Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

SIMPLE SUMMARY: Breast cancer is the most common cancer in women in the United States. Around 15% of all breast cancers overexpress the HER2 protein. These HER2-positive tumors have been associated with aggressive behavior if left untreated. Drugs targeting HER2 have greatly improved the outcomes of patients with HER2-positive tumors in the last decades. Despite these improvements, many patients with early breast cancer have recurrences, and many with advanced disease experience progression of disease on HER2-targeted drugs, suggesting that patients can develