HER2-overexpressing Metastatic Breast Cancer Research Articles

Abstract P6-11-01: Cost-effectiveness of pertuzumab in HER2+ metastatic breast cancer

Abstract Purpose The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab (P) to docetaxel and trastuzumab (TH) as first-line treatment for patients with HER2 overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of the addition of pertuzumab to docetaxel and trastuzumab. Patient and Methods We developed a decision-analytic Markov model to evaluate the cost-effectiveness of TH with or without P in U.S. patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included: stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. One-way and multi-way deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions. Results Modeled median survival was 39.4 months (TH) and 56.9 months (THP). The addition of pertuzumab resulted in an additional 1.81 life years gained (0.62 QALYs) at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost-effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost-effectiveness at a willingness-to-pay of $100,000 per QALY gained. Conclusion The addition of pertuzumab to docetaxel and trastuzumab in patients with metastatic HER2+ breast cancer is unlikely to be cost-effective in the United States. Citation Format: Qian Y, Durkee BY, Pollom EL, King M, Dudley SA, Shaffer JB, Chang DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC. Cost-effectiveness of pertuzumab in HER2+ metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-11-01.

Abstract OT3-01-05: PANACEA (IBCSG 45-13/BIG 4-13): A phase Ib/II trial evaluating the efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant, HER2-positive, metastatic breast cancer

Abstract Background Preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immunotherapeutic approaches. We hypothesize that immune evasion contributes to tumor growth and progression in HER2-positive tumors and anti-PD1 restores T cell cytotoxicity reverting trastuzumab resistance. Eligibility criteria Patients with HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast cancer with disease progression during treatment with trastuzumab or subsequent anti-HER2 therapy of not more than 3 lines. HER2 overexpression and PD-L1 expression confirmed in central laboratories based on tissue obtained within 1 year prior to study entry. Objective The primary objectives of this phase Ib/II study are to determine the recommended dose (RP2D) of pembrolizumab in combination with standard dose trastuzumab, and to evaluate the efficacy and safety profile of the drug combination in patients with PD-L1 positive, HER2 overexpressing unresectable loco-regional or metastatic breast cancer. Trial design The phase Ib portion of the trial will use a standard 3+3 design to determine the RP2D of standard-dose trastuzumab with three pembrolizumab dose levels: 2 mg/kg, 10 mg/kg, or a fall-back dose of 1 mg/kg. A Simon optimal two-stage design will be used in the phase II portion to assess the primary outcome of objective response. Pembrolizumab at the RP2D will be given with trastuzumab (6 mg/kg i.v. every 3 weeks) until disease progression or lack of tolerability. The null hypothesis that the true objective response rate (ORR) is 7% will be tested against a one-sided alternative rate of 22%. In the first stage, 17 patients will be enrolled. If there are zero or one responses, enrollment will stop. Otherwise, 23 additional patients will be accrued. The null hypothesis will be rejected if 6 or more objective responses are observed in 40 evaluable patients. This design has a type-I error of 0.05 and 85% power. If the null hypothesis is true, the probability is 0.66 that enrollment will stop at the end of the first stage. Two concurrent analyses of the data will take place at the end of the first stage. One analysis will assess ORR using the criteria described above. The second will be a detailed review of safety data. Statistical methods Primary and secondary endpoints will be based on patients enrolled in the phase II trial. ORR will be presented with a two-sided 90% confidence interval calculated using the method of Atkinson and Brown. The distributions of time-to-event secondary endpoints, such as duration of response and time to progression, will be summarized using the method of Kaplan-Meier. Present accrual and target accrual As of 3 June 2015 11 patients have been screened for HER2 and PD-L1 positivity, and 3 successfully enrolled, completing the first dose cohort. Target enrollment of this phase Ib/II trial is 6-46 evaluable patients. Discussions are ongoing to include a PD-L1 negative cohort. Contact information Conducted by the International Breast Cancer Study Group and the Breast International Group in collaboration with Merck Sharp & Dohme Corp. Citation Format: Loi S, Andre F, Maibach R, Hui R, Bartsch R, Jerusalem G, Gombos A, Campone M, Bonnefoi H, Bachelot T, Curigliano G, Biganzoli L, Giobbie-Hurder A. PANACEA (IBCSG 45-13/BIG 4-13): A phase Ib/II trial evaluating the efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant, HER2-positive, metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-05.

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial

Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Boehringer Ingelheim.

Abstract A14: Overcoming therapeutic MAb resistance in agressive HER2 positive breast carcinomas by adoptive immunotherapy using optizimed effectors cells

Abstract 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 Trastuzumab develop resistance within one year of treatment initiation. Alteration of Antibodies Dependant Cellular Cytotoxicity (ADCC) mechanisms 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 FCεRIγ to generate NK-CD16/γ cells that allow recognition and interaction with Mab, inducing ADCC and (ii) NK cells expressing Trastuzumab sequence fused to the transduction chain FCεRIγ to generate NK-Her/γ that directly kill the HER2 positively cells. In vitro, both strategies demonstrated high cytotoxic efficacy against HER2 positive cells, with direct killing systematically more efficient (reaching up to 95% with ratio E:T 5:1). Interestingly, two steps killing with NK-CD16/γ enabled a very specific cytotoxicity only in the presence of specific antibody. We demonstrated that efficacy of 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 vivo, in Trastuzumab resistant HER2+ xenograft immunodeficient NSG mice model, complete regression was obtained only when using NK-CD16/γ in the presence of Trastuzumab. Even if the NK-Her/γ was found by IF or FACS in the tumor after IV or IP injection, they could not induce tumor regression. Analyses of NK dysfunction will be presented. Restoration or improvement of effectors cells might be considerate as an issue in therapeutic 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. Citation Format: Sandrine Valsesia-Wittmann, Beatrice Clemenceau, Anne-Catherine Jallas, Jean-Yves Blay, Aurelien Marabelle, 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: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A14.

Abstract 2627: Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes

Abstract Purpose: Lapatinib has been used in combination with capecitabine or paclitaxel in treating patients with progressive HER2-overexpressing metastatic breast cancer. Unfortunately, an increased hepatotoxicity had been found in the combinational therapy. The aim of this study was to investigate the potential mechanism of the increased hepatotoxicity during the combination treatment of lapatinib and chemotherapeutic agent. Experimental design: The incidence of hepatotoxicity was analyzed in the patients and Swiss mice with combinational treatment of lapatinib and paclitaxel or doxorubicin. Pharmacokinetic studies of paclitaxel and doxorubicin were carried out in mice. The chemotherapeutic agent accumulation was performed in ABCB1 overexpressing hepatocellular cancer cells and normal liver tissues. Results:The patients received lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those received paclitaxel alone. The in vivo experiments showed that the subjects in group of lapatinib plus chemotherapeutic agent had significantly higher levels of alanine aminotransferase and serious hepatocyte injury compared with that in group of single drug. Pharmacokinetic studies revealed that lapatinib could increase the exposed level of paclitaxel and doxorubicin without inhibiting the activity of CYP 3A4. Further study demonstrated that lapatinib could increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Conclusion: The higher incidence of hepatotoxicity during the treatment of lapatinib plus chemotherapeutic agent was due to the increased agent accumulation in liver cells via inhibiting the function of ABC transporters inhibited by lapatinib. This is important information direction for the design of combinational therapy in clinic. Citation Format: Chunling Dai, Shaolin Ma, Zhesheng Chen, Kenneth To, Liwu Fu. Lapatinib promotes promoted the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2627. doi:10.1158/1538-7445.AM2015-2627

Improved biological activity of a single chain antibody fragment against human epidermal growth factor receptor 2 (HER2) expressed in the periplasm of Escherichia coli

A novel monoclonal antibody against human epidermal growth factor receptor 2 (HER2), i.e., pertuzumab (Perjeta®) developed by Genentech, has been verified to be effective in treating metastatic HER2-overexpressing breast cancer. The fact that the presence of the Fc region of the anti-HER2 is uncritical for growth inhibition of tumor cells suggests the potential biological activity of the associated antibody fragments. In the present study, we report functional expression of anti-HER2his-scFv, a single-chain variable fragment (scFv) derived from pertuzumab, in the periplasm of Escherichia coli and its purification. Biological activity of the soluble scFv produced in this manner was characterized using immunofluorescent staining, immunocytochemistry, flow cytometry and cytotoxicity assay. The effect of anti-HER2his-scFv on HER2 dimerization was also assessed by tyrosine kinase assay. It was observed that the purified scFv had a high specificity and affinity to HER2 receptors expressed on the surface of tumor cells with a selective cytotoxic effect on HER2-overexpressing SK-OV-3 cells. In addition, anti-HER2his-scFv was able to suppress phosphorylation of HER2 in the presence of heregulin. The results suggest that anti-HER2his-scFv can be a potential candidate for various therapeutic and diagnosis applications.

Phase II study of weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer (MBC): Updated progression-free survival with overall survival result.

607 Background: We previously reported results of the phase II breast cancer (BC) trial of weekly paclitaxel (T), trastuzumab (H) and pertuzumab (P) with its primary endpoint of 6-month (mo) progre...

Phase I study of HER3 targeted antibody patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

584 Background: It is considered that HER2-HER3 heterodimerization is mechanically important in HER2-overexpressing breast cancer. Patritumab is a fully human anti-HER3 monoclonal antibody, which i...

Abstract P5-19-01: Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1

Abstract Background: Afatinib is an oral, irreversible ErbB family blocker with anti-tumour activity in patients (pts) with HER2-positive metastatic breast cancer (MBC) after failure on trastuzumab.1 Preclinically, afatinib + vinorelbine (AV) showed an additive effect; clinically, the AV combination had a manageable safety profile and showed activity in two Phase I trials.2,3 This randomized, open-label, Phase III trial (LUX-Breast 1) compared AV with trastuzumab + vinorelbine (TV) in pts with HER2-positive MBC who had progressed on a prior T-based regimen. Methods: Pts with HER2-positive MBC and failure of one T-based regimen (adjuvant/first-line) were randomized 2:1 to AV (40 mg/day oral + 25 mg/m2/week iv) or TV (2 mg/kg/week iv after 4 mg/kg loading dose + 25 mg/m2/week iv). Treatment continued until progressive disease (PD) or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) by investigator review; secondary endpoints included objective response rate (ORR), overall survival (OS) and safety. Planned accrual was 780 pts. Results Between August 2010 and April 2013, 508 patients were randomized (AV:339, TV:169). Baseline characteristics were balanced in both arms (mean age 52 yrs, Asian 50.6%, White 41.6%, ER/PR positive 28.7%). 41.1% of pts failed on prior adjuvant and 58.9% on 1st line T-based treatment. A pre-planned risk/benefit assessment was found unfavorable by the DMC and recruitment was stopped. Pts ongoing on AV therapy were switched to TV, received A or V monotherapy, or stopped treatment. Primary endpoint analysis was performed with 307 of the originally 484 planned PFS events (211 [62.2%] AV arm; 96 [56.8%] TV arm). Median PFS was 5.5 months with AV vs 5.6 months with TV (HR 1.10; 95% CI 0.86, 1.41; P=0.4272). ORR was 46.1% with AV and 47.0% with TV (OR 1.04; 95% CI 0.71, 1.51; P=0.8510). OS analysis was based on 144 (28.4%) OS events (108 [31.9%] in AV arm; 36 [21.3%] in TV arm). Median OS was 19.6 months with AV and 28.6 months with TV (HR 1.76; 95% CI 1.20, 2.59; P=0.0036). The most common drug-related AEs were diarrhea (80.1%), neutropenia (75.1%) and rash (45.1%) with AV, and neutropenia (78.7%), leukopenia (37.3%) and anemia (27.8%) with TV. Rate of infections (53.0% vs 40.5%) was higher with AV vs TV. More AV than TV pts discontinued due to AEs (15.4% vs 7.1%). Fatal AEs were reported for 18 (5.3%) in the AV vs 5 (3.0%) pts in the TV arm, and were mainly associated with PD (9 pts in AV and 1 in TV arm). Three AV pts died due to treatment-related causes (sepsis/multi-organ failure; septic shock; pulmonary fibrosis). Conclusions: AV and TV demonstrated similar PFS and ORR, but OS diverged and was shorter for AV compared to TV in pts with HER2-positive MBC. The safety profile of AV was consistent with the individual monotherapies, but its tolerability compared unfavorably to TV. Analyses are ongoing to elucidate potential factors (e.g. impact of follow up treatments) contributing to the diverging PFS and OS outcomes. 1. Lin NU et al. Breast Cancer Res Treat 2012;133:1057-65 2. Bahleda R et al. J Clin Oncol 2011;29; abs 2585 3. Masuda N et al. SABCS 2013 abs P4-16-11. Citation Format: Nadia Harbeck, Chiun-Sheng Huang, Sara Hurvitz, Dah-Cherng Yeh, Zhimin Shao, Seock-Ah Im, Kyung Hae Jung, Kunwei Shen, Jungsil Ro, Jacek Jassem, Qingyuan Zhang, Young-Hyuck Im, Marek Wojtukiewicz, Qiang Sun, Shin-Cheh Chen, Rainer-Georg Goeldner, Annick Lahogue, Martina Uttenreuther-Fischer, Binghe Xu, Martine Piccart-Gebhart, on Behalf of the LUX-Breast 1 Study Group. Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-01.

Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes.

Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy.

Biomedical applications of trastuzumab: as a therapeutic agent and a targeting ligand.

Trastuzumab (TZ) is a humanized monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor 2 (HER2), a tyrosine kinase receptor. TZ is approved by the Food and Drug Administration (FDA) for the treatment of HER2-overexpressing early stage and metastatic breast cancer and HER2-overexpressing metastatic gastric cancer. For breast cancer, it is recommended as both a single agent and in combination with standard chemotherapy. In the last few years, TZ has also been used as a targeting ligand. Overexpression of HER2 in breast cancer and the presence of free surface functional groups on TZ provide an opportunity to use it as a targeting ligand. TZ can be conjugated to various nanoparticulate systems such as dendrimers, polymeric, and protein nanoparticles to target drug delivery. TZ-conjugated inorganic nanoparticles have been reported for imaging and diagnostic purposes. This review summarizes the applications of TZ both as a therapeutic agent and as a targeting ligand.

β2-AR signaling controls trastuzumab resistance-dependent pathway.

Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that β2-adrenergic receptor (β2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and β2-AR affects the bio-behaviors of breast cancer cells, suggesting that the β2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of β2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced β2-AR activation. The data indicate that β2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that β-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of β-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus β-blocker in Her2-overexpressing breast cancer.

Resistance to HER2-targeted therapies: a potential role for FOXM1.

Despite the tremendous efficacy of trastuzumab against HER2-overexpressing metastatic breast cancers, a significant fraction of women demonstrate progressive disease during treatment. Multiple mechanisms have been proposed to mediate trastuzumab resistance. In this mini-review, we discuss the evidence supporting FOXM1 as a mediator of resistance and potential new therapeutic target in trastuzumab-refractory breast cancer. FOXM1 expression is significantly elevated in multiple breast cancer data sets. Some studies suggest a direct correlation between FOXM1 and HER2 expression levels. In addition, overexpression of FOXM1 reduces the sensitivity of HER2-positive breast cancer cells to trastuzumab or lapatinib. Conversely, knockdown or pharmacological inhibition of FOXM1 rescues resistance to HER2-targeted therapies. Current pre-clinical information supports further investigation of the role of FOXM1 in trastuzumab-resistant breast cancer.

Assay of lapatinib in murine models of cigarette smoke carcinogenesis.

Lapatinib, a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), is prescribed for the treatment of patients with metastatic breast cancer overexpressing HER-2. Involvement of this drug in pulmonary carcinogenesis has been poorly investigated. We used murine models suitable to evaluate cigarette smoke-related molecular and histopathological alterations. A total of 481 Swiss H mice were used. The mice were exposed to mainstream cigarette smoke (MCS) during the first four months of life. After 10 weeks, MCS caused an elevation of bulky DNA adducts, oxidative DNA damage and an extensive downregulation of microRNAs in lung. After four months, an increase in micronucleus frequency was observed in peripheral blood erythrocytes. After 7.5 months, histopathological alterations were detected in the lung, also including benign tumors and malignant tumors, and in the urinary tract. A subchronic toxicity study assessed the non-toxic doses of lapatinib, administered daily with the diet after weaning. After 10 weeks, lapatinib significantly attenuated the MCS-related nucleotide changes and upregulated several low-intensity microRNAs in lung. The drug poorly affected the MCS systemic genotoxicity and had modest protective effects on MCS-induced preneoplastic lesions in lung and kidney, when administered under conditions that temporarily mimicked interventions either in current smokers or ex-smokers. On the other hand, it caused some toxicity to the liver. Thus, on the whole, lapatinib appears to have a low impact in the smoke-related lung carcinogenesis models used, especially in terms of tumorigenic response.

HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development.

