Standard-of-Care Treatment for HER2+ Metastatic Breast Cancer and Emerging Therapeutic Options

Prior to the advent of the HER2-targeted monoclonal antibody trastuzumab, HER2+ breast cancer (BC) was considered an aggressive disease with a poor prognosis. Over the past 25 years, innovations in molecular biology, pathology, and early therapeutics have transformed the treatment landscape. With the advent of multiple HER2-directed therapies, there have been immense improvements in oncological outcomes in both adjuvant and metastatic settings. Currently, 8 HER2-targeted therapies are approved by the Food and Drug Administration (FDA) for the treatment of early-stage and/or advanced/metastatic disease. Nonetheless, approximately 25% of patients develop recurrent disease or metastasis after HER2-targeted therapy and most patients with HER2+ metastatic breast cancer (MBC) die from their disease. Given the many mechanisms of resistance to HER2-directed therapy, there is a pressing need to further personalize care for patients with HER2+ MBC, by the identification of reliable predictive biomarkers, and the development of novel therapies and combination regimens to overcome therapeutic resistance. Of particular interest are established and novel antibody-drug conjugates, as well as other novel therapeutics and multifaceted approaches to harness the immune system (checkpoint inhibitors, bispecific antibodies, and vaccine therapy). Herein, we discuss standard-of-care treatment of HER2+ MBC, including the management of breast cancer brain metastases (BCBM). Furthermore, we highlight novel treatment approaches for HER2+ MBC, including endeavors to personalize therapy, and discuss ongoing controversies and challenges.