Here we review these HER2-targeted therapies, and discuss novel, promising agents for treatment of HER2-positive MBC that may become available in the next few years. Currently, four of these HER2-targeted agents are approved by the US Food and Drug Administration (FDA) for use: trastuzumab, lapatinib, pertuzumab, and T-DM1, with the last approved in February of this year. Over the last 15 years, several HER2-targeted therapies have been developed, including HER2-specific monoclonal antibodies that bind to the external domain of the molecule (trastuzumab and pertuzumab ), small-molecule tyrosine kinase inhibitors that inhibit signaling within the cell (lapatinib, neratinib, and afatinib ), and HER2-specific monoclonal antibodies conjugated to cytotoxic molecules (trastuzumab emtansine ). The National Comprehensive Cancer Network (NCCN) guidelines recommend HER2 testing at relapse, particularly if HER2 expression was originally unknown or negative. In patients with metastatic breast cancer (MBC), accurate determination of HER2 status is thus critical for guiding treatment decisions. Multiple studies have shown discordance in HER2 expression levels in up to 25% of paired primary and metastatic breast cancers, and a substantial proportion of women with HER2-negative primary tumors acquire HER2 protein overexpression in their tumors at the time of relapse. Importantly, HER2 overexpression strongly predicts response to HER2-targeted therapies, highlighting the importance of accurately defining the level of HER2 expression in both primary and metastatic tumors. HER2 overexpression is clearly associated with more aggressive disease and worse clinical outcomes. The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase that is overexpressed in approximately 20% of invasive breast cancers, primarily due to gene amplification. In this article, we review clinical data informing the effective management of HER2-positive MBC. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients.
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