targeted cancer therapy. PMID:21356476

Cost-effectiveness analysis of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2): positive advanced breast cancer.

PubMed

Le, Quang A; Bae, Yuna H; Kang, Jenny H

2016-10-01

The EMILIA trial demonstrated that trastuzumab emtansine (T-DM1) significantly increased the median profession-free and overall survival relative to combination therapy with lapatinib plus capecitabine (LC) in patients with HER2-positive advanced breast cancer (ABC) previously treated with trastuzumab and a taxane. We performed an economic analysis of T-DM1 as a second-line therapy compared to LC and monotherapy with capecitabine (C) from both perspectives of the US payer and society. We developed four possible Markov models for ABC to compare the projected life-time costs and outcomes of T-DM1, LC, and C. Model transition probabilities were estimated from the EMILIA and EGF100151 clinical trials. Direct costs of the therapies, major adverse events, laboratory tests, and disease progression, indirect costs (productivity losses due to morbidity and mortality), and health utilities were obtained from published sources. The models used 3 % discount rate and reported in 2015 US dollars. Probabilistic sensitivity analysis and model averaging were used to account for model parametric and structural uncertainty. When incorporating both model parametric and structural uncertainty, the resulting incremental cost-effectiveness ratios (ICER) comparing T-DM1 to LC and T-DM1 to C were $183,828 per quality-adjusted life year (QALY) and $126,001/QALY from the societal perspective, respectively. From the payer's perspective, the ICERs were $220,385/QALY (T-DM1 vs. LC) and $168,355/QALY (T-DM1 vs. C). From both perspectives of the US payer and society, T-DM1 is not cost-effective when comparing to the LC combination therapy at a willingness-to-pay threshold of $150,000/QALY. T-DM1 might have a better chance to be cost-effective compared to capecitabine monotherapy from the US societal perspective.

Demands for 'off-licence' access to trastuzumab (Herceptin): content analysis of UK newspaper articles.

PubMed

Hind, Daniel; Wailoo, Allan J; Sutcliffe, Paul

2011-03-01

Sensationalized reporting styles and a distorted framing of health-care issues in newspapers may trigger inappropriate commissioning decisions. We evaluated UK press coverage of pre-licensing access to trastuzumab (Herceptin) for early breast cancer as a case study. Content analysis of newspaper articles published between April 2005 and May 2006 were coded by two researchers for interest groups represented, claims made and sensationalized reporting. Disagreements in coding were resolved by a third researcher. One thousand and ninety published articles were identified in the study period and a 20% sample (n = 218) was included in the content analysis. Most articles (76%, 95% CI 71-82) included claims about the clinical benefits of trastuzumab, and this was significantly higher than those expressing the uncertainty surrounding such benefits (6%, 95% CI 3-9) or those that discussed the potential harms (5%, 95% CI 2-8). Articles were significantly more likely to feature claims made by a breast cancer survivor or family member than any other interest group (P < 0.0001). Almost half of the articles carried some message to the effect that trastuzumab would make the difference between life and death (47%, 95% CI 40-53). Over a quarter (28%, 95% CI 22-34) suggested that trastuzumab is a 'miracle drug' or similar. The benefits of drugs are highlighted, frequently using sensationalist language, without equal consideration of uncertainty or risks. Health-care purchasers should express decisions in opportunity cost terms; journalists should give fairer coverage to such arguments. © 2010 Blackwell Publishing Ltd.

Treatment of metastatic breast cancer: a large observational study on adherence to French prescribing guidelines and financial cost of the anti-HER2 antibody trastuzumab.

PubMed

Poncet, Bénédicte; Colin, Cyrille; Bachelot, Thomas; Jaisson-Hot, Isabelle; Derain, Laure; Magaud, Laurent; Fournel-Federico, Cécile; Mousseau, Mireille; Tigaud, Jean-Dominique; Jacquin, Jean-Philippe; Trillet-Lenoir, Véronique

2009-08-01

This observational study aimed at analyzing adherence to prescribing guidelines of anti-HER2 monoclonal antibody trastuzumab treatment for metastatic breast cancer. Efficacy and costs were also evaluated. The adherence to the trastuzumab treatment plan was analyzed according to both the French postlicensing guidelines published in 2001 and clinical guidelines from the regional cancer network in a cohort of 131 consecutive patients. The level of appropriateness to the molecular target was very high (92% of the patients showed a positive HER2 status, defined as HER2 3+ confirmed by immunohistochemistry or 2+ confirmed by fluorescent in situ hybridization). The treatment plan was made according to the French postlicensing guidelines in 41 patients (31.3%) and to the regional clinical guidelines for 109 patients (83.2%). The main reason for the difference was the type of molecules authorized for combination to trastuzumab. The median overall survival of the studied population was 18.6 months and the median progression-free survival rate was 7.7 months. Up to death or end of the study, the overall cost for the treatment of breast cancer with trastuzumab per patient and per year was 47,832 euro. This quite low adherence of clinicians to the French postlicensing guidelines is in contrast with the high level of adherence to the regional clinical guidelines. The reason is that the latter are less rigid about previously received treatments and enlarge the potential associated cytotoxics to vinorelbine. This supports the French National Cancer Institute decision to get expert clinicians involved together with the French agency for sanitary security of health products and the high health authority in a common elaboration of guidelines.

Boron neutron capture therapy: Moving toward targeted cancer therapy.

PubMed

Mirzaei, Hamid Reza; Sahebkar, Amirhossein; Salehi, Rasoul; Nahand, Javid Sadri; Karimi, Ehsan; Jaafari, Mahmoud Reza; Mirzaei, Hamed

2016-01-01

Boron neutron capture therapy (BNCT) occurs when a stable isotope, boton-10, is irradiated with low-energy thermal neutrons to yield stripped down helium-4 nuclei and lithium-7 nuclei. It is a binary therapy in the treatment of cancer in which a cytotoxic event is triggered when an atom placed in a cancer cell. Here, we provide an overview on the application of BNCT in cancer therapy as well as current preclinical and clinical evidence on the efficacy of BNCT in the treatment of melanoma, brain tumors, head and neck cancer, and thyroid cancer. Several studies have shown that BNCT is effective in patients who had been treated with a full dose of conventional radiotherapy, because of its selectivity. In addition, BNCT is dependent on the normal/tumor tissue ratio of boron distribution. Increasing evidence has shown that BNCT can be combined with different drug delivery systems to enhance the delivery of boron to cancer cells. The flexibility of BNCT to be used in combination with different tumor-targeting approaches has made this strategy a promising option for cancer therapy. This review aims to provide a state-of-the-art overview of the recent advances in the use of BNCT for targeted therapy of cancer.

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,

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Cell surface receptors and associated signaling pathways).

PubMed

Aguilar-Company, J; Fernández-Ruiz, M; García-Campelo, R; Garrido-Castro, A C; Ruiz-Camps, I

2018-06-01

The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies. To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations. Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family. Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host's susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia. With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low. Copyright © 2018 European Society of Clinical

Conformational flexibility of the ErbB2 ectodomain and trastuzumab antibody complex as revealed by molecular dynamics and principal component analysis.

PubMed

Franco-Gonzalez, Juan Felipe; Cruz, Victor L; Ramos, Javier; Martínez-Salazar, Javier

2013-03-01

Human epidermal growth factor receptor 2 (ErbB2) is a transmembrane oncoprotein that is over expressed in breast cancer. A successful therapeutic treatment is a monoclonal antibody called trastuzumab which interacts with the ErbB2 extracellular domain (ErbB2-ECD). A better understanding of the detailed structure of the receptor-antibody interaction is indeed of prime interest for the design of more effective anticancer therapies. In order to discuss the flexibility of the complex ErbB2-ECD/trastuzumab, we present, in this study, a multi-nanosecond molecular dynamics simulation (MD) together with an analysis of fluctuations, through a principal component analysis (PCA) of this system. Previous to this step and in order to validate the simulations, we have performed a detailed analysis of the variable antibody domain interactions with the extracellular domain IV of ErbB2. This structure has been statically elucidated by x-ray studies. Indeed, the simulation results are in excellent agreement with the available experimental information during the full trajectory. The PCA shows eigenvector fluctuations resulting in a hinge motion in which domain II and C(H) domains approach each other. This move is likely stabilized by the formation of H-bonds and salt bridge interactions between residues of the dimerization arm in the domain II and trastuzumab residues located in the C(H) domain. Finally, we discuss the flexibility of the MD/PCA model in relation with the static x-ray structure. A movement of the antibody toward the dimerization domain of the ErbB2 receptor is reported for the first time. This finding could have important consequences on the biological action of the monoclonal antibody.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

PubMed Central

Sun, Hongguang; Zhu, Xun; Lu, Patrick Y; Rosato, Roberto R; Tan, Wen; Zu, Youli

2014-01-01

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. PMID:25093706

Apatinib as targeted therapy for sarcoma

PubMed Central

Li, Feng; Liao, Zhichao; Zhang, Chao; Zhao, Jun; Xing, Ruwei; Teng, Sheng; Zhang, Jin; Yang, Yun; Yang, Jilong

2018-01-01

Sarcomas are a group of malignant tumors originating from mesenchymal tissue with a variety of cell subtypes. Despite several major treatment breakthroughs, standard treatment using surgery, radiation, and chemotherapy has failed to improve overall survival. Therefore, there is an urgent need to explore new strategies and innovative therapies to further improve the survival rates of patients with sarcomas. Pathological angiogenesis has an important role in the growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) play a central role in tumor angiogenesis and represent potential targets for anticancer therapy. As a novel targeted therapy, especially with regard to angiogenesis, apatinib is a new type of small molecule tyrosine kinase inhibitor that selectively targets VEGFR-2 and has shown encouraging anticancer activity in a wide range of malignancies, including gastric cancer, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, and sarcomas. In this review, we summarize the preclinical and clinical data for apatinib, focusing primarily on its use in the treatment of sarcomas. PMID:29849960

Clinical Practice Patterns and Cost-Effectiveness of HER2 Testing Strategies in Breast Cancer Patients

PubMed Central

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

2009-01-01

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

Chemoresistance and targeted therapies in ovarian and endometrial cancers

PubMed Central

Brasseur, Kevin; Gévry, Nicolas; Asselin, Eric

2017-01-01

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers. PMID:28008141

Preliminary Results of Whole Brain Radiotherapy With Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients

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

Chargari, Cyrus; Idrissi, Hind Riahi; Pierga, Jean-Yves

2011-11-01

Purpose: To assess the use of trastuzumab concurrently with whole brain radiotherapy (WBRT) for patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer. Methods and Materials: Between April 2001 and April 2007, 31 patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer were referred for WBRT with concurrent trastuzumab. At brain progression, the median age was 55 years (range, 38-73), and all patients had a performance status of 0-2. The patients received trastuzumab 2 mg/kg weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26 patients, concurrent WBRTmore » delivered 30 Gy in 10 daily fractions. In 6 patients, other fractionations were chosen because of either poor performance status or patient convenience. Results: After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. Clinical responses were observed in 27 patients (87.1%). The median survival time from the start of WBRT was 18 months (range, 2-65). The median interval to brain progression was 10.5 months (range, 2-27). No Grade 2 or greater acute toxicity was observed. Conclusion: The low toxicity of trastuzumab concurrently with WBRT should probably not justify delays. Although promising, these preliminary data warrant additional validation of trastuzumab as a potential radiosensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial.« less

Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model.

PubMed

Pastuskovas, Cinthia V; Mundo, Eduardo E; Williams, Simon P; Nayak, Tapan K; Ho, Jason; Ulufatu, Sheila; Clark, Suzanna; Ross, Sarajane; Cheng, Eric; Parsons-Reponte, Kathryn; Cain, Gary; Van Hoy, Marjie; Majidy, Nicholas; Bheddah, Sheila; dela Cruz Chuh, Josefa; Kozak, Katherine R; Lewin-Koh, Nicholas; Nauka, Peter; Bumbaca, Daniela; Sliwkowski, Mark; Tibbitts, Jay; Theil, Frank-Peter; Fielder, Paul J; Khawli, Leslie A; Boswell, C Andrew

2012-03-01

Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography-X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes.

Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

PubMed Central

Hughes, Juliana Bentes; Rødland, Marianne Skeie; Hasmann, Max; Madshus, Inger Helene; Stang, Espen

2012-01-01

ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. PMID:24281706

Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report.

