HER2-Directed Therapy for 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. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. 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. 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. In this article, we review clinical data informing the effective management of HER2-positive MBC.

Introduction

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.[1] HER2 overexpression is clearly associated with more aggressive disease and worse clinical outcomes.[2] 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. Multiple studies have shown discordance in HER2 expression levels in up to 25% of paired primary and metastatic breast cancers,[3-5] and a substantial proportion of women with HER2-negative primary tumors acquire HER2 protein overexpression in their tumors at the time of relapse.[6-8] In patients with metastatic breast cancer (MBC), accurate determination of HER2 status is thus critical for guiding treatment decisions. The National Comprehensive Cancer Network (NCCN) guidelines recommend HER2 testing at relapse, particularly if HER2 expression was originally unknown or negative.[9]

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 [Herceptin] and pertuzumab [Perjeta]), small-molecule tyrosine kinase inhibitors that inhibit signaling within the cell (lapatinib [Tykerb], neratinib [HKI-272], and afatinib [BIBW 2992]), and HER2-specific monoclonal antibodies conjugated to cytotoxic molecules (trastuzumab emtansine [T-DM1, Kadcyla]). 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. 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.

Trastuzumab

The first HER2-targeted therapy approved by the FDA is trastuzumab, a humanized monoclonal antibody (IgG1) that binds to the extracellular domain of HER2. It has preferential activity against breast cancers driven by HER2 homodimers.[10] Since receiving FDA approval in 1998, trastuzumab has become clearly established as the key component of treatment for HER2-positive breast cancer in both the adjuvant and metastatic settings.[11-17] The addition of trastuzumab to chemotherapy is associated with significant improvement in time to tumor progression (TTP), objective response rate (ORR), duration of response, and overall survival (OS) in patients with HER2-positive MBC.[15] Patients with metastatic HER2-positive tumors may derive benefit from treatment with trastuzumab as a single agent, or in combination with cytotoxic or endocrine therapy.

Trastuzumab as a single agent in metastatic disease

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