Current approaches and future directions in the treatment of HER2-positive breast cancer

Summary

Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.

Introduction

Breast cancer (BC) remains one of the leading causes of cancer-related death worldwide.¹ Although chemotherapy has improved outcomes for patients, the marginal benefits achieved with cytotoxic agents seem to have reached a plateau. Fortunately, technological advances have enabled characterization of the molecular subtypes2, 3 of BC and this in turn has facilitated the development of molecularly targeted therapeutics for this disease. One subtype that has been identified is distinguished by amplification of the gene encoding the human epidermal growth factor receptor 2 (HER2). This subtype accounts for approximately 20–30% of invasive BCs and is associated with reduced disease-free survival (DFS), increased risk of metastases and shorter overall survival (OS).4, 5 HER2 is a member of the ErbB family of receptor tyrosine kinases (RTKs), which include HER1 (epidermal growth factor receptor [EGFR]), HER3, and HER4. HER2-mediated signal transduction is believed to depend largely on heterodimerization with other family members.⁶ Trastuzumab is a humanized monoclonal antibody targeted against the extracellular portion of HER2. This is the first HER2-targeted agent to be approved by the United States Food and Drug Administration (FDA) for the treatment of both early stage and metastatic HER2-overexpressing (HER2+) BC.7, 8 Subsequently, lapatinib, an orally bioavailable small molecule dual HER2- and EGFR/HER1-specific tyrosine kinase inhibitor (TKI), received FDA approval in combination with capecitabine for patients with advanced HER2+ BC.⁹

Although HER2-targeted therapies have had a significant impact on patient outcomes, resistance to these agents is common. In clinical trials, 74% of patients with HER2+ metastatic BC (MBC) did not have a tumor response to first-line trastuzumab monotherapy¹⁰ and 50% did not respond to trastuzumab in combination with chemotherapy.⁷ These examples illustrate the problem that inherent (de novo) resistance to HER2-targeted agents poses for effective treatment of HER2+ BC. Moreover, only approximately one-quarter of patients with HER2+ MBC who were previously treated with trastuzumab achieved a response with lapatinib plus capecitabine.⁹ These limitations have led to efforts to better understand the molecular determinants of resistance to these agents in order to better select patients who are most likely to benefit from specific therapies, and to develop new agents that can overcome resistance. This review article will focus on the HER2 signaling pathway, proposed mechanisms of resistance to HER2-targeted therapies, and current approaches to overcoming resistance to HER2-targeted therapies in BC.