PubMed

Kawahara, Kenta; Hiraki, Akimitsu; Yoshida, Ryoji; Arita, Hidetaka; Matsuoka, Yuichiro; Yamashita, Toshio; Koga, Kan-Ichi; Nagata, Masashi; Hirosue, Akiyuki; Fukuma, Daiki; Nakayama, Hideki

2017-06-01

Salivary duct carcinoma is a highly aggressive disease with a poor prognosis. Surgical resection is currently the only curative treatment, as there is no effective systemic therapy for this malignancy. Recently, trastuzumab has been shown to exhibit therapeutic efficacy in the treatment of salivary duct carcinoma; similarly, molecularly targeted agents, such as cetuximab, are expected to be useful for salivary duct carcinoma treatment. We herein describe the case of a 56-year-old man diagnosed with salivary duct carcinoma in the left submandibular region, with ipsilateral multiple metastases to the neck lymph nodes. Radical resection of the tumor and submandibular gland with neck dissection were performed. One month after radical surgery, computed tomography (CT) scans indicated metastasis in the lower lobe of the left lung. CT-guided transthoracic fine-needle aspiration biopsy revealed a single metastasis and lung metastasectomy was immediately performed. The tumor cells of the primary lesion and those of the lung metastasis were immunohistochemically positive for epidermal growth factor receptor. One month later, multiple right lung metastases appeared, and the patient was treated with cisplatin/5-fluorouracil (5-FU) chemotherapy plus cetuximab, achieving a complete radiographic response. However, multiple lung metastases developed during adjuvant weekly cetuximab monotherapy. Subsequently, treatment with S-1 and weekly cetuximab was initiated, and the multiple lung metastases have been maintained as stable disease for 5 months. To the best of our knowledge, this is the first report of cetuximab use for the treatment of salivary duct carcinoma. Although cisplatin/5-FU chemotherapy plus cetuximab was efficacious in treating the lung metastasis, cetuximab monotherapy was insufficient for controlling tumor growth.

Mechanisms and Therapy for Cancer Metastasis to the Brain.

PubMed

Franchino, Federica; Rudà, Roberta; Soffietti, Riccardo

2018-01-01

(NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other "druggable" alterations seen in up to 5% of NSCLC patients are the rearrangements of the "anaplastic lymphoma kinase" gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).

Safety Evaluation of Trastuzumab Emtansine in Japanese Patients with HER2-Positive Advanced Breast Cancer

PubMed Central

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

2017-01-01

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

EGFR-targeted therapies in the post-genomic era.

PubMed

Xu, Mary Jue; Johnson, Daniel E; Grandis, Jennifer R

2017-09-01

Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1 E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.

Novel Targeted Therapies for Inflammatory Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

Targeted therapies for the treatment of leukemia.

PubMed

Stull, Dawn Marie

2003-05-01

To review novel targeted therapies for the treatment of leukemia. Professional journals, books, and government publications. Nonspecific cytotoxic chemotherapeutic agents provide marginal therapeutic benefit and significant toxicity when used in the treatment of leukemia. There is a tremendous need for new therapies with increased efficacy and decreased adverse effects. Advances in molecular science, genetics, and immunology, along with improved laboratory technology, have led to the discovery of unique targets integral to the growth and proliferation of malignant cells which are providing the foundation for the development of a new generation of antitumor agents. Nurses must be prepared to educate patients, administer novel therapies, and manage side effects.

Demands for ‘off‐licence’ access to trastuzumab (Herceptin): content analysis of UK newspaper articles

PubMed Central

Hind, Daniel; Wailoo, Allan J.; Sutcliffe, Paul

2010-01-01

Abstract Background  Sensationalized reporting styles and a distorted framing of health‐care issues in newspapers may trigger inappropriate commissioning decisions. We evaluated UK press coverage of pre‐licensing access to trastuzumab (Herceptin) for early breast cancer as a case study. Methods and findings  Content analysis of newspaper articles published between April 2005 and May 2006 were coded by two researchers for interest groups represented, claims made and sensationalized reporting. Disagreements in coding were resolved by a third researcher. One thousand and ninety published articles were identified in the study period and a 20% sample (n = 218) was included in the content analysis. Most articles (76%, 95% CI 71–82) included claims about the clinical benefits of trastuzumab, and this was significantly higher than those expressing the uncertainty surrounding such benefits (6%, 95% CI 3–9) or those that discussed the potential harms (5%, 95% CI 2–8). Articles were significantly more likely to feature claims made by a breast cancer survivor or family member than any other interest group (P < 0.0001). Almost half of the articles carried some message to the effect that trastuzumab would make the difference between life and death (47%, 95% CI 40–53). Over a quarter (28%, 95% CI 22–34) suggested that trastuzumab is a ‘miracle drug’ or similar. Conclusions  The benefits of drugs are highlighted, frequently using sensationalist language, without equal consideration of uncertainty or risks. Health‐care purchasers should express decisions in opportunity cost terms; journalists should give fairer coverage to such arguments. PMID:20673243

Basal/HER2 breast carcinomas

PubMed Central

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

2013-01-01

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

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.

PubMed

Murthy, Rashmi; Borges, Virginia F; Conlin, Alison; Chaves, Jorge; Chamberlain, Marc; Gray, Todd; Vo, Alex; Hamilton, Erika

2018-05-24

Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases. In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m 2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192. Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

PubMed

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

2012-07-01

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

Upregulation of Mucin4 in ER-positive/HER2-Overexpressing Breast Cancer Xenografts with Acquired Resistance to Endocrine and HER2-Targeted Therapies

PubMed Central

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

2012-01-01

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

Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes.

PubMed

Spraggs, C F; Parham, L R; Briley, L P; Warren, L; Williams, L S; Fraser, D J; Jiang, Z; Aziz, Z; Ahmed, S; Demetriou, G; Mehta, A; Jackson, N; Byrne, J; Andersson, M; Toi, M; Harris, L; Gralow, J; Zujewski, J A; Crescenzo, R; Armour, A; Perez, E; Piccart, M

2018-05-22

HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10 -26 , n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.

Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars.

PubMed

Jackisch, Christian; Lammers, Philip; Jacobs, Ira

2017-04-01

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer comprises approximately 15%-20% of all breast cancers and is associated with a poor prognosis. The introduction of anti-HER2 therapy has significantly improved clinical outcomes for patients with HER2+ breast cancer, and multiple HER2-directed agents (ie, trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine [T-DM1]) are approved for clinical use in various settings. The treatment landscape for patients with HER2+ breast cancer is continuing to evolve. While novel agents and therapeutic strategies are emerging, biologic therapies, particularly trastuzumab, are likely to remain a mainstay of treatment. However, access issues create barriers to the use of biologics, and there is evidence for underuse of trastuzumab worldwide. A biosimilar is a biologic product that is highly similar to a licensed biologic in terms of product safety and effectiveness. Biosimilars of trastuzumab are in development and may soon become available. The introduction of biosimilars may improve access to anti-HER2 therapies by providing additional treatment options and lower-cost alternatives. Because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies, biosimilars have the potential to result in significant savings for healthcare systems. Herein we review current and emerging treatment options for, and discuss the possible role of biosimilars in, treating patients with HER2+ breast cancer. Copyright © 2017 Authors, Pfizer Inc. Published by Elsevier Ltd.. All rights reserved.

Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects?

PubMed

Nasr, Rihab; El Hajj, Hiba; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-06-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Predictive value of quantitative HER2, HER3 and p95HER2 levels in HER2-positive advanced breast cancer patients treated with lapatinib following progression on trastuzumab.

PubMed

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

2017-11-28

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

Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.

PubMed

Awada, Ahmad; Colomer, Ramon; Inoue, Kenichi; Bondarenko, Igor; Badwe, Rajendra A; Demetriou, Georgia; Lee, Soo-Chin; Mehta, Ajay O; Kim, Sung-Bae; Bachelot, Thomas; Goswami, Chanchal; Deo, Suryanarayan; Bose, Ron; Wong, Alvin; Xu, Feng; Yao, Bin; Bryce, Richard; Carey, Lisa A

2016-12-01

Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed. To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer. In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety. The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was

Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy

PubMed Central

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-01

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration. PMID:25606974

Bacteriophage-derived vectors for targeted cancer gene therapy.

PubMed

Pranjol, Md Zahidul Islam; Hajitou, Amin

2015-01-19

Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration.

Multi-arm Cost-Effectiveness Analysis (CEA) comparing different durations of adjuvant trastuzumab in early breast cancer, from the English NHS payer perspective

PubMed Central

Hunter, Rachael M.; Shemilt, Ian; Serra-Sastre, Victoria

2017-01-01

Background Trastuzumab improves survival in HER2+ breast cancer patients, with some evidence of adverse cardiac side effects. Current recommendations are to give adjuvant trastuzumab for one year or until recurrence, although trastuzumab treatment for only 9 or 10 weeks has shown similar survival rates to 12-month treatment. We present here a multi-arm joint analysis examining the relative cost-effectiveness of different durations of adjuvant trastuzumab. Methods and findings Network meta-analysis (NMA) was used to examine which trials’ data to include in the cost-effectiveness analysis (CEA). A network using FinHer (9 weeks vs. zero) and BCIRG006 (12 months vs. zero) trials offered the only jointly randomisable network so these trials were used in the CEA. The 3-arm CEA compared costs and quality-adjusted life-years (QALYs) associated with zero, 9-week and 12-month adjuvant trastuzumab durations in early breast cancer, using a decision tree followed by a Markov model that extrapolated the results to a lifetime time horizon. Pairwise incremental cost-effectiveness ratios (ICERs) were also calculated for each pair of regimens and used in budget impact analysis, and the Bucher method was used to check face validity of the findings. Addition of the PHARE trial (6 months vs. 12 months) to the network, in order to create a 4-arm CEA including the 6-month regimen, was not possible as late randomisation in this trial resulted in recruitment of a different patient population as evidenced by the NMA findings. The CEA results suggest that 9 weeks’ trastuzumab is cost-saving and leads to more QALYs than 12 months’, i.e. the former dominates the latter. The cost-effectiveness acceptability frontier (CEAF) favours zero trastuzumab at willingness-to-pay levels below £2,500/QALY and treatment for 9 weeks above this threshold. The combination of the NMA and Bucher investigations suggests that the 9-week duration is as efficacious as the 12-month duration for distant

Multi-arm Cost-Effectiveness Analysis (CEA) comparing different durations of adjuvant trastuzumab in early breast cancer, from the English NHS payer perspective.

PubMed

Clarke, Caroline S; Hunter, Rachael M; Shemilt, Ian; Serra-Sastre, Victoria

2017-01-01

Trastuzumab improves survival in HER2+ breast cancer patients, with some evidence of adverse cardiac side effects. Current recommendations are to give adjuvant trastuzumab for one year or until recurrence, although trastuzumab treatment for only 9 or 10 weeks has shown similar survival rates to 12-month treatment. We present here a multi-arm joint analysis examining the relative cost-effectiveness of different durations of adjuvant trastuzumab. Network meta-analysis (NMA) was used to examine which trials' data to include in the cost-effectiveness analysis (CEA). A network using FinHer (9 weeks vs. zero) and BCIRG006 (12 months vs. zero) trials offered the only jointly randomisable network so these trials were used in the CEA. The 3-arm CEA compared costs and quality-adjusted life-years (QALYs) associated with zero, 9-week and 12-month adjuvant trastuzumab durations in early breast cancer, using a decision tree followed by a Markov model that extrapolated the results to a lifetime time horizon. Pairwise incremental cost-effectiveness ratios (ICERs) were also calculated for each pair of regimens and used in budget impact analysis, and the Bucher method was used to check face validity of the findings. Addition of the PHARE trial (6 months vs. 12 months) to the network, in order to create a 4-arm CEA including the 6-month regimen, was not possible as late randomisation in this trial resulted in recruitment of a different patient population as evidenced by the NMA findings. The CEA results suggest that 9 weeks' trastuzumab is cost-saving and leads to more QALYs than 12 months', i.e. the former dominates the latter. The cost-effectiveness acceptability frontier (CEAF) favours zero trastuzumab at willingness-to-pay levels below £2,500/QALY and treatment for 9 weeks above this threshold. The combination of the NMA and Bucher investigations suggests that the 9-week duration is as efficacious as the 12-month duration for distant-disease-free survival and overall survival

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

PubMed Central

Nasr, Rihab; Hajj, Hiba El; Kfoury, Youmna; de Thé, Hugues; Hermine, Olivier; Bazarbachi, Ali

2011-01-01

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL. PMID:21994752

Assessing the Real-World Cost-Effectiveness of Adjuvant Trastuzumab in HER-2/neu Positive Breast Cancer