Effective targeting of the human epidermal growth factor receptor 2 (HER2) has changed the natural history of HER2 overexpressing (HER2+) metastatic breast cancer. The initial success of trastuzumab improving time to progression and survival rates led to the clinical development of pertuzumab, ado-trastuzumab emtansine and lapatinib. These biologic therapies represent significant additions to the breast medical oncology armamentarium. However, drug resistance ultimately develops and most tumours progress within 1 year. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in tumours, including inhibition of PI3K/TOR, HSP90, IGF-IR and angiogenesis. Mounting experimental data support the clinical testing of immune checkpoint modulators and vaccines. The central nervous system remains a sanctuary site for HER2+ breast cancer and further studies are needed for the prevention and treatment of brain metastases in this population. Despite efforts to identify predictors of preferential benefit from HER2-targeted therapies (e.g., truncated HER2, PTEN loss and SRC activation), HER2 protein overexpression and/or gene amplification remains the most important predictive factor of response to HER2-targeted therapies. In this article, we review the optimal sequence of HER2-targeted therapies and describe ongoing efforts to improve the outcome of HER2+ advanced breast cancer through rational drug development.

The natural history of HER2-overexpressing (HER2+) metastatic breast cancer (MBC) treated with trastuzumab (T): Practical points to consider in developing treatment strategies.

e11565 Background: Trastuzumab has dramatically improved the prognosis of patients with HER2+ BC. This study reports the practice patterns across different treatment lines and the major clinical outcome of MBC patients receiving T. Methods: We analyzed an institutional database containing the treatment history patients who received at least one trastuzumab-based regimen for HER2+ MBC. Time to progression (TTP) was evaluated for each line of therapy; a Cox regression model with treatment line as continuous predictor was evaluated, and a linear and a quadratic term were introduced in the model. Results: A total of 112 patients were analyzed. Median patient age was 50 (range 26 – 74) years, 16% were metastatic at debut, 71% presented with hormone receptor positive disease, 58% had soft tissue metastases (met), 49.5% visceral met, 42% bone met and 4.5% brain met. The median number of lines of treatment was 6 (range 1-17). A combination of chemo- and/or targeted-therapy was the most frequently used regimen acr...

A phase 1 dose-escalation study of anti-HER3 monoclonal antibody LJM716 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast or gastric cancer.

2519 Background: TheHER2-HER3 heterodimer, a key driver in HER2-positive tumors, is not completely blocked by available therapies. LJM716 is a fully human anti-HER3 monoclonal antibody (mAb) shown ...

A phase 1 study of LJM716 in patients with esophageal squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic breast or gastric cancer.

2517 Background: The HER3 receptor is important for maintenance of EGFR- and HER2-driven cancers and targeted therapy resistance. LJM716 is a fully human HER3 monoclonal antibody active in ligand-d...

Phase II study of lapatinib in combination with vinorelbine, as first or second-line therapy in women with HER2 overexpressing metastatic breast cancer.

BackgroundLapatinib in combination with capecitabine is approved for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal growth factor receptor 2 (HER2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Based on our phase I trial, we conducted a single arm, multicenter phase II study of lapatinib in combination with vinorelbine.Patient and methodsWomen with HER2-positive advanced breast cancer, who had received up to one prior regimen for metastatic disease, were eligible. Prior trastuzumab was allowed. Patients received daily lapatinib 1500 mg orally and vinorelbine 20 mg/m2 intravenously on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR).ResultsForty-four patients received the combination treatment, including 48% as second-line therapy. The ORR was 41% (95% confidence interval [CI] 26–55%), including 9% with a complete response. Median progression-free survival was 24.1 weeks (95% CI 17–37 weeks) and median duration of response was 32 weeks (95% CI 18–42 weeks). Nearly 80% of patients did not require a dose reduction in lapatinib, although most patients required one dose reduction of vinorelbine secondary to neutropenia. The most common toxicities were grade 1 and 2 diarrhea, nausea, fatigue and rash, and grade 3 and 4 neutropenia. One case of grade 3 asymptomatic decreased left ventricular ejection fraction event was reported.ConclusionThe combination of lapatinib and vinorelbine was active, feasible and well tolerated in patients with HER2-positive advanced breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-108) contains supplementary material, which is available to authorized users.

Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer.

Dual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results. This is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival. A total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade≥3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%). These findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.