Therapeutic Considerations When Treating HER2-positive Metastatic Breast Cancer

Despite advances in detection and treatment, metastatic breast cancer (MBC) remains the second highest cause of cancer-related death for women in the United States. Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30 % of breast cancers and is associated with aggressive disease and, historically, with poorer outcome. The advent of trastuzumab, a monoclonal antibody to HER2, revolutionized the management of HER2-positive breast cancer (BC) in the metastatic and adjuvant settings. However, relapse despite adjuvant trastuzumab and resistance to trastuzumab in the metastatic setting remain substantial clinical problems for many patients with HER2-positive BC. As such, analyzing the mechanisms of trastuzumab resistance and developing new therapies to overcome it are research priorities. There has been progress, with the approval of three additional HER2-targeted agents in the last six years: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). Other HER2-targeted therapies, including neratinib and afatinib, are in clinical development, and trials of novel agents such as heat shock protein-90 (HSP90) inhibitors, phosphatidylinositol-3-kinase (PI3K) inhibitors, and HER2-targeted vaccines, are in progress. In addition to developing newtherapies, research is addressing several unique challenges in the management of HER2-positive MBC. In this article, we discuss advances in the treatment of HER2-positive MBC, focusing on novel HER2-targeted therapies and HER2-targeted agents recently approved by the United States Food and Drug Administration (FDA). We also address the management of brain metastases (BM) and hormone receptor (HR)positive, HER2-positive MBC.