PubMed Central

Hedden, Lindsay; O'Reilly, Susan; Lohrisch, Caroline; Chia, Stephen; Speers, Caroline; Kovacic, Laurel; Taylor, Suzanne

2012-01-01

Background. Among women with surgically removed, high-risk HER-2/neu-positive breast cancer, trastuzumab has demonstrated significant improvements in disease-free and overall survival. The objective of this study is to evaluate the cost-effectiveness of the currently recommended 12-month adjuvant protocol of trastuzumab using a Markov modeling approach and real-world cost data. Methods. A 10-health-state Markov model tracked patients' quarterly transitions between health states in the local and advanced states of breast cancer. Clinical data were obtained from the joint analysis of the National Surgical Adjuvant Breast and Bowel Project and North Central Cancer Treatment Group, as well as from the metastatic study conducted by Norum et al. Clinical outcomes were adjusted for quality of life using utility estimates published in a systematic review. Real cost data were obtained from the British Columbia Cancer Agency and were evaluated from a payer perspective. Costs and utilities were discounted at 5% per year, respectively, for a 28-year time horizon. Results. In the base case analysis, treatment with a 12-month adjuvant trastuzumab regimen resulted in a gain of 1.38 quality-adjusted life years or 1.17 life years gained at a cost of $18,133 per patient. Thus, the cost per QALY gained for the base case is $13,095. Cost per LYG is $15,492. Conclusions. Over the long term, treatment of HER-2/neu mutation positive breast cancer with a 12-month protocol of trastuzumab in the adjuvant setting is predicted to be cost-effective in a Canadian context. PMID:22302231

In silico design, construction and cloning of Trastuzumab humanized monoclonal antibody: A possible biosimilar for Herceptin

PubMed Central

Akbarzadeh-Sharbaf, Soudabeh; Yakhchali, Bagher; Minuchehr, Zarrin; Shokrgozar, Mohammad Ali; Zeinali, Sirous

2012-01-01

Background: There is a novel hypothesis in that antibodies may have specificity for two distinct antigens that have been named “dual specificity”. This hypothesis was evaluated for some defined therapeutic monoclonal antibodies (mAbs) such as Trastuzumab, Pertuzumab, Bevacizumab, and Cetuximab. In silico design and construction of expression vectors for trastuzumab monoclonal antibody also in this work were performed. Materials and Methods: First, in bioinformatics studies the 3D structures of concerned mAbs were obtained from the Protein Data Bank (PDB). Three-dimensional structural alignments were performed with SIM and MUSTANG softwares. AutoDock4.2 software also was used for the docking analysis. Second, the suitable genes for trastuzumab heavy and light chains were designed, synthesized, and cloned in the prokaryotic vector. These fragments individually were PCR amplified and cloned into pcDNA™ 3.3-TOPO® and pOptiVEC™ TOPO® shuttle vectors, using standard methods. Results: First, many bioinformatics tools and softwares were applied but we did not meet any new dual specificity in the selected antibodies. In the following step, the suitable expression cascade for the heavy and light chains of Trastuzumab therapeutic mAb were designed and constructed. Gene cloning was successfully performed and created constructs were confirmed using gene mapping and sequencing. Conclusions: This study was based on a recently developed technology for mAb expression in mammalian cells. The obtained constructs could be successfully used for biosimilar recombinant mAb production in CHO DG44 dihydrofolate reductase (DHFR) gene deficient cell line in the suspension culture medium. PMID:23210080

Mucin-based targeted pancreatic cancer therapy.

PubMed

Torres, Maria P; Chakraborty, Subhankar; Souchek, Joshua; Batra, Surinder K

2012-01-01

The prognosis of pancreatic cancer (PC) patients is very poor with a five-year survival of less than 5%. One of the major challenges in developing new therapies for PC is the lack of expression of specific markers by pancreatic tumor cells. Mucins are heavily Oglycosylated proteins characterized by the presence of short stretches of amino acid sequences repeated several times in tandem. The expression of several mucins including MUC1, MUC4, MUC5AC, and MUC16 is strongly upregulated in PC. Recent studies have also demonstrated a link between the aberrant expression and differential overexpression of mucin glycoproteins to the initiation, progression, and poor prognosis of the disease. These studies have led to increasing recognition of mucins as potential diagnostic markers and therapeutic targets in PC. In this focused review we present an overview of the therapies targeting mucins in PC, including immunotherapy (i.e. vaccines, antibodies, and radioimmunoconjugates), gene therapy, and other novel therapeutic strategies.

Imatinib: A Breakthrough of Targeted Therapy in Cancer

PubMed Central

Iqbal, Naveed

2014-01-01

Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology. PMID:24963404

Improving patient outcomes to targeted therapies in melanoma.

PubMed

Eroglu, Zeynep; Smalley, Keiran S M; Sondak, Vernon K

2016-06-01

The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years. In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas. Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.

Target marketing strategies for occupational therapy entrepreneurs.

PubMed

Kautzmann, L N; Kautzmann, F N; Navarro, F H

1989-01-01

Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival.

PubMed

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

2018-05-10

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

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.

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT.

PubMed

Chan, Conrad; Scollard, Deborah A; McLarty, Kristin; Smith, Serena; Reilly, Raymond M

2011-08-17

Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen radioactivity were observed for 64Cu-DOTA-trastuzumab

A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

PubMed Central

2011-01-01

Background Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Methods Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE and HPLC. HER2 binding affinity was determined in saturation radioligand binding assays using SKBR-3 cells (1.3 × 106 HER2/cell). MicroSPECT/CT and microPET/CT were performed in athymic mice bearing s.c. BT-20 and MDA-MB-231 xenografts with low (0.5 to 1.6 × 105 receptors/cell), MDA-MB-361 tumors with intermediate (5.1 × 105 receptors/cell) or SKOV-3 xenografts with high HER2 expression (1.2 × 106 receptors/cell) at 24 h p.i. of 70 MBq (10 μg) of 111In-DOTA-trastuzumab Fab or 22 MBq (10 μg) of 64Cu-DOTA-trastuzumab Fab or irrelevant 111In- or 64Cu-DOTA-rituximab Fab. Tumor and normal tissue uptake were quantified in biodistribution studies. Results 111In- and 64Cu-DOTA-trastuzumab were > 98% radiochemically pure and bound HER2 with high affinity (Kd = 20.4 ± 2.5 nM and 40.8 ± 3.5 nM, respectively). MDA-MB-361 and SKOV-3 tumors were most clearly imaged using 111In- and 64Cu-DOTA-trastuzumab Fab. Significantly higher tumor/blood (T/B) ratios were found for 111In-DOTA-trastuzumab Fab than 111In-DOTA-rituximab Fab for BT-20, MDA-MB-231 and MDA-MB-361 xenografts, and there was a direct association between T/B ratios and HER2 expression. In contrast, tumor uptake of 64Cu-DOTA-trastuzumab Fab was significantly higher than 64Cu-DOTA-rituximab Fab in MDA-MB-361 tumors but no direct association with HER2 expression was found. Both 111In- and 64Cu-DOTA-trastuzumab Fab imaged small (5 to 10 mm) or larger (10 to 15 mm) MDA-MB-361 tumors. Higher blood, liver, and spleen

The role of neratinib in HER2-driven breast cancer.

PubMed

Cherian, Mathew A; Ma, Cynthia X

2017-06-30

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

Anthocyanins potentiate the activity of trastuzumab in human epidermal growth factor receptor 2-positive breast cancer cells in vitro and in vivo.

PubMed

Liu, Weihua; Xu, Jinmei; Liu, Yilun; Yu, Xiaoping; Tang, Xi; Wang, Zhi; Li, Xin

2014-10-01

Human epidermal growth factor receptor 2 (HER2) has been found to be overexpressed in ~25% of invasive breast cancer and is significantly associated with a poor prognosis in breast cancer patients. The anthocyanins cyanidin-3-glucoside (C3G) and peonidin-3-glucoside have been identified as potential drugs for the therapy of HER2‑positive breast cancer. They have been used as supplements in targeted therapeutics and chemotherapeutics in Asia, however, the underlying mechanism remains to be elucidated. The aim of the present study was to investigate the synergism between C3G and trastuzumab (Trast). To address this question, the response to C3G, Trast and a combination of the two drugs, in three representative HER2‑positive cell lines was evaluated. The combination treatments induced apoptosis, inhibited cell growth and affected HER2 and its downstream signaling pathway in MDA‑MB‑453, BT474 and HCC1569 cells, and the effects were synergistic. The combination of 3CG and Trast inhibited tumor growth in an in vivo xenograft model. The data from the present study suggested that C3G exhibits potent antitumor activity when combined with Trast under the investigated conditions.

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

PubMed

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

2011-10-11

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

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524)

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

Michaelson, M. Dror, E-mail: dmichaelson1@partners.org; Hu, Chen; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Purpose: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completionmore » rate, and survival. Results: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.« less

How Can Gastric Cancer Molecular Profiling Guide Future Therapies?

PubMed

Corso, Simona; Giordano, Silvia

2016-07-01

Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Efficient production of Trastuzumab Fab antibody fragments in Brevibacillus choshinensis expression system.

PubMed

Mizukami, Makoto; Onishi, Hiromasa; Hanagata, Hiroshi; Miyauchi, Akira; Ito, Yuji; Tokunaga, Hiroko; Ishibashi, Matsujiro; Arakawa, Tsutomu; Tokunaga, Masao

2018-10-01

The Brevibacillus expression system has been successfully employed for the efficient productions of a variety of recombinant proteins, including enzymes, cytokines, antigens and antibody fragments. Here, we succeeded in secretory expression of Trastuzumab Fab antibody fragments using B. choshinensis/BIC (Brevibacillus in vivocloning) expression system. In the fed-batch high-density cell culture, recombinant Trastuzumab Fab with amino-terminal His-tag (His-BcFab) was secreted at high level, 1.25 g/liter, and Fab without His-tag (BcFab) at ∼145 mg/L of culture supernatant. His-BcFab and BcFab were purified to homogeneity using combination of conventional column chromatographies with a yield of 10-13%. This BcFab preparation exhibited native structure and functions evaluated by enzyme-linked immunosorbent assay, surface plasmon resonance, circular dichroism measurements and size exclusion chromatography. To our knowledge, this is the highest production of Fab antibody fragments in gram-positive bacterial expression/secretion systems. Copyright © 2018 Elsevier Inc. All rights reserved.

High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance).

PubMed

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

2018-03-12

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

For Some Breast Cancers, New Drug May Be Treatment Option

Cancer.gov

Results from an international clinical trial suggest that women with metastatic, HER2-positive breast cancer that is no longer responding to the targeted therapy trastuzumab (Herceptin) may soon have a new treatment option.

Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial

PubMed Central

De Maio, Ermelinda; Pacilio, Carmen; Gravina, Adriano; Morabito, Alessandro; Di Rella, Francesca; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Rossi, Emanuela; Silvestro, Pasqualina; Botti, Gerardo; Di Bonito, Maurizio; Curcio, Maria Pia; Formichelli, Franca; La Vecchia, Franca; Staiano, Maria; Maurea, Nicola; D'Aiuto, Giuseppe; D'Aiuto, Massimiliano; Thomas, Renato; Signoriello, Giuseppe; Perrone, Francesco; de Matteis, Andrea

2007-01-01

Background After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks. Methods Patients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization), PS ≤2, normal left-ventricular ejection fraction (LVEF) and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m2) was given on days 1&8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg) every 21 days). A single-stage phase 2 design, with p0 = 0.45, p1 = 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients. Results From Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31–81). Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8–66.2); 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3–12.3), median overall survival 22.7 months (95% CI 19.5-NA). Fifteen patients (30%) developed brain metastases at a median time of 12 months (range 1–25). There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46%) had grade 3–4 neutropenia, 2 (4%) grade 3 anemia, 4 (8%) febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF. Conclusion Although lower than in initial

Neoadjuvant therapy in the treatment of breast cancer

PubMed Central

Teshome, Mediget; Hunt, Kelly K.

2014-01-01

Synopsis Neoadjuvant systemic therapy in the treatment of breast cancer was initially employed for patients with inoperable disease. Over the past several decades this treatment approach has proved beneficial in many other patients including those with early-stage, operable breast cancer. Several randomized prospective studies have shown comparable survival rates when compared with adjuvant systemic therapy. Additionally, neoadjuvant chemotherapy can decrease the tumor burden facilitating breast conservation in selected patients without significant increases in local recurrence. Response to therapy has proven to be a strong predictor of outcome, with patients achieving pathologic complete response (pCR) demonstrating improved survival compared with those achieving less than a pCR. Furthermore, molecular subtype analysis has shown improved response following neoadjuvant chemotherapy in certain tumor types providing patients with the most aggressive subtypes a chance at cure with targeted therapies. In particular, targeting the HER2-positive subtype with trastuzumab and other HER2-directed therapies has markedly improved the outcome in these patients. Conversely, the early recognition of poor responders is important in limiting the toxicity of ineffective therapy and altering management. Neoadjuvant endocrine therapy in postmenopausal women with hormone receptor-positive tumors consistently decreases tumor size improving rates of breast conservation. Aromatase inhibitors have demonstrated superiority to tamoxifen with improved response and favorable toxicity profiles. Imaging modalities have shown promise in predicting patients with pCR, however they have not yet eliminated the need for surgical intervention. Less invasive surgical strategies such as breast conserving surgery and sentinel lymph node dissection have been shown to be safe following neoadjuvant chemotherapy in selected patients. A multidisciplinary approach with primary systemic therapy when indicated

A New Era for Cancer Target Therapies: Applying Systems Biology and Computer-Aided Drug Design to Cancer Therapies.

PubMed

Wong, Yung-Hao; Chiu, Chia-Chiun; Lin, Chih-Lung; Chen, Ting-Shou; Jheng, Bo-Ren; Lee, Yu-Ching; Chen, Jeremy; Chen, Bor-Sen

In recent years, many systems biology approaches have been used with various cancers. The materials described here can be used to build bases to discover novel cancer therapy targets in connection with computer-aided drug design (CADD). A deeper understanding of the mechanisms of cancer will provide more choices and correct strategies in the development of multiple target drug therapies, which is quite different from the traditional cancer single target therapy. Targeted therapy is one of the most powerful strategies against cancer and can also be applied to other diseases. Due to the large amount of progress in computer hardware and the theories of computational chemistry and physics, CADD has been the main strategy for developing novel drugs for cancer therapy. In contrast to traditional single target therapies, in this review we will emphasize the future direction of the field, i.e., multiple target therapies. Structure-based and ligand-based drug designs are the two main topics of CADD. The former needs both 3D protein structures and ligand structures, while the latter only needs ligand structures. Ordinarily it is estimated to take more than 14 years and 800 million dollars to develop a new drug. Many new CADD software programs and techniques have been developed in recent decades. We conclude with an example where we combined and applied systems biology and CADD to the core networks of four cancers and successfully developed a novel cocktail for drug therapy that treats multiple targets.

Choosing a therapy electron accelerator target.

PubMed

Hutcheon, R M; Schriber, S O; Funk, L W; Sherman, N K

1979-01-01

Angular distributions of photon depth dose produced by 25-MeV electrons incident on several fully stopping single-element targets (C, Al, Cu, Mo, Ta, Pb) and two composite layered targets (Ni-Al, W-Al) were studied. Depth-dose curves measured using TLD-700 (thermoluminescent dosimeter) chips embedded in lucite phantoms. Several useful therapy electron accelerator design curves were determined, including relative flattener thickness as a function of target atomic number, "effective" bremsstrahlung endpoint energy or beam "hardness" as a function of target atomic number and photon emission angle, and estimates of shielding thickness as a function of angle required to reduce the radiation outside the treatment cone to required levels.

Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-14-2-0159 TITLE: Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies PRINCIPAL INVESTIGATOR...Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for...AND SUBTITLE Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer.

PubMed

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

2017-07-13

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

Breast Cancer: Current Molecular Therapeutic Targets and New Players.

PubMed

Nagini, Siddavaram

2017-01-01

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

SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab.

PubMed

Meattini, Icro; Curigliano, Giuseppe; Terziani, Francesca; Becherini, Carlotta; Airoldi, Mario; Allegrini, Giacomo; Amoroso, Domenico; Barni, Sandro; Bengala, Carmelo; Guarneri, Valentina; Marchetti, Paolo; Martella, Francesca; Piovano, Pierluigi; Vannini, Agnese; Desideri, Isacco; Tarquini, Roberto; Galanti, Giorgio; Barletta, Giuseppe; Livi, Lorenzo

2017-05-01

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

Association Studies of Fcγ Receptor Polymorphisms with Outcome in HER2+ Breast Cancer Patients Treated with Trastuzumab in NCCTG (Alliance) Trial N9831

PubMed Central

Norton, Nadine; Olson, Rebecca M.; Pegram, Mark; Tenner, Kathleen; Ballman, Karla V.; Clynes, Raphael; Knutson, Keith L.; Perez, Edith A.

2014-01-01

Patients with HER2+ breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. Polymorphisms within FCGR2A and FCGR3A are associated with binding affinity of natural killer cells to the IgG1 portion of trastuzumab and a polymorphism in FCGR2B (I232T) is associated with impaired regulatory activity. The association of these polymorphisms with clinical response among trastuzumab-treated patients is equivocal with both positive and negative associations. We performed genotyping analysis on the FCGR3A V158F, FCGR2A R131H, and FCGR2B I232T genes in 1,325 patients from the N9831 clinical trial. Patients in Arm A (N=419) received chemotherapy only. Patients in Arms B (N=469) and C (N=437) were treated with chemotherapy and trastuzumab, (sequentially in Arm B and concurrently in Arm C). Using log-rank test and Cox proportional hazard models, we compared disease-free survival (DFS) among genotypic groups within pooled Arms B/C. We found no differences in DFS between trastuzumab-treated patients who had the FCGR3A 158 V/V and/or FCGR2A 131 H/H high affinity genotypes and patients without those genotypes. Furthermore, there was no significant interaction between FCGR3A and FCGR2A and treatment. However, there was a difference in DFS for FCGR2B I232T with I/I patients deriving benefit from trastuzumab (p<0.001) compared to the T carriers who did not (p=0.81). The interaction between FCGR2B genotype and treatment was statistically significant (p=0.03). Our analysis did not reveal an association between FcγR high affinity genotypes and outcomes. However, it appears that the FCGR2B inhibitory gene may be predictive of adjuvant trastuzumab benefit. PMID:24989892

Molecular targeting agents in cancer therapy: science and society.

PubMed

Shaikh, Asim Jamal

2012-01-01

The inception of targeted agents has revolutionized the cancer therapy paradigm, both for physicians and patients. A large number of molecular targeted agents for cancer therapy are currently available for clinical use today. Many more are in making, but there are issues that remain to be resolved for the scientific as well as social community before the recommendation of their widespread use in may clinical scenarios can be done, one such issue being cost and cost effectiveness, others being resistance and lack of sustained efficacy. With the current knowledge about available targeted agents, the growing knowledge of intricate molecular pathways and unfolding of wider spectrum of molecular targets that can really matter in the disease control, calls for only the just use of the agents available now, drug companies need to make a serious attempt to reduce the cost of the agents. Research should focus on agents that show sustained responses in preclinical data. More needs to be done in laboratories and by the pharmaceutical industries, before we can truly claim to have entered a new era of targeted therapy in cancer care.

Molecular mechanisms for vascular complications of targeted cancer therapies.

PubMed

Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

2016-10-01

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach

PubMed Central

Chen, Lian; Cui, Hengmin

2015-01-01

Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. PMID:26402672

Targeted therapies in the treatment of urothelial cancers.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2017-07-01

Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene Therapy Targeting Glaucoma: Where Are We?

PubMed Central

Liu, Xuyang; Rasmussen, Carol A.; Gabelt, B’Ann T.; Brandt, Curtis R.; Kaufman, Paul L.

2010-01-01

In a chronic disease such as glaucoma, a therapy that provides a long lasting local effect, with minimal systemic side effects, while circumventing the issue of patient compliance, is very attractive. The field of gene therapy is growing rapidly and ocular applications are expanding. Our understanding of the molecular pathogenesis of glaucoma is leading to greater specificity in ocular tissue targeting. Improvements in gene delivery techniques, refinement of vector construction methods, and development of better animal models combine to bring this potential therapy closer to reality. PMID:19539835

Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis.

PubMed

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

2016-09-01

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

Development and preclinical studies of 64Cu-NOTA-pertuzumab F(ab′)2 for imaging changes in tumor HER2 expression associated with response to trastuzumab by PET/CT

PubMed Central

Lam, Karen; Chan, Conrad; Reilly, Raymond M.

2017-01-01

ABSTRACT We previously reported that microSPECT/CT imaging with 111In-labeled pertuzumab detected decreased HER2 expression in human breast cancer (BC) xenografts in athymic mice associated with response to treatment with trastuzumab (Herceptin). Our aim was to extend these results to PET/CT by constructing F(ab′)2 of pertuzumab modified with NOTA chelators for complexing 64Cu. The effect of the administered mass (5–200 µg) of 64Cu-NOTA-pertuzumab F(ab′)2 was studied in NOD/SCID mice engrafted with HER2-positive SK-OV-3 human ovarian cancer xenografts. Biodistribution studies were performed in non-tumor bearing Balb/c mice to predict radiation doses to normal organs in humans. Serial PET/CT imaging was conducted on mice engrafted with HER2-positive and trastuzumab-sensitive BT-474 or trastuzumab-insensitive SK-OV-3 xenografted mice treated with weekly doses of trastuzumab. There were no significant effects of the administered mass of 64Cu-NOTA-pertuzumab F(ab′)2 on tumor or normal tissue uptake. The predicted total body dose in humans was 0.015 mSv/MBq, a 3.3-fold reduction compared to 111In-labeled pertuzumab. MicroPET/CT images revealed specific tumor uptake of 64Cu-NOTA-pertuzumab F(ab′)2 at 24 or 48 h post-injection in mice with SK-OV-3 tumors. Image analysis of mice treated with trastuzumab showed 2-fold reduced uptake of 64Cu-NOTA-pertuzumab F(ab′)2 in BT-474 tumors after 1 week of trastuzumab normalized to baseline, and 1.9-fold increased uptake in SK-OV-3 tumors after 3 weeks of trastuzumab, consistent with tumor response and resistance, respectively. We conclude that PET/CT imaging with 64Cu-NOTA-pertuzumab F(ab′)2 detected changes in HER2 expression in response to trastuzumab while delivering a lower total body radiation dose compared to 111In-labeled pertuzumab. PMID:27813707

Management of pulmonary toxicity associated with targeted anticancer therapies.

PubMed

Teuwen, Laure-Anne; Van den Mooter, Tom; Dirix, Luc

2015-01-01

Targeted anticancer therapies act by interfering with defined molecular entities and/or biologic pathways. Because of their more specific mechanism of action, adverse events (AEs) on healthy tissues are intended to be minimal, resulting in a different toxicity profile from that observed with conventional cytotoxic chemotherapy. Pulmonary AEs are rare but potentially life-threatening and it is, therefore, critical to recognize early on and manage appropriately. In this review, we aim to offer an overview of both more frequent and rare pulmonary AEs caused by targeted anticancer therapies and discuss possible treatment algorithms. Anti-vascular endothelial growth factor, anti-human epidermal growth factor receptor and anti-CD20 therapy will be reviewed, as well as immune checkpoint inhibitors, anaplastic lymphoma kinase inhibitors and mammalian target of rapamycin inhibitors. Novel agents used in the treatment of cancer have specific side-effects, the result of allergic reactions, on-target and off-target effects. Clinical syndromes associated with pulmonary toxicity vary from bronchospasms, hypersensitivity reactions, pneumonitis, acute respiratory distress, lung bleeding, pleural effusion to pneumothorax. Knowledge of risk factors, a high index of suspicion and a complete diagnostic work-up are essential for limiting the risk of these events becoming life threatening. The development of treatment algorithms is extremely helpful in managing these events. It is probable that these toxicities will be even more frequent with the introduction of combination therapies with the obvious challenge of discerning the responsible agent.

Targeted therapy according to next generation sequencing-based panel sequencing.

PubMed

Saito, Motonobu; Momma, Tomoyuki; Kono, Koji

2018-04-17

Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next-generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials. For that purpose, a NGS-based sequencing panel that can simultaneously target multiple genes in a single investigation has been used in daily clinical practice. To date, various types of sequencing panels have been developed to investigate genetic aberrations with tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics. Because sequencing panels are efficient and cost-effective, they are quickly being adopted outside the lab, in hospitals and clinics, in order to identify personal targeted therapy for individual cancer patients.

