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HER2-positive advanced breast cancer: optimizing patient outcomes and opportunities for drug development
J C Singh1, K Jhaveri1, F J Esteva1
1Division of Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, 160 East 34th Street, New York, NY 10016, USA.
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.
Insights
Targeting human epidermal growth factor receptor 2 (HER2) improved outcomes for HER2+ metastatic breast cancer. Research now focuses on overcoming drug resistance and treating brain metastases for better patient survival.
Area of Science:
- Oncology
- Medical Research
- Pharmacology
Background:
- Targeting human epidermal growth factor receptor 2 (HER2) has significantly altered the prognosis for HER2-overexpressing (HER2+) metastatic breast cancer.
- Trastuzumab, pertuzumab, and ado-trastuzumab emtansine have improved progression-free survival and overall survival rates.
Purpose of the Study:
- To review the current landscape of HER2-targeted therapies for advanced breast cancer.
- To discuss strategies for overcoming primary and secondary drug resistance.
- To highlight ongoing research into novel therapeutic approaches and the management of brain metastases.
Main Methods:
- Review of existing clinical data and ongoing research in HER2+ metastatic breast cancer.
- Analysis of therapeutic strategies including targeted agents, PI3K/TOR inhibitors, HSP90, IGF-IR, and angiogenesis inhibitors.
- Exploration of immunotherapy, vaccines, and management of central nervous system metastases.
Main Results:
- HER2-targeted therapies have shown initial success but drug resistance remains a significant challenge, with most tumors progressing within a year.
- Novel therapeutic targets and approaches are under investigation to overcome resistance.
- HER2 protein overexpression/gene amplification is the primary predictor of response to HER2-targeted therapies.
Conclusions:
- Optimal sequencing of HER2-targeted therapies is crucial for managing advanced HER2+ breast cancer.
- Continued research into novel drug development and combination therapies is essential to improve outcomes.
- Addressing drug resistance and central nervous system metastases are key priorities for future treatment strategies.
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