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Br J Cancer. 2014 Nov 11;111(10):1888-98. doi: 10.1038/bjc.2014.388. Epub 2014 Jul 15.

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

Author information

1
Division 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.

PMID:
25025958
PMCID:
PMC4229628
DOI:
10.1038/bjc.2014.388
[Indexed for MEDLINE]
Free PMC Article

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