New PARP targets for cancer therapy

PubMed Central

Vyas, Sejal; Chang, Paul

2015-01-01

Poly(ADP-ribose) polymerases (PARPs) modify target proteins post-translationally with poly(ADP-ribose) (PAR) or mono(ADP-ribose) (MAR) using NAD+ as substrate. The best-studied PARPs generate PAR modifications and include PARP1 and the tankyrase PARP5a, both of which are targets for cancer therapy with inhibitors in either clinical trials or preclinical development. There are 15 additional PARPs, the majority of which modify proteins with MAR, and their biology is less well understood. Recent data identify potentially cancer relevant functions for these PARPs, indicating that we need to understand more about these PARPs in order to target them effectively. PMID:24898058

Enhancing Targeted Therapy for Myeloproliferative Neoplasms

DTIC Science & Technology

2013-10-01

Myeloproliferative Neoplasms PRINCIPAL INVESTIGATOR: Gary W. Reuther CONTRACTING...2. REPORT TYPE Annual 3. DATES COVERED 30 2012-2 2013 4. TITLE AND SUBTITLE Enhancing Targeted Therapy for Myeloproliferative Neoplasms ...AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Myeloproliferative neoplasms

Costs of subcutaneous and intravenous administration of trastuzumab for patients with HER2-positive breast cancer.

PubMed

Olsen, Jens; Jensen, Kenneth Forsstrøm; Olesen, Daniel Sloth; Knoop, Ann

2018-05-01

Trastuzumab is available in an intravenous (iv.) and a subcutaneous (sc.) formulation. The objective of this study was to estimate the costs of administration of iv. and sc. trastuzumab treatment. Via interviews, we identified all the activities associated with iv. and sc. administration. The outcome was time estimates. To estimate the administration costs, the time estimates were valued by average gross wages.  The iv. administration takes longer time as infusion time is longer (25 or 85 min). The iv. administration is associated with higher cost for 17 cycles; €971 (€1858 vs €887). sc. administration is associated with lower administration costs. Switching patients from iv. to sc. would make it possible to treat more patients without increasing the personnel resources.

Targeted and Nontargeted α-Particle Therapies.

PubMed

McDevitt, Michael R; Sgouros, George; Sofou, Stavroula

2018-06-04

α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease.

Targeted and Nontargeted α-Particle Therapies

PubMed Central

McDevitt, Michael R.; Sgouros, George; Sofou, Stavroula

2018-01-01

α-Particle irradiation of cancerous tissue is increasingly recognized as a potent therapeutic option. We briefly review the physics, radiobiology, and dosimetry of α-particle emitters, as well as the distinguishing features that make them unique for radiopharmaceutical therapy. We also review the emerging clinical role of α-particle therapy in managing cancer and recent studies on in vitro and preclinical α-particle therapy delivered by antibodies, other small molecules, and nanometer-sized particles. In addition to their unique radiopharmaceutical characteristics, the increased availability and improved radiochemistry of α-particle radionuclides have contributed to the growing recent interest in α-particle radiotherapy. Targeted therapy strategies have presented novel possibilities for the use of α-particles in the treatment of cancer. Clinical experience has already demonstrated the safe and effective use of α-particle emitters as potent tumor-selective drugs for the treatment of leukemia and metastatic disease. PMID:29345977

Successes and limitations of targeted therapies in renal cell carcinoma.

PubMed

Pracht, Marc; Berthold, Dominik

2014-01-01

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. © 2014 S. Karger AG, Basel.

Chronic lymphocytic leukemia therapy: new targeted therapies on the way

PubMed Central

Vitale, Candida; Burger, Jan A

2016-01-01

Introduction The critical role of the tissue microenvironment and B cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development. Areas covered In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway. PMID:26988407

Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.

PubMed

Janmaat, Vincent T; Steyerberg, Ewout W; van der Gaast, Ate; Mathijssen, Ron Hj; Bruno, Marco J; Peppelenbosch, Maikel P; Kuipers, Ernst J; Spaander, Manon Cw

2017-11-28

Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased

Cancer-targeted therapies and radiopharmaceuticals

PubMed Central

Rachner, Tilman D; Jakob, Franz; Hofbauer, Lorenz C

2015-01-01

The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed. PMID:26131359

Targeting RNA Splicing for Disease Therapy

PubMed Central

Havens, Mallory A.; Duelli, Dominik M.

2013-01-01

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics. PMID:23512601

Targeting RNA splicing for disease therapy.

PubMed

Havens, Mallory A; Duelli, Dominik M; Hastings, Michelle L

2013-01-01

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for the expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics. Copyright © 2013 John Wiley & Sons, Ltd.

Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

PubMed Central

Thaker, Nikhil G; Pollack, Ian F

2010-01-01

Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

Targeted Agents Active Against Breast Cancer: Q&A

Cancer.gov

ALTTO was a clinical trial designed to determine whether the combination of the monoclonal antibody trastuzumab (Herceptin) and the drug lapatinib (Tykerb) was more effective in treating HER2/ErbB2-positive breast cancer when combined with chemotherapy than either agent alone. Results from ALTTO did not show additional benefit from combining lapatinib and trastuzumab compared with trastuzumab treatment alone.

Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents.

PubMed

Wilkes, Gail M

2018-01-01

Today, personalized cancer therapy with targeted agents has taken center stage, and offers individualized treatment to many. As the mysteries of the genes in a cell's DNA and their specific proteins are defined, advances in the understanding of cancer gene mutations and how cancer evades the immune system have been made. This article provides a basic and simplified understanding of the available (Food and Drug Administration- approved) molecularly and immunologically targeted agents in the USA. Other agents may be available in Asia, and throughout the USA and the world, many more agents are being studied. Nursing implications for drug classes are reviewed.

Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells.

PubMed

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

2013-04-01

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

Personalized targeted therapy for esophageal squamous cell carcinoma

PubMed Central

Kang, Xiaozheng; Chen, Keneng; Li, Yicheng; Li, Jianying; D'Amico, Thomas A; Chen, Xiaoxin

2015-01-01

Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial. PMID:26167067

Tes, a potential Mena-related cancer therapy target.

PubMed

Li, X

2008-02-01

Cancer remains one of the world's most prominent causes of human morbidity and mortality, particularly in developing countries. According to 2005 statistics from the WHO, approximately 7.6 million people died of cancer out of 58 million deaths worldwide, with 9 million people estimated to die from cancer in 2015 and 11.4 million to die in 2030 (http://www.who.int/mediacentre/factsheets/fs297/en/index.html). The principal and internationally recognized methods of cancer treatment are surgery, radiotherapy, chemotherapy, or multimodality therapy. With the recent development of cancer biology, more and more tumor-related targets have been identified, ushering in a new era for target therapy. Every possible step that causes cellular cancer, such as signal transduction pathways, oncogenes and anti-oncogenes, cytokines and receptors, antiangiogenesis, suicide genes, and telomerase (Shay JW, Keith WN. Br J Cancer 2008), that is biologically relevant, reproducibly measurable, and definably correlated with clinical benefit represents a target for target therapies like targeting gene-virotherapy and monoclonal antibody-directed therapy. These therapies can specifically inhibit the growth of tumor cells at the molecular level and even kill them. Generally speaking, cancer-related targets should be crucial to the tumor's malignant phenotype, easily measurable in readily obtained clinical samples, and yield a significant clinical response. Since tumorigenesis is a very complex process involving the interaction of multiple factors and pathways, target treatment offers hopes to maximize efficacy while minimizing toxicity and specificity. More importantly, treatment should have little or no toxicity on normal cells, thus representing the most promising aspect of cancer research (Friday BB, Adjei AA. Clin Cancer Res 2008; 14:342-346). A recent cancer study has provided exciting information. According to Xinhua News from London, Michael Way and fellow researchers from Cancer

Development of targeted therapy and immunotherapy for treatment of small cell lung cancer.

PubMed

Saito, Motonobu; Shiraishi, Kouya; Goto, Akiteru; Suzuki, Hiroyuki; Kohno, Takashi; Kono, Koji

2018-05-14

Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC.

Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK

PubMed Central

Rothschild, Sacha I.

2015-01-01

Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID:26018876

Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK.

PubMed

Rothschild, Sacha I

2015-05-26

Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed.

Advances in Systemic Therapy for Metastatic or Advanced Gastric Cancer.

PubMed

Shitara, Kohei; Ohtsu, Atsushi

2016-10-01

In recent years, various new agents have been investigated for the treatment of advanced gastric cancer (AGC). The anti-HER2 antibody trastuzumab has been shown to prolong the overall survival of patients with HER2-positive AGC and has become a standard treatment. However, lapatinib, or ado-trastuzumab emtansine (T-DM1), did not show survival benefit in AGC, although it has shown remarkable efficacy for HER2-positive breast cancer. The efficacy of the anti-vascular endothelial growth factor receptor monoclonal antibody ramucirumab for pretreated gastric cancer is a milestone for antiangiogenic therapy for AGC. Early clinical trials of TAS-118, TAS-102, and STAT3 inhibitors; IMAB362 (anti-Claudin 18.2); and immune checkpoint inhibitors are all encouraging. These findings warrant further evaluation in larger clinical trials. Copyright © 2016 by the National Comprehensive Cancer Network.

Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy

PubMed Central

Zhou, Jiehua; Rossi, John J.

2014-01-01

One hundred years ago, Dr. Paul Ehrlich popularized the “magic bullet” concept for cancer therapy in which an ideal therapeutic agent would only kill the specific tumor cells it targeted. Since then, “targeted therapy” that specifically targets the molecular defects responsible for a patient's condition has become a long-standing goal for treating human disease. However, safe and efficient drug delivery during the treatment of cancer and infectious disease remains a major challenge for clinical translation and the development of new therapies. The advent of SELEX technology has inspired many groundbreaking studies that successfully adapted cell-specific aptamers for targeted delivery of active drug substances in both in vitro and in vivo models. By covalently linking or physically functionalizing the cell-specific aptamers with therapeutic agents, such as siRNA, microRNA, chemotherapeutics or toxins, or delivery vehicles, such as organic or inorganic nanocarriers, the targeted cells and tissues can be specifically recognized and the therapeutic compounds internalized, thereby improving the local concentration of the drug and its therapeutic efficacy. Currently, many cell-type-specific aptamers have been developed that can target distinct diseases or tissues in a cell-type-specific manner. In this review, we discuss recent advances in the use of cell-specific aptamers for targeted disease therapy, as well as conjugation strategies and challenges. PMID:24936916

Breast cancer: complete response with the combination of sunitinib and trastuzumab in a patient with grade III ductal carcinoma.

PubMed

Puente, Javier; Manzano, Aranzazu; Martin, Miguel; López-Tarruella, Sonia; Díaz-Rubio, Eduardo

2010-01-01

In August 2000, a previously healthy postmenopausal 52-year-old woman was diagnosed with grade III invasive ductal carcinoma. The tumor had an ER -, PR -, and HER2 + profile. Adjuvant treatment with FEC was initiated followed by radiotherapy. In October 2004, the patient presented a clinically asymptomatic supraclavicular and mediastinal lymph node recurrence and treatment with paclitaxel and trastuzumab was initiated. A complete response was achieved after 20 weeks of treatment, and in January 2006 treatment was interrupted due to toxicity. After a 34-month free-of-relapse period, a local recurrence was detected in the chest wall. In September 2007, the patient joined a phase II trial with sunitinib (37.5 mg once a day in 28 days cycles) and trastuzumab (6 mg/kg every 3 weeks), after having verified a normal cardiac function. After two courses, a partial cutaneous response and a complete radiological response were obtained. The most relevant toxicities included cutaneous hyperpigmentation, dysgeusia, mucositis, grade II diarrhea and hypertension. The development of grade III diarrhea led to sunitinib dose reduction (25mg/day). In January 2008, the patient developed hypothyroidism and a significant drop in the left ventricular ejection fraction that led to treatment interruption. In March 2008, once cardiac function was recovered, treatment at the same dose was reinitiated. After two months of treatment, a new descent in cardiac function was noted which led to the suspension of sunitinib, and the interruption of the trastuzumab treatment until recovery of normal cardiac function. In July 2008, trastuzumab monotherapy was resumed and since then no cardiac events have been reported, while maintaining a radiological and clinical response.

IMPLICATIONS OF GLOBAL PRICING POLICIES ON ACCESS TO INNOVATIVE DRUGS: THE CASE OF TRASTUZUMAB IN SEVEN LATIN AMERICAN COUNTRIES.

