HER2-targeted Monoclonal Antibody Research Articles

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

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

HSP27 phosphorylation inhibitor regulates Her2 expression in human breast cancer cell line SK-BR-3 with induced Herceptin resistance

Herceptin, HER2-targeted monoclonal antibody, is one of the main treatments for breast cancer. However, the majority of patients that initially respond to Herceptin begin to progress again within 1 year. Thus, it is very important to clarify how to overcome resistance as much as to identify breast cancer patients who will be benefit from Herceptin. We previously reported that HSP27 can interact with Her2 protein, and up-regulated HSP27 may cause Herceptin resistance by increasing Her2 protein stability in human breast cancer cell line SK-BR-3 with induced Herceptin resistance (SK-BR-3 HR). In the present study we investigated whether HSP27 phosphorylation inhibitor can reduce the resistance of Herceptin by breaking interaction between Her2 and HSP27 protein. HSP27 phosphorylation inhibitor not only suppressed cell proliferation but also augmented apoptotic cell death in both SK-BR-3 HR and its parent cell line. Such anti-cancer effects were much stronger in SK-BR-3 HR compared to its parent cell line, and regulation of Her2 after HSP27 phosphorylation inhibitor treatment was found only in SK-BR-3 HR. However, the interaction between HSP27 and Her2 was not broken, but became increased by HSP27 phosphorylation inhibitor in a concentration dependent manner. Overall results demonstrate that even HSP27 phosphorylation inhibitor does not directly target the interaction of HSP27 with Her2; it would be useful to alternative option to overcome Herceptin resistance because it may induce effective down-regulation of Her2.

Abstract OT1-1-09: ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) and endocrine therapy

Abstract On behalf of the ALTERNATIVE (EGF114299) Steering Committee. Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) gene in breast cancer is associated with an aggressive phenotype, poor prognosis, and resistance to endocrine therapies. Of HER-positive (+) patients, ∼50% are also hormone receptor (HR)+. For patients who are both HER+ and HR+, combining the aromatase inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) has been shown to improve outcomes compared with letrozole alone. The combination of L and trastuzumab (T), a humanized monoclonal antibody-targeting HER2, has been shown to improve outcomes compared with L alone. Trial Design: The ALTERNATIVE study is a Phase III, randomized, open-label, multicenter trial which will examine the efficacy of L/T/AI in combination vs T/AI alone as first- or second-line therapy in metastatic breast cancer (MBC). Patients will be randomized to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of 8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of AI include letrozole, anastrozole, or exemestane. Eligibility Criteria: Postmenopausal female patients with HER2+/HR+ MBC who have received prior T and endocrine therapies and are not candidates for chemotherapy. Specific Aims: The primary efficacy endpoint is overall survival (OS), defined as the time from randomization until death due to any cause, for L/T/AI compared with T/AI alone. Secondary efficacy objectives include comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI in addition to comparisons of progression-free survival, overall response rate, time to response, and duration of response. The safety objective is to evaluate the safety and tolerability for all 3 treatment groups. A 5.75-year recruitment is anticipated. Around 200 centers across 36 countries are planned; approximately 182 centers are currently open for enrollment. Statistical Methods: The study is powered to detect a 42% reduction in risk of death (hazard ratio = 0.70) in patients who receive L/T/AI (median 34.3 months) vs T/AI (median 24 months) using a 1-sided test for superiority with α = 0.025. The required number of total events to achieve a power of 80% is 247. Secondary comparisons are not powered and all analyses will be based on the intent-to-treat population. Present and Target Accrual: Eighty (80) of 525 patients have been randomized. The original study population included only first-line patients. The study has recently undergone a protocol amendment to expand the eligible patient population to include both first- and second-line patients. The study is currently recruiting, with an anticipated target accrual of 525 patients by 2017. Contact Info: Susan Wroblewski (susan.l.wroblewski@gsk.com). Clinical trial registry number: NCT01160211 Funding: GlaxoSmithKline. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-09.

Marked radiographic response of a HER-2-overexpressing biliary cancer to trastuzumab

Trastuzumab is a monoclonal antibody targeting HER-2. HER-2 overexpression has been described in gallbladder cancer and in cholangiocarcinoma. This report describes the first case of a patient with HER-2 overexpressing metastatic gallbladder adenocarcinoma and responding radiographically and biochemically to trastuzumab alone.

Overcoming therapeutic MAb resistance in agressive HER2 positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells

Herceptin (Trastuzumab), a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse after one year of treatment despite Herceptin-based therapy. Alteration of Antibodies Dependant Cellular Cytotoxicity (ADCC) is one of the rational mechanisms for resistance to therapeutic Mab. The goal of this project is to overcome this resistance by adoptive transfer using genetically engineered optimized NK cells. We thus compare efficacy of two different approaches : (i) NK cells armed with a high affinity Fc domain (FcγRIIIα, CD16) linked to its transduction chain FCeRIγ (CD16/γ) to allow recognition and interaction with Mab, inducing ADCC and (ii) NK cells expressing Herceptin sequence fused to the transduction chain FCeRIγ(CD16/γ) to directly kill the HER2 positively cells. Results obtained in vitro demonstrated higher direct killing efficacy of NK expressing Herceptin/γ against HER2 amplified breast carcinoma cells. However, abnormal reactivity against cells with undetectable HER2 expression by FACS analysis was observed. This last point might represent an important limitation point for clinical use. On the other hand, “two step killing by ADCC” with NK-CD16/γ demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of antibody. We demonstrated that efficacy of specific lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression but not level on target cells In Herceptin resistant HER2+ xenograft immunodeficient NSG mice model, complete regression was obtained only with NK- CD16/γ in the presence of Herceptin. Our last results will be discussed. Restoration or improvement of effectors cells might be considerate as an issue in therapeutic humanized Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs, in order to maximize their antitumor activity.

Use of Pertuzumab for the Treatment of HER2-Positive Metastatic Breast Cancer

Targeting the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 (HER2)-positive breast cancer. Since resistance to trastuzumab occurs relatively frequently, particularly in the metastatic setting, novel anti-HER2 targeted therapies with complementary and/or synergistic mechanisms of action have been under development. Pertuzumab, a HER2-targeted monoclonal antibody that prevents HER2 dimerisation, is the first of a class of promising targeted agents for the treatment of HER2-positive breast cancer. A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed. ClinicalTrials.gov was searched for appropriate clinical trials. The search terms used included breast neoplasm, pertuzumab, dimerisation, and HER2-positive. Abstracts of studies presented at the ASCO and ESMO Annual Meetings, and San Antonio Breast Cancer Symposium were also included. Pertuzumab represents a novel anti-HER2 targeted therapy for HER2-positive breast cancers. In this article, we describe the mechanism of action of pertuzumab, as well as its drug development process and preclinical testing results. Based on the results of ancillary studies, dual inhibition using pertuzumab and trastuzumab was shown to be effective for the management of HER2-positive metastatic breast cancers pre-treated with trastuzumab-based therapy. For the first-line setting, the combination of both pertuzumab and trastuzumab with docetaxel (CLEOPATRA trial; clinical evaluation of pertuzumab and trastuzumab) has changed the paradigm of patient management. Pertuzumab provided a more comprehensive inhibition of HER2-driven signalling pathways. When administered together with trastuzumab, pertuzumab represent a significant advancement for the treatment of HER2-positive metastatic breast cancer patients.

Effects of Simultaneous Knockdown of HER2 and PTK6 on Malignancy and Tumor Progression in Human Breast Cancer Cells

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.

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

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 pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes. The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degradation. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estimated to be ~0.4L/day. Proteolytic degradation clearances for T-DM1 and trastuzumab were similar (~0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one additional steady state cycle. This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degradation and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance versus that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.

Evaluación económica del trastuzumab como tratamiento adyuvante en cáncer de mama HER2-positivo en Colombia

Trastuzumab (Herceptin), a recombinant, humanized, monoclonal antibody targeting HER2 is well established as an effective treatment for HER2-positive breast cancer. Evidence from developed countries showed that trastuzumab was cost-effective; but there are few evidences in developing countries. This study assesses the cost-effectiveness of adjuvant trastuzumab treatment in Colombia. A Markov health-state transition model was built to estimate clinical and economic outcomes in HER2-positive breast cancer with or without 12 months trastuzumab adjuvant chemotherapy over a lifetime perspective with annual transition cycles. The model incorporated five health states (diseasefree, local recurrence, distant recurrence, cardiac failure, and death). Baseline event rates and 3-year hazard ratio (HR=0.51, IC 95% 0.44-0.59; p<0.0001) were derived from 4-year follow up of the N9831 and NSABP B-31 trial. Costs and utility weights were obtained from the literature and were discounted by 5% annually. The model showed that the utilization of adjuvant trastuzumab treatment in early breast cancer can prolong 0.80 quality-adjusted life-years (QALY), compared with standard chemotherapy, an incremental cost-effectiveness ratio (ICER) of US$ 71,491 per QALY gained. The results suggest that 1-year adjuvant Trastuzumab treatment is not cost-effective in Colombia, using the definition of WHO cost-effectiveness threshold of 3 times GDP per capita.

Abstract A22: Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells.

Abstract The HER2 receptor is overexpressed in 25% of breast cancers and is associated with poor prognosis. Herceptin (Trastuzumab), a monoclonal antibody targeting HER2 has been demonstrated to improve survival of HER2 overexpressing metastatic breast cancer. However, half of patients who initially respond to Herceptin develop resistance within one year of treatment initiation, and in the adjuvant setting 15% of patients still relapse after one year of treatment despite Herceptin-based therapy. The goal of this project is to compare efficacy of two adoptive immunotherapies approaches by genetically engineered NK cells to overcome this resistance. For the first approach, we developed NK cells armed with an high affinity Fc domain (FcγRIIIα, CD16) linked to its transduction chain FCϵRIγ (CD16/γ) to allow recognition and interaction with Mab, inducing Antibodies Dependant Cellular Cytotoxicity (ADCC). For the second approaches, we developed NK cells expressing Herceptin sequence fused to the transduction chain FCϵRIγ (CD16/γ) to directly kill the HER2 positively cells. Results obtained in vitro demonstrated higher direct killing efficacy of NK expressing Herceptin/γ against HER2 amplified breast carcinoma cells BT474 or SKBR3. However, abnormal reactivity against cells with low or undetectable HER2 expression by FACS analysis was observed (15 to 30% of lysis). This might represent an important limitation point for clinical use. On the other hand, “two step killing by ADCC” with NK-CD16/γ demonstrated a very specific cytotoxicity against HER2 positive cells through ADCC only in the presence of Herceptin. We demonstrated that efficacy of specific lysis is linked (i) to effector dose, (ii) levels of CD16/γ expression on effectors cells, (iii) HER2 expression on target cells but not HER2 level of expression. We then compared in vivo efficacy of both approaches (“one step” vs “two step”ADCC) in HER2+ xenograft model using immunodeficient NOD-SCID mβ2-/- mice. Complete regression of herceptin resistant HER2+ xenograft was obtained only with NK- CD16γ in the presence of herceptin. Our last results will be presented. Because the alteration of ADCC mechanisms during Herceptin treatment is one rational explanation for the acquired resistance, restoring or improving effectors cells might represent next step in therapeutic humanized Mab resistance treatment. Successful immune-based therapies will likely ultimately integrate strategies that combine immunotherapy approaches and immune-modulating drugs (including toll-like receptor modulators, antibodies specific for the PD-1, the OX-40 ore the CD40 pathways, in order to maximize their antitumor activity. Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Christophe Caux, Henri Vie. Overcoming therapeutic MAb resistance in agressive HER2-positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A22.

Abstract OT1-1-04: ALTERNATIVE: safety and efficacy of lapatinib (L), trastuzumab (T), or both in combination with an aromatase inhibitor (AI) for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer

Abstract Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) gene in breast cancer is associated with an aggressive phenotype, poor prognosis, and resistance to endocrine therapies. Of HER2+ patients, ∼50% are also hormone receptor-positive (HR+). For patients who are both HER2+ and HR+, combining the AI letrozole with the dual tyrosine kinase inhibitor L has been shown to improve outcomes compared with letrozole alone. The combination of L and T, a humanized monoclonal antibody-targeting HER2, has been shown to improve outcomes compared with L alone. Trial design: The ALTERNATIVE study is a Phase III, randomized, open-label, multicenter trial, which will examine the efficacy of L/T/AI in combination versus T/AI alone. Patients will be randomized to 1 of 3 treatment arms: L 1000 mg po QD plus T (loading dose of 8 mg/kg followed by maintenance with 6 mg/kg IV q3w plus an AI po QD); T plus an AI; or L 1500 mg po QD plus an AI. Choices of AI include letrozole, anastrozole, or exemestane. Eligibility criteria: Postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have received neo/adjuvant T and endocrine therapy, are treatment naïve for MBC, and are not candidates for chemotherapy. Specific aims: The primary efficacy endpoint is overall survival (OS), defined as the time from randomization until death due to any cause, for L/T/AI compared with T/AI alone. Secondary efficacy objectives include comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI in addition to comparisons of progression-free survival, overall response rate, time to response, and duration of response. The safety objective is to evaluate the safety and tolerability for all 3 treatment groups. A 4-year recruitment is anticipated. More than 200 centers across 37 countries are planned; approximately 110 centers are currently open for enrollment. Statistical methods: The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) versus T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the intent-to-treat population. Present and target accrual: Twenty-six (26) of 525 patients have been randomized. Patients who have participated in previous neo-/adjuvant trials including a T regimen are eligible, provided they meet all other inclusion criteria. The study is currently recruiting patients, with an anticipated target accrual of 525 patients by March 2016. Clinical trial registry number: NCT01160211 Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-04.

