title: 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.
authors.affiliation: 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.
authors.forename: J C
authors.initials: JC
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: K
authors.initials: K
authors.lastname: Jhaveri
authors.affiliation: 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.
authors.forename: F J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D015195:Drug Design; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human