PubMed

Pichon-Riviere, Andres; Garay, Osvaldo Ulises; Augustovski, Federico; Vallejos, Carlos; Huayanay, Leandro; Bueno, Maria del Pilar Navia; Rodriguez, Alarico; de Andrade, Carlos José Coelho; Buendía, Jefferson Antonio; Drummond, Michael

2015-01-01

Differential pricing, based on countries' purchasing power, is recommended by the World Health Organization to secure affordable medicines. However, in developing countries innovative drugs often have similar or even higher prices than in high-income countries. We evaluated the potential implications of trastuzumab global pricing policies in terms of cost-effectiveness (CE), coverage, and accessibility for patients with breast cancer in Latin America (LA). A Markov model was designed to estimate life-years (LYs), quality-adjusted life-years (QALYs), and costs from a healthcare perspective. To better fit local cancer prognosis, a base case scenario using transition probabilities from clinical trials was complemented with two alternative scenarios with transition probabilities adjusted to reflect breast cancer epidemiology in each country. Incremental discounted benefits ranged from 0.87 to 1.00 LY and 0.51 to 0.60 QALY and incremental CE ratios from USD 42,104 to USD 110,283 per QALY (2012 U.S. dollars), equivalent to 3.6 gross domestic product per capita (GDPPC) per QALY in Uruguay and to 35.5 GDPPC in Bolivia. Probabilistic sensitivity analysis showed 0 percent probability that trastuzumab is CE if the willingness-to-pay threshold is one GDPPC per QALY, and remained so at three GDPPC threshold except for Chile and Uruguay (4.3 percent and 26.6 percent, respectively). Trastuzumab price would need to decrease between 69.6 percent to 94.9 percent to became CE in LA. Although CE in other settings, trastuzumab was not CE in LA. The use of health technology assessment to prioritize resource allocation and support price negotiations is critical to making innovative drugs available and affordable in developing countries.

Application of stem cells in targeted therapy of breast cancer: a systematic review.

PubMed

Madjd, Zahra; Gheytanchi, Elmira; Erfani, Elham; Asadi-Lari, Mohsen

2013-01-01

The aim of this systematic review was to investigate whether stem cells could be effectively applied in targeted therapy of breast cancer. A systematic literature search was performed for original articles published from January 2007 until May 2012. Nine studies met the inclusion criteria for phase I or II clinical trials, of which three used stem cells as vehicles, two trials used autologous hematopoetic stem cells and in four trials cancer stem cells were targeted. Mesenchymal stem cells (MSCs) were applied as cellular vehicles to transfer therapeutic agents. Cell therapy with MSC can successfully target resistant cancers. Cancer stem cells were selectively targeted via a proteasome-dependent suicide gene leading to tumor regression. Wnt/β-catenin signaling pathway has been also evidenced to be an attractive CSC-target. This systematic review focused on two different concepts of stem cells and breast cancer marking a turning point in the trials that applied stem cells as cellular vehicles for targeted delivery therapy as well as CSC-targeted therapies. Applying stem cells as targeted therapy could be an effective therapeutic approach for treatment of breast cancer in the clinic and in therapeutic marketing; however this needs to be confirmed with further clinical investigations.

Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents

PubMed Central

Wilkes, Gail M.

2018-01-01

Today, personalized cancer therapy with targeted agents has taken center stage, and offers individualized treatment to many. As the mysteries of the genes in a cell's DNA and their specific proteins are defined, advances in the understanding of cancer gene mutations and how cancer evades the immune system have been made. This article provides a basic and simplified understanding of the available (Food and Drug Administration- approved) molecularly and immunologically targeted agents in the USA. Other agents may be available in Asia, and throughout the USA and the world, many more agents are being studied. Nursing implications for drug classes are reviewed. PMID:29607374

Targeting neutrophils for host-directed therapy to treat tuberculosis.

PubMed

Dallenga, Tobias; Linnemann, Lara; Paudyal, Bhesh; Repnik, Urska; Griffiths, Gareth; Schaible, Ulrich E

2017-10-07

M. tuberculosis is one of the prime killers from infectious diseases worldwide. Infections with multidrug-resistant variants counting for almost half a million new cases per year are steadily on the rise. Tuberculosis caused by extensively drug-resistant variants that are even resistant against newly developed or last resort antibiotics have to be considered untreaTable Susceptible tuberculosis already requires a six-months combinational therapy which requires further prolongation to treat drug-resistant infections. Such long treatment schedules are often accompanied by serious adverse effects causing patients to stop therapy. To tackle the global tuberculosis emergency, novel approaches for treatment need to be urgently explored. Host-directed therapies that target components of the defense system represent such a novel approach. In this review, we put a spotlight on neutrophils and neutrophil-associated effectors as promising targets for adjunct host-directed therapies to improve antibiotic efficacy and reduce both, treatment time and long-term pathological sequelae. Copyright © 2017 Elsevier GmbH. All rights reserved.

The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831.

PubMed

Perez, Edith A; Baehner, Frederick L; Butler, Steven M; Thompson, E Aubrey; Dueck, Amylou C; Jamshidian, Farid; Cherbavaz, Diana; Yoshizawa, Carl; Shak, Steven; Kaufman, Peter A; Davidson, Nancy E; Gralow, Julie; Asmann, Yan W; Ballman, Karla V

2015-10-01

The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with

Review of the current targeted therapies for non-small-cell lung cancer

PubMed Central

Nguyen, Kim-Son H; Neal, Joel W; Wakelee, Heather

2014-01-01

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come. PMID:25302162

Drifts in ADCC-related quality attributes of Herceptin®: Impact on development of a trastuzumab biosimilar.

PubMed

Kim, Seokkyun; Song, Jinsu; Park, Seungkyu; Ham, Sunyoung; Paek, Kyungyeol; Kang, Minjung; Chae, Yunjung; Seo, Heewon; Kim, Hyung-Chan; Flores, Michael

A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biologic properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July 2018, a high degree of consistency was observed for all the tested properties. However, among the lots expiring in August 2018 or later, a downward drift was observed in %afucose (G0+G1+G2). Furthermore, the upward drift of %high mannose (M5+M6) was observed in the lots with expiry dates from June 2019 to December 2019. As a result, the combination of %afucose and %high mannose showed 2 marked drifts in the lots with expiry dates from August 2018 to December 2019, which was supported by the similar trend of biologic data, such as FcγRIIIa binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab.

Drifts in ADCC-related quality attributes of Herceptin®: Impact on development of a trastuzumab biosimilar

PubMed Central

Kim, Seokkyun; Song, Jinsu; Park, Seungkyu; Ham, Sunyoung; Paek, Kyungyeol; Kang, Minjung; Chae, Yunjung; Seo, Heewon; Kim, Hyung-Chan; Flores, Michael

2017-01-01

ABSTRACT A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biologic properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July 2018, a high degree of consistency was observed for all the tested properties. However, among the lots expiring in August 2018 or later, a downward drift was observed in %afucose (G0+G1+G2). Furthermore, the upward drift of %high mannose (M5+M6) was observed in the lots with expiry dates from June 2019 to December 2019. As a result, the combination of %afucose and %high mannose showed 2 marked drifts in the lots with expiry dates from August 2018 to December 2019, which was supported by the similar trend of biologic data, such as FcγRIIIa binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab. PMID:28296619

Molecular targeted therapy for the treatment of gastric cancer.

PubMed

Xu, Wenting; Yang, Zhen; Lu, Nonghua

2016-01-04

Despite the global decline in the incidence and mortality of gastric cancer, it remains one of the most common malignant tumors of the digestive system. Although surgical resection is the preferred treatment for gastric cancer, chemotherapy is the preferred treatment for recurrent and advanced gastric cancer patients who are not candidates for reoperation. The short overall survival and lack of a standard chemotherapy regimen make it important to identify novel treatment modalities for gastric cancer. Within the field of tumor biology, molecular targeted therapy has attracted substantial attention to improve the specificity of anti-cancer efficacy and significantly reduce non-selective resistance and toxicity. Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c-Met, mTOR signaling and insulin-like growth factor receptors, to exert a stronger anti-tumor effect. An in-depth understanding of the mechanisms that underlie molecular targeted therapies will provide new insights into gastric cancer treatment.

Bacteriophages and medical oncology: targeted gene therapy of cancer.

PubMed

Bakhshinejad, Babak; Karimi, Marzieh; Sadeghizadeh, Majid

2014-08-01

Targeted gene therapy of cancer is of paramount importance in medical oncology. Bacteriophages, viruses that specifically infect bacterial cells, offer a variety of potential applications in biomedicine. Their genetic flexibility to go under a variety of surface modifications serves as a basis for phage display methodology. These surface manipulations allow bacteriophages to be exploited for targeted delivery of therapeutic genes. Moreover, the excellent safety profile of these viruses paves the way for their potential use as cancer gene therapy platforms. The merge of phage display and combinatorial technology has led to the emergence of phage libraries turning phage display into a high throughput technology. Random peptide libraries, as one of the most frequently used phage libraries, provide a rich source of clinically useful peptide ligands. Peptides are known as a promising category of pharmaceutical agents in medical oncology that present advantages such as inexpensive synthesis, efficient tissue penetration and the lack of immunogenicity. Phage peptide libraries can be screened, through biopanning, against various targets including cancer cells and tissues that results in obtaining cancer-homing ligands. Cancer-specific peptides isolated from phage libraries show huge promise to be utilized for targeting of various gene therapy vectors towards malignant cells. Beyond doubt, bacteriophages will play a more impressive role in the future of medical oncology.

Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer.

PubMed

Janjigian, Yelena Y; Sanchez-Vega, Francisco; Jonsson, Philip; Chatila, Walid K; Hechtman, Jaclyn F; Ku, Geoffrey Y; Riches, Jamie C; Tuvy, Yaelle; Kundra, Ritika; Bouvier, Nancy; Vakiani, Efsevia; Gao, Jianjiong; Heins, Zachary J; Gross, Benjamin E; Kelsen, David P; Zhang, Liying; Strong, Vivian E; Schattner, Mark; Gerdes, Hans; Coit, Daniel G; Bains, Manjit; Stadler, Zsofia K; Rusch, Valerie W; Jones, David R; Molena, Daniela; Shia, Jinru; Robson, Mark E; Capanu, Marinela; Middha, Sumit; Zehir, Ahmet; Hyman, David M; Scaltriti, Maurizio; Ladanyi, Marc; Rosen, Neal; Ilson, David H; Berger, Michael F; Tang, Laura; Taylor, Barry S; Solit, David B; Schultz, Nikolaus

2018-01-01

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14 See related article by Pectasides et al., p. 37 This article is highlighted in the In This Issue feature, p. 1 . ©2017 American Association for Cancer Research.

Targeting gene therapy to cancer: a review.

PubMed

Dachs, G U; Dougherty, G J; Stratford, I J; Chaplin, D J

1997-01-01

In recent years the idea of using gene therapy as a modality in the treatment of diseases other than genetically inherited, monogenic disorders has taken root. This is particularly obvious in the field of oncology where currently more than 100 clinical trials have been approved worldwide. This report will summarize some of the exciting progress that has recently been made with respect to both targeting the delivery of potentially therapeutic genes to tumor sites and regulating their expression within the tumor microenvironment. In order to specifically target malignant cells while at the same time sparing normal tissue, cancer gene therapy will need to combine highly selective gene delivery with highly specific gene expression, specific gene product activity, and, possibly, specific drug activation. Although the efficient delivery of DNA to tumor sites remains a formidable task, progress has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods. In this report emphasis will be placed on targeted rather than high-efficiency delivery, although those would need to be combined in the future for effective therapy. To date delivery has been targeted to tumor-specific and tissue-specific antigens, such as epithelial growth factor receptor, c-kit receptor, and folate receptor, and these will be described in some detail. To increase specificity and safety of gene therapy further, the expression of the therapeutic gene needs to be tightly controlled within the target tissue. Targeted gene expression has been analyzed using tissue-specific promoters (breast-, prostate-, and melanoma-specific promoters) and disease-specific promoters (carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC). Alternatively, expression could be regulated externally with the use of radiation-induced promoters or tetracycline-responsive elements. Another novel possibility that will be

Practical issues of biomarker-assisted targeted therapy in precision medicine and immuno-oncology era.