Targeting the Human Epidermal Growth Factor Receptor 2 Pathway in Breast Cancer

The discovery of amplification of human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, was an important milestone in our understanding of the biology of breast cancers. This heralded the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2-positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Unfortunately, most tumors will inevitably develop resistance to trastuzumab, necessitating the need for alternate HER2-directed therapeutic approaches. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. In this article, we review the molecular biology of the ERbb receptor family, the use of HER2-targeted agents in early and advanced breast cancer, and the next-generation anti-HER2 agents that are currently in clinical evaluation.

Advances in the Management of HER2-positive Advanced Gastric and Gastroesophageal Junction Cancer

In the past, patients with advanced or metastatic gastric or gastroesophageal junction cancer have had few treatment options and generally poor survival rates. The human epidermal growth factor receptor 2 (HER2) has been identified as a potential therapeutic target because of its overexpression or gene amplification in 6% to 35% of gastric or gastroesophageal junction cancers, although the methods of assessment and prognostic value of HER2 have been subject to debate. The phase III Trastuzumab for Gastric Cancer (ToGA) trial showed that adding the HER2-targeted humanized monoclonal antibody trastuzumab to chemotherapy significantly improves survival without negatively impacting quality of life in patients with advanced gastric or gastroesophageal junction cancer. As a result, trastuzumab is now the sole HER2-targeted therapy approved in several countries for this indication. The ToGA trial also demonstrated that patients who expressed higher levels of HER2 (determined by immunohistochemical screening) received the greatest benefit from trastuzumab therapy. This finding underlines the importance of accurate HER2 testing. Because of the unique characteristics of gastric cancer, a new gastric cancer-specific scoring system for HER2 expression was proposed during the ToGA trial. The aim of this review is to inform the gastroenterologist of the potential role of HER2-targeted therapy, to discuss the importance of accurate and reliable HER2 testing, and to discuss ongoing studies with HER2-targeted therapies that may have an impact on the future treatment of HER2-positive gastric cancer.

The potential for trastuzumab emtansine in human epidermal growth factor receptor 2 positive metastatic breast cancer: latest evidence and ongoing studies.

The treatment of breast cancer that is driven by amplification and overexpression of human epidermal growth factor receptor 2 (HER2) has been drastically improved by the development of HER2-targeted therapies including trastuzumab and lapatinib. While outcomes for patients diagnosed with HER2-positive breast cancer have been greatly impacted by these therapies, treatment resistance is common and toxicity to standard regimens remains a therapeutic challenge. Trastuzumab emtansine (T-DM1) is a novel antibody drug conjugate that consists of the HER2-targeted monoclonal antibody, trastuzumab, joined via a stable linker to a derivative of maytansine, a highly potent cytotoxic chemotherapy. While other antibody drug conjugates have been developed clinically, this is the first in its class that maintains the antitumor properties of the HER2-targeted antibody, trastuzumab, and also avoids release of the chemotherapy until the molecule is taken up inside the HER2-overexpressing cancer cell. Several phase I studies have shown T-DM1 is safe, tolerable and has activity in trastuzumab- and lapatinib-pretreated breast cancer. Moreover, phase II studies are now being reported that confirm its safety and clinical efficacy in both the frontline and heavily pretreated settings. Preliminary data from phase II studies evaluating its use in combination with other cytotoxics have also been reported and several large phase III trials are underway to evaluate its use in the HER2-positive metastatic breast cancer setting. This paper aims to provide a detailed review of the preclinical and clinical evidence relating to the mechanism of action, efficacy and safety of T-DM1 for the treatment of HER2-positive breast cancer.

Effect of neratinib (N) alone and in combination with trastuzumab (T) in HER2-positive breast cancer (BC) cell lines.

