Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

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

Abstract: 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 Evolving Landscape of HER2 Targeting in Breast Cancer

Abstract: The development of human epidermal growth factor receptor 2 (HER2)-targeting agents for the treatment of HER2-amplified breast cancer has dramatically improved outcomes for patients with this disease. The value of HER2 as a therapeutic target encompasses 2 entirely different mechanistic dimensions. The first approach exploits the fact that HER2 is clearly a disease-driving oncogene to deliver HER2 kinase inhibitors, apparently a highly rational approach to the treatment of HER2-amplified cancers. However, the functionally relevant HER2-HER3 complex has proven much more difficult to inhibit than had been anticipated, and because of its modest efficacy, the HER2 inhibitor lapatinib is currently used predominantly in combinations and in very advanced stages of disease. The second approach exploits the massive cell surface expression of HER2 and delivers of a variety of cytotoxic or immunologic effectors with great selectivity to these cancer cells. This approach has proven transformative, with 3 such drugs introduced into practice to date. The HER2-specific antibody trastuzumab, in combination with chemotherapy, has shown substantial effect in the management of HER2-amplifed breast cancer at all stages of disease and lines of therapy—and the addition of the second HER2 antibody pertuzumab substantially increases the magnitude of this effect in all of the contexts tested thus far. While the immunologic effectors stimulated by these naked HER2 antibodies provide only modest activity as monotherapy, the toxin-carrying antibody trastuzumab-emtansine provides substantial single-agent activity and is being developed for both early- and late-stage disease. The diverse mechanistic landscape afforded by the target HER2 has proven to be fertile ground for drug development, but it has also created complexity and misconception in understanding these agents’ modes of action, undermining the development of clinically useful predictive biomarkers. This accounts for the failure of signaling-based biomarkers to predict clinical trastuzumab resistance and shifted the focus to markers of immunologic activity with greater success. The evolving world of HER2 targeting is reviewed herein.

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

Abstract: PurposeTo 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.MethodsAn 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.ResultsThe 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 ad...

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

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