PubMed

Lee, Dae Ho

2018-01-01

The concept of precision medicine is not new, as multiplex and very sensitive methods, or next-generation sequencing and matched targeted cancer therapies, have come to clinical practice. Substantial progress has been made from the discovery to the development and clinical application of biomarkers and matched targeted therapies. However, there still remain many challenges and issues to be overcome in each step, from acquisition of tumour tissues through validation of biomarkers to the final decision on targeted therapy. This review will briefly touch on these issues, hoping to provide a better understanding and application of targeted therapy in cancer treatment in the era of precision medicine and immuno-oncology. It also helps to understand that the meaning or value of biomarker(s) and matched targeted therapy changes along with expansion of knowledge and advance of methodology, and constant efforts have to be made in evaluating the meaning and clinical value during the development and after the establishment of biomarkers or the approval of matched targeted therapies, which might be more complicated by the advent of new therapeutic agents and new diagnostic methods.

Advances in targeted therapy for acute myeloid leukaemia.

PubMed

Kayser, Sabine; Levis, Mark J

2018-02-01

In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next-generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and pro-apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML. © 2017 John Wiley & Sons Ltd.

Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer - An observational study prospectively recording resource utilization in a Swedish healthcare setting.

PubMed

Olofsson, Sara; Norrlid, Hanna; Karlsson, Eva; Wilking, Ulla; Ragnarson Tennvall, Gunnel

2016-10-01

Trastuzumab is part of the standard treatment for HER2-positive breast cancer. The aim of this study was to estimate the societal value of trastuzumab administered through subcutaneous (SC) injection compared to intravenous (IV) infusion. Female patients with HER2-positive breast cancer receiving SC or IV trastuzumab were consecutively enrolled from five Swedish oncology clinics from 2013 to 2015. Data on time and resource utilization was collected prospectively using patient and nurse questionnaires. Societal costs were calculated by multiplying the resource use by its corresponding unit price, including direct medical costs (pharmaceuticals, materials, nurse time, etc.), direct non-medical costs (transportation) and indirect costs (production loss, lost leisure time). Costs were reported separately for patients receiving trastuzumab for the first time and non-first time ("subsequent treatment"). In total, 101 IV and 94 SC patients were included in the study. The societal costs were lower with SC administration. For subsequent treatments the cost difference was €117 (IV €2099; SC €1983), partly explained by a higher time consumption both for nurses (14 min) and patients (23 min) with IV administration. Four IV and 16 SC patients received trastuzumab for the first time and were analysed separately, resulting in a difference in societal costs of €897 per treatment. A majority of patients preferred SC to IV administration. SC administration resulted in both less direct medical costs and indirect costs, and was consequently less costly than IV administration from a societal perspective in a Swedish setting. Copyright © 2016 Elsevier Ltd. All rights reserved.

Folate-targeted nanoparticles for rheumatoid arthritis therapy.

PubMed

Nogueira, Eugénia; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

2016-05-01

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. Although the cause of RA remains unknown, the complex interaction between immune mediators (cytokines and effector cells) is responsible for the joint damage that begins at the synovial membrane. Activated macrophages are critical in the pathogenesis of RA and showed specifically express a receptor for the vitamin folic acid (FA), folate receptor β (FRβ). This particular receptor allows internalization of FA-coupled cargo. In this review we will address the potential of nanoparticles as an effective drug delivery system for therapies that will directly target activated macrophages. Special attention will be given to stealth degree of the nanoparticles as a strategy to avoid clearance by macrophages of the mononuclear phagocytic system (MPS). This review summarizes the application of FA-target nanoparticles as drug delivery systems for RA and proposes prospective future directions. Rheumatoid arthritis is a debilitating autoimmune disease of the joints which affects many people worldwide. Up till now, there is a lack of optimal therapy against this disease. In this review article, the authors outlined in depth the current mechanism of disease for rheumatoid arthritis and described the latest research in using folic acid-targeted nanoparticles to target synovial macrophages in the fight against rheumatoid arthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

Costs of trastuzumab in combination with chemotherapy for HER2-positive advanced gastric or gastroesophageal junction cancer: an economic evaluation in the Chinese context.

PubMed

Wu, Bin; Ye, Ming; Chen, Huafeng; Shen, Jinfang F

2012-02-01

Adding trastuzumab to a conventional regimen of chemotherapy can improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (GEJ) cancer, but the economic impact of this practice is unknown. The purpose of this cost-effectiveness analysis was to estimate the effects of adding trastuzumab to standard chemotherapy in patients with HER2-positive advanced gastric or GEJ cancer on health and economic outcomes in China. A Markov model was developed to simulate the clinical course of typical patients with HER2-positive advanced gastric or GEJ cancer. Five-year quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) were estimated. Model inputs were derived from the published literature and government sources. Direct costs were estimated from the perspective of Chinese society. One-way and probabilistic sensitivity analyses were conducted. On baseline analysis, the addition of trastuzumab increased cost and QALY by $56,004.30 (year-2010 US $) and 0.18, respectively, relative to conventional chemotherapy, resulting in an ICER of $251,667.10/QALY gained. Probabilistic sensitivity analyses supported that the addition of trastuzumab was not cost-effective. Budgetary impact analysis estimated that the annual increase in fiscal expenditures would be ~$1 billion. On univariate sensitivity analysis, the median overall survival time for conventional chemotherapy was the most influential factor with respect to the robustness of the model. The findings from the present analysis suggest that the addition of trastuzumab to conventional chemotherapy might not be cost-effective in patients with HER2-positive advanced gastric or GEJ cancer. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Virus-Based Cancer Therapeutics for Targeted Photodynamic Therapy.

PubMed

Cao, Binrui; Xu, Hong; Yang, Mingying; Mao, Chuanbin

2018-01-01

Cancer photodynamic therapy (PDT) involves the absorption of light by photosensitizers (PSs) to generate cytotoxic singlet oxygen for killing cancer cells. The success of this method is usually limited by the lack of selective accumulation of the PS at cancer cells. Bioengineered viruses with cancer cell-targeting peptides fused on their surfaces are great drug carriers that can guide the PS to cancer cells for targeted cancer treatment. Here, we use cell-targeting fd bacteriophages (phages) as an example to describe how to chemically conjugate PSs (e.g., pyropheophorbide-a (PPa)) onto a phage particle to achieve targeted PDT.

Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer.

PubMed

Morrow, Phuong Khanh H; Zambrana, Francisco; Esteva, Francisco J

2009-01-01

Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer.

Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab.

PubMed

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

2009-06-15

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

Targeted therapy using nanotechnology: focus on cancer

PubMed Central

Sanna, Vanna; Pala, Nicolino; Sechi, Mario

2014-01-01

Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication. PMID:24531078

Targeted Drug and Gene Delivery Systems for Lung Cancer Therapy

PubMed Central

Sundaram, Sneha; Trivedi, Ruchit; Durairaj, Chandrasekar; Ramesh, Rajagopal; Ambati, Balamurali K.; Kompella, Uday B.

2009-01-01

Purpose To evaluate the efficacy of a novel docetaxel derivative of deslorelin, a luteinizing hormone releasing hormone (LHRH) agonist, and its combination in-vivo with RGD peptide conjugated nanoparticles encapsulating an anti-angiogenic, anti-VEGF intraceptor (Flt23k) (RGD-Flt23k-NP) in H1299 lung cancer cells and/or xenografts in athymic nude BALB/c mice. Experimental Design The in-vitro and in-vivo efficacy of the deslorelin-docetaxel conjugate (D-D) was evaluated in H1299 cells and xenografts in athymic nude mice. Co-administration of D-D and RGD-Flt23k-NP was tested in-vivo in mice. Tumor inhibition, apoptosis and VEGF inhibition were estimated in each of the treatment groups. Results The conjugate enhanced in-vitro docetaxel efficacy by 13-fold in H1299 cells compared to docetaxel at 24h, and this effect was inhibited following reduction of LHRH-receptor expression by an antisense oligonucleotide. Combination of the conjugate with the RGD-Flt23k-NP in-vivo resulted in an 82- and 15-fold tumor growth inhibition on day 39 following repeated weekly intravenous injections and a single intratumoral injection, respectively. These effects were significantly greater than individual targeted therapies or docetaxel alone. Similarly, apoptotic indices for the combination therapy were 14 and 10% in the intravenous and intratumoral groups, respectively, and higher than the individual therapies. Combination therapy groups exhibited greater VEGF inhibition in both the intravenous and intratumoral groups. Conclusions Docetaxel efficacy was enhanced by LHRH-receptor targeted deslorelin conjugate and further improved by combination with targeted anti-angiogenic nanoparticle gene therapy. Combination of novel targeted therapeutic approaches described here provides an attractive alternative to the current treatment options for lung cancer therapy. PMID:19920099

A small molecule nanodrug consisting of amphiphilic targeting ligand-chemotherapy drug conjugate for targeted cancer therapy.

PubMed

Mou, Quanbing; Ma, Yuan; Zhu, Xinyuan; Yan, Deyue

2016-05-28

Targeted drug delivery is a broadly applicable approach for cancer therapy. However, the nanocarrier-based targeted delivery system suffers from batch-to-batch variation, quality concerns and carrier-related toxicity issues. Thus, to develop a carrier-free targeted delivery system with nanoscale characteristics is very attractive. Here, a novel targeting small molecule nanodrug self-delivery system consisting of targeting ligand and chemotherapy drug was constructed, which combined the advantages of small molecules and nano-assemblies together and showed excellent targeting ability and long blood circulation time with well-defined structure, high drug loading ratio and on-demand drug release behavior. As a proof-of-concept, lactose (Lac) and doxorubicin (DOX) were chosen as the targeting ligand and chemotherapy drug, respectively. Lac and DOX were conjugated through a pH-responsive hydrazone group. For its intrinsic amphiphilic property, Lac-DOX conjugate could self-assemble into nanoparticles in water. Both in vitro and in vivo assays indicated that Lac-DOX nanoparticles exhibited enhanced anticancer activity and weak side effects. This novel active targeting nanodrug delivery system shows great potential in cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Current therapies and targets for type 2 diabetes mellitus: a review.

PubMed

Chellapan, Dinesh K; Sheng Yap, Wei; Bt Ahmad Suhaimi, Nurfatihah A; Gupta, Gaurav; Dua, Kamal

2018-04-24

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing at an alarming rate. With an increased understanding of the pathophysiology and pathogenesis of T2DM, various new therapeutic options have been developed to target different key defects in T2DM. Incremental innovations of existing therapies either through unprecedented drug combinations, modified drug molecules, or improved delivery systems are capable to nullify some of the undesirable side effects of traditional therapies as well as to enhance effectiveness. The existing administration routes include inhalation, nasal, buccal, parenteral and oral. Newer drug targets such as protein kinase B (Akt/PKB), AMPactivated protein kinase (AMPK), sirtuin (SIRT), and others are novel approaches that act via different mechanisms and possibly treating T2DM of distinct variations and aetiologies. Other therapies such as endobarrier, gene therapy, and stem cell technology utilize advanced techniques to treat T2DM, and the potential of these therapies are still being explored. Gene therapy is plausible to fix the underlying pathology of T2DM instead of using traditional reactive treatments, especially with the debut of Clustered Regularly Interspaced Short Palindromic RepeatsCRISPR associated protein9 (CRISPRCas9) gene editing tool. Molecular targets in T2DM are also being extensively studied as it could target the defects at the molecular level. Furthermore, antibody therapies and vaccinations are also being developed against T2DM; but the ongoing clinical trials are relatively lesser and the developmental progress is slower. Although, there are many therapies designed to cure T2DM, each of them has their own advantages and disadvantages. The preference for the treatment plan usually depends on the health status of the patient and the treatment goal. Therefore, an ideal treatment should take patient's compliance, efficacy, potency, bioavailability, and other pharmacological and nonpharmacological properties

The roles of pathology in targeted therapy of women with gynecologic cancers.

PubMed

Murali, Rajmohan; Grisham, Rachel N; Soslow, Robert A

2018-01-01

The role of the pathologist in the multidisciplinary management of women with gynecologic cancer has evolved substantially over the past decade. Pathologists' evaluation of parameters such as pathologic stage, histologic subtype, grade and microsatellite instability, and their identification of patients at risk for Lynch syndrome have become essential components of diagnosis, prognostic assessment and determination of optimal treatment of affected women. Despite the use of multimodality treatment and combination cytotoxic chemotherapy, the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore, expanding the arsenal of available systemic therapies with targeted therapeutic agents is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase (PARP) inhibitors are now routinely used for the treatment of advanced gynecologic cancer, and many more are under investigation. Pathologists remain important in the clinical management of patients with targeted therapy, by identifying potentially targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers that are predictive of response to targeted therapy (e.g. microsatellite instability, PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists are also vital to research efforts exploring novel targeted therapies by identifying homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming expression in tumor tissues of novel targets identified in genomic, epigenetic or other screening studies. In the era of precision gynecologic oncology, the roles of pathologists in the discovery, development and implementation of targeted therapeutic strategies remain as central as they are for traditional (surgery-chemotherapy-radiotherapy) management of women with gynecologic cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

PubMed

Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

2016-01-01

Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

Financial relationships in economic analyses of targeted therapies in oncology.

PubMed

Valachis, Antonis; Polyzos, Nikolaos P; Nearchou, Andreas; Lind, Pehr; Mauri, Davide

2012-04-20

A potential financial relationship between investigators and pharmaceutical manufacturers has been associated with an increased likelihood of reporting favorable conclusions about a sponsor's proprietary agent in pharmacoeconomic studies. The purpose of this study is to investigate whether there is an association between financial relationships and outcome in economic analyses of new targeted therapies in oncology. We searched PubMed (last update June 2011) for economic analyses of targeted therapies (including monoclonal antibodies, tyrosine-kinase inhibitors, and mammalian target of rapamycin inhibitors) in oncology. The trials were qualitatively rated regarding the cost assessment as favorable, neutral, or unfavorable on the basis of prespecified criteria. Overall, 81 eligible studies were identified. Economic analyses that were funded by pharmaceutical companies were more likely to report favorable qualitative cost estimates (28 [82%] of 34 v 21 [45%] of 47; P = .003). The presence of an author affiliated with manufacturer was not associated with study outcome. Furthermore, if only studies including a conflict of interest statement were included (66 of 81), studies that reported any financial relationship with manufacturers (author affiliation and/or funding and/or other financial relationship) were more likely to report favorable results of targeted therapies compared with studies without financial relationship (32 [71%] of 45 v nine [43%] of 21; P = .025). Our study reveals a potential threat for industry-related bias in economic analyses of targeted therapies in oncology in favor of analyses with financial relationships between authors and manufacturers. A more balanced funding of economic analyses from other sources may allow greater confidence in the interpretation of their results.

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

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

Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.

2012-07-01

Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there hasmore » been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free

A cMUT probe for ultrasound-guided focused ultrasound targeted therapy.

PubMed

Gross, Dominique; Coutier, Caroline; Legros, Mathieu; Bouakaz, Ayache; Certon, Dominique

2015-06-01

Ultrasound-mediated targeted therapy represents a promising strategy in the arsenal of modern therapy. Capacitive micromachined ultrasonic transducer (cMUT) technology could overcome some difficulties encountered by traditional piezoelectric transducers. In this study, we report on the design, fabrication, and characterization of an ultrasound-guided focused ultrasound (USgFUS) cMUT probe dedicated to preclinical evaluation of targeted therapy (hyperthermia, thermosensitive liposomes activation, and sonoporation) at low frequency (1 MHz) with simultaneous ultrasonic imaging and guidance (15 to 20 MHz). The probe embeds two types of cMUT arrays to perform the modalities of targeted therapy and imaging respectively. The wafer-bonding process flow employed for the manufacturing of the cMUTs is reported. One of its main features is the possibility of implementing two different gap heights on the same wafer. All the design and characterization steps of the devices are described and discussed, starting from the array design up to the first in vitro measurements: optical (microscopy) and electrical (impedance) measurements, arrays' electroacoustic responses, focused pressure field mapping (maximum peak-to-peak pressure = 2.5 MPa), and the first B-scan image of a wire-target phantom.

An exploratory analysis of the factors leading to delays in cancer drug reimbursement in the European Union: the trastuzumab case.

PubMed

Ades, Felipe; Senterre, Chistelle; Zardavas, Dimitrios; de Azambuja, Evandro; Popescu, Razvan; Parent, Florence; Piccart, Martine

2014-12-01

The European Union (EU) has adopted a common procedure for granting marketing authorisation for cancer drugs. Nevertheless, pricing and reimbursement decisions are a competency of EU national governments, and their policies are diverse. We aimed to evaluate the time for trastuzumab reimbursement approval and its association to health expenditure, to health policy performance, to the availability of cost-effectiveness studies and to breast cancer outcome. Breast cancer outcome was estimated by the mortality/incidence (M/I) ratio. Trastuzumab reimbursement approval dates were provided by Roche. Spearman's rank correlation and Wilcoxon rank-sum test were used to evaluate associations and/or differences between the variables studied. Additional analyses were made by grouping countries according to compliance to the 180 day timeframe stipulated in the EU 89/105/EEC Directive for drug pricing and reimbursement. A statistically significant inverse and strong correlation between breast cancer M/I ratio and health expenditure (r(s)=-0.730, p<0.001) and health policy performance (r(s)=-0.711, p<0.001) was found, meaning the better the score and the higher the expenditure, the fewer patients died after a breast cancer diagnosis. Factors associated with trastuzumab faster reimbursement and compliance to the 89/105/EEC Directive were better health policy score, higher health expenditure and availability of cost-effectiveness studies. Higher health policy scores and health expenditure are associated with faster reimbursement of trastuzumab and better breast cancer outcome. Although the study design does not allow inference of causal associations, a marked difference is observed between Eastern and Western Europe, with long delays and increased breast cancer mortality identified in Eastern European countries. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

PubMed Central

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies

PubMed Central

Brandi, Giovanni; Farioli, Andrea; Astolfi, Annalisa; Biasco, Guido; Tavolari, Simona

2015-01-01

Cholangiocarcinoma (CC) encompasses a group of related but distinct malignancies whose lack of a stereotyped genetic signature makes challenging the identification of genomic landscape and the development of effective targeted therapies. Accumulated evidences strongly suggest that the remarkable genetic heterogeneity of CC may be the result of a complex interplay among different causative factors, some shared by most human cancers while others typical of this malignancy. Currently, considerable efforts are ongoing worldwide for the genetic characterization of CC, also using advanced technologies such as next-generation sequencing (NGS). Undoubtedly this technology could offer an unique opportunity to broaden our understanding on CC molecular pathogenesis. Despite this great potential, however, the high complexity in terms of factors potentially contributing to genetic variability in CC calls for a more cautionary application of NGS to this malignancy, in order to avoid possible biases and criticisms in the identification of candidate actionable targets. This approach is further justified by the urgent need to develop effective targeted therapies in this disease. A multidisciplinary approach integrating genomic, functional and clinical studies is therefore mandatory to translate the results obtained by NGS into effective targeted therapies for this orphan disease. PMID:26142706

Drug-targeting strategies in cancer therapy.

PubMed

Huang, P S; Oliff, A

2001-02-01

Genetic changes in cell-cycle, apoptotic, and survival pathways cause tumorigenesis, leading to significant phenotypic changes in transformed cells. These changes in the tumor environment - elevated expression of surface proteases, increased angiogenesis and glucuronidase activity - can be taken advantage of to improve the therapeutic index of existing cancer therapies. Targeting cytotoxics to tumor cells by enzymatic activation is a promising strategy for improving chemotherapeutics.

Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

PubMed Central

Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

2012-01-01

Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

[Targeted therapies in hepatocellular carcinomas: recent results and future development].

PubMed

Marijon, H; Faivre, S; Raymond, E

2009-05-01

Hepatocellular carcinoma (HCC) is one of the 5th most common cancers around the world with a limited number of systemic therapeutic options. Cytotoxic agents, hormonotherapy and immunotherapy have failed to demonstrate benefit compared to best supportive care in patients with advanced HCC. The recent development of targeted therapies provided hope for the treatment of advanced HCC. We reviewed phases II-III trials presented in 2007 and 2008. Results are promising with a clinical benefit reported with molecular therapies targeting EGF/EGFR and VEGF/VEGFR pathways.

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.

PubMed

Gump, Jacob M; Donson, Andrew M; Birks, Diane K; Amani, Vladimir M; Rao, Karun K; Griesinger, Andrea M; Kleinschmidt-DeMasters, B K; Johnston, James M; Anderson, Richard C E; Rosenfeld, Amy; Handler, Michael; Gore, Lia; Foreman, Nicholas; Hankinson, Todd C

2015-05-21

Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP. Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples. We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

Evolving targeted therapies for right ventricular failure.

PubMed

Di Salvo, Thomas G

2015-01-01

Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial. This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering. Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.

RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

PubMed Central

Le Masson, Gwendal

2018-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS. PMID:29342921

RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

PubMed

Mathis, Stéphane; Le Masson, Gwendal

2018-01-15

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

Molecular Approach to Targeted Therapy for Multiple Sclerosis.

PubMed

Sherbet, Gajanan V

2016-01-01

The development and evolution of targeted therapy to any disease require the identification of targets amenable to treatment of patients. Here the pathogenetic signalling systems involved in multiple sclerosis are scrutinised to locate nodes of deregulation and dysfunction in order to devise strategies of drug development for targeted intervention. Oliogoclonal bands (OCB) are isoelectric focusing profiles of immunoglobulins synthesised in the central nervous system. OCBs enable the diagnosis of multiple sclerosis with high sensitivity and specificity and are related to the course of the disease and progression. The OCB patterns can be linked with the expression of angiogenic molecular species. Angiogenic signalling which has also been implicated in demyelination provides the option of using angiogenesis inhibitors in disease control. The PI3K (phosphoinositide 3-kinase)/Akt axis has emerged with a key role in myelination with its demonstrable links with mTOR mediated transcription of downstream target genes. Inflammatory signals and innate and acquired immunity from the activation of NF-κB (nuclear factor κB) responsive genes are considered. NF-κB signalling could be implicated in myelination. The transcription factor STAT (signal transducers and activators of transcription) and the EBV (Epstein- Barr virus) transcription factor BZLF1 contributing significantly to the disease process are a major environmental factor linked to MS. EBV can activate TGF (transforming growth factor) and VEGF (vascular endothelial growth factor) signalling. EBV microRNAs are reviewed as signalling mediators of pathogenesis. Stem cell transplantation therapy has lately gained much credence, so the current status of mesenchymal and hematopoietic stem cell therapy is reviewed with emphasis on the differential expression immune-related genes and operation of signalling systems.

New perspectives on targeted therapy in ovarian cancer

PubMed Central

Coward, Jermaine IG; Middleton, Kathryn; Murphy, Felicity

2015-01-01

Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose) inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. PMID:25678824

Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.

PubMed

Diéras, Véronique; Miles, David; Verma, Sunil; Pegram, Mark; Welslau, Manfred; Baselga, José; Krop, Ian E; Blackwell, Kim; Hoersch, Silke; Xu, Jin; Green, Marjorie; Gianni, Luca

2017-06-01

The antibody-drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m 2 self-administered orally twice daily on days 1-14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1-21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov, number NCT00829166. Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned

Administrative risk quantification of subcutaneous and intravenous therapies in Italian centers utilizing the Failure Mode and Effects Analysis approach.

PubMed

Ponzetti, Clemente; Canciani, Monica; Farina, Massimo; Era, Sara; Walzer, Stefan

2016-01-01

In oncology, an important parameter of safety is the potential treatment error in hospitals. The analyzed hypothesis is that of subcutaneous therapies would provide a superior safety benefit over intravenous therapies through fixed-dose administrations, when analyzed with trastuzumab and rituximab. For the calculation of risk levels, the Failure Mode and Effect Analysis approach was applied. Within this approach, the critical treatment path is followed and risk classification for each individual step is estimated. For oncology and hematology administration, 35 different risk steps were assessed. The study was executed in 17 hematology and 16 breast cancer centers in Italy. As intravenous and subcutaneous were the only injection routes in medical available for trastuzumab and rituximab in oncology at the time of the study, these two therapies were chosen. When the risk classes were calculated, eight high-risk areas were identified for the administration of an intravenous therapy in hematology or oncology; 13 areas would be defined as having a median-risk classification and 14 areas as having a low-risk classification (total risk areas: n=35). When the new subcutaneous formulation would be applied, 23 different risk levels could be completely eliminated (65% reduction). Important high-risk classes such as dose calculation, preparation and package labeling, preparation of the access to the vein, pump infusion preparation, and infusion monitoring were included in the eliminations. The overall risk level for the intravenous administration was estimated to be 756 (ex-ante) and could be reduced by 70% (ex-post). The potential harm compensation for errors related to pharmacy would be decreased from eight risk classes to only three risk classes. The subcutaneous administration of trastuzumab (breast cancer) and rituximab (hematology) might lower the risk of administration and treatment errors for patients and could hence indirectly have a positive financial impact for

Drug resistance to targeted therapies: déjà vu all over again.

PubMed

Groenendijk, Floris H; Bernards, René