632 Background: HER-2, a member of the transmembrane receptor tyrosine kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2 targeted therapies, in particular, T, a monoclonal antibody targeting HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have been shown to significantly improve the prognosis for HER-2 positive BC patients. However, resistance to T and/or L is a significant clinical problem. The aim of this study is to assess the activity of N (HKI-272), an irreversible HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines, including T and/or L resistant cells. Methods: Using proliferation assays, the effect of N was assessed alone and in combination with T in HER-2 positive BC cell lines, including T and/or L resistant cell lines. The effect of N on HER-2 and downstream signalling molecules, Erk and Akt, was determined by immunoblotting. Results: HER-2 positive BC cell lines, including T and/or L resistant cells, are sensitive to N alone with IC50 values (concentration which inhibits 50% of growth) ranging from 1 to 280 nM. The combination of N and T has additive effects in SkBR3 and BT474 which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL which are resistant to T, combined treatment with T and N showed no enhancement compared to N alone. Finally, N decreased phosphorylation of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results suggest that N should be studied in patients with HER-2 positive BC, including patients with T and/or L resistant BC. We also demonstrate that N in combination with T may be more effective than either agent alone in T sensitive cells.

BOLERO-1: A randomized, phase III, double-blind, placebo-controlled multicenter trial of everolimus in combination with trastuzumab and paclitaxel as first-line therapy in women with HER2-positive (HER2+), locally advanced or metastatic breast cancer (BC).

TPS648 Background: Up to 25% of BCs overexpress human epidermal growth factor receptor 2 (HER2). Patients with HER2+ disease have a higher rate of relapse and shorter overall survival (OS). Trastuzumab, a monoclonal antibody targeting HER2, is the standard of care and improves OS for HER2+ BC, but acquired resistance is common. The combination of trastuzumab and paclitaxel has shown good tolerability and excellent objective response rates (ORR) in up to 84% of patients with HER2+ metastatic BC (MBC) (Gasparini G, et al. BCRT. 2007;101:355-65). Everolimus is an orally bioavailable inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to multiple protein synthesis pathways and implicated in trastuzumab resistance. Everolimus-containing regimens have shown promising results in patients with ER+, HER2– advanced BC in phase II/III trials; everolimus plus trastuzumab/paclitaxel or vinorelbine has shown encouraging ORR with an acceptable safety profile in phase I/II trials in patients with HER2+ MBC. The present phase III study was undertaken to assess the effectiveness of adding everolimus to first-line standard therapy in HER2+ advanced BC. Methods: Women with HER2+, locally advanced or metastatic BC who have received no prior systemic therapy (except endocrine) are eligible. Local disease must not be amenable to resection with curative intent. Women with a history of central nervous system metastasis are excluded. Patients are randomized 2:1 (everolimus vs control) to receive standard therapy (paclitaxel and trastuzumab) plus everolimus (10 mg daily) or placebo. The primary endpoint is progression-free survival. Secondary endpoints include OS, ORR, and clinical benefit rate. Additional endpoints are safety, performance status, and biomarkers. This trial is sponsored by Novartis Pharmaceuticals and is registered (ClinicalTrials.gov: NCT00876395). Enrollment began September 2009, with a planned accrual of 717. The current accrual is 719, and the estimated primary completion date is October 2012.

ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) and endocrine therapy.

TPS661 Background: Approximately 50% of human epidermal growth factor receptor 2 positive (HER2+) breast cancers are also hormone receptor-positive (HR+). For patients with HER2+/HR+ disease, combining the aromatase inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) has been shown to improve outcomes vs letrozole alone. Similar results were found for the combination of trastuzumab (T; a humanized monoclonal antibody targeting HER2) and anastrozole vs anastrozole alone. Finally, the combination of L and T has been shown to improve outcomes vs L alone. Methods: This phase III, randomized, open-label, multicenter trial (ALTERNATIVE) will enroll postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have not received prior treatment for MBC, have received neo/adjuvant T and endocrine therapy, and are not candidates for chemotherapy. Patients will be randomized 1:1:1 to 1 of 3 treatment arms: L plus T plus an AI; T plus an AI; or L plus an AI. The AI can be letrozole, anastrozole, or exemestane, to be selected by the investigator. The primary objective of ALTERNATIVE is to examine the efficacy of L/T/AI compared with T/AI alone. The primary efficacy endpoint is overall survival (OS; time from randomization until death due to any cause) for L/T/AI vs T/AI. Secondary efficacy objectives include: comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI, comparisons of progression-free survival, overall response rate, time to response, duration of response, safety, and tolerability for all 3 treatment groups. The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) vs T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the ITT population. This study is currently recruiting, with a target of 525 patients. If its objectives are reached, it will provide a valuable, chemotherapy-free treatment option for HER2+/HR+ MBC patients. Clinical trial registry number: NCT01160211.

Abstract 1888: MM-111, a bispecific HER2 and HER3 antibody, inhibits trastuzumab-resistant tumor cell growth

Abstract Amplification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 25% of breast cancers and is associated with increased disease recurrence and poor prognosis. Trastuzumab, a monoclonal antibody targeting HER2, has demonstrated clinical benefit in HER2 over-expressing tumors. However, acquired resistance and disease progression is widely observed in patients treated with trastuzumab. In this experiment our objectives were to dissect the dynamic, molecular mechanisms involved in acquired resistance to trastuzumab and to determine whether MM-111, a novel bispecific antibody fusion protein that specifically targets the HER2/HER3 heterodimer and blocks heregulin binding to HER3, has activity in trastuzumab-resistant tumor cells. BT474 cells were cultured in the presence of trastuzumab and cells were periodically tested for response to trastuzumab and MM-111. Samples were also collected for protein and RNA analyses. Resistance to trastuzumab gradually increased in BT474 cells after four months of exposure to trastuzumab, as measured by a cell proliferation assay. Quantitative flow cytometry analysis showed EGFR, HER2, and HER3 levels on the cell surface of resistant cells were similar to the parental cells. Phospho-protein kinase antibody arrays revealed that signaling pathways associated with the ERK cascade were activated during the development of drug resistance. Western blotting further confirmed that phosphorylation of EGFR, ERK, CREB, c-Jun, and AFT-1 was increased in the resistant cells. Real-time polymerase chain reaction also showed transcript levels of HER ligands, including HRG1α, HRG1α, betacellulin, amphiregulin, epigen, TGFβ, and HB-EGF, dramatically increased in tumor cells that acquired resistance to trastuzumab. Compared to the BT474 parental cells, MM-111 showed a greater inhibition in trastuzumab-resistant cells in a spheroid growth assay. Furthermore, trastuzumab-resistant cells became more sensitive to gefitinib and erlotinib, both EGFR inhibitors. The combination of gefitinib or erlotinib with MM-111 showed greater inhibition than either drug alone. In conclusion, our data suggest that one mechanism by which HER2 overexpressing breast cancer cells develop resistance to trastuzumab is to up-regulate ligand-dependent EGFR and HER3 signaling pathways. The use of MM-111 and EGFR inhibitors may provide an effective therapeutic strategy for the treatment of trastuzumab-resistant cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1888. doi:1538-7445.AM2012-1888

Fast, positive data from neosphere

Before the advent of HER2-targeted therapies, the 20–25% of patients with breast tumors that overexpressed HER2 had a poor prognosis. The approval and use of the HER2-targeted monoclonal antibody trastuzumab has gone some way to ameliorating this problem; however, more treatment options are still needed.

Trastuzumab, pertuzumab, and docetaxel: CLEOPATRA

Use of trastuzumab and pertuzumab—anti-HER2 monoclonal antibodies—with docetaxel as a first-line therapy prolonged survival for patients with HER2-positive metastatic breast cancer, according to a new study. Further progress in HER2-directed therapyOutcomes for women with early stage HER2-positive breast cancer have improved markedly since the introduction of the HER2-targeted monoclonal antibody trastuzumab. Women with node-positive disease can expect relapse-free survival to exceed 80% when treated with multi-agent chemotherapy and trastuzumab.1,2 However, there is still room for improvement, both by further reducing recurrence rates and by decreasing the toxicities of treatment. For some patients, the option may ultimately exist to eliminate chemotherapy entirely. Full-Text PDF 34th San Antonio Breast Cancer SymposiumPostmenopausal women with metastatic breast cancer given first-line treatment of fulvestrant (F) and anastrozole (A) have a better progression-free survival (PFS) than those given anastrozole alone (median PFS 15 vs 13·5 months; hazard ratio [HR] 0·80, 95%CI 0·68–0·94; p=0·007) reported Rita S Mehta (Irvine, CA, USA). The benefit was particularly seen in the 60% of patients (n=414) who had not received previous adjuvant tamoxifen (median PFS 12·6 [A] vs 17·0 months [F+A]; HR 0·74, 0·59–0·92). However, there were three deaths in the fulvestrant group and two grade 4 toxicities compared with no deaths and four grade 4 toxicities in the anastrozole alone group. Full-Text PDF Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trialPatients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Full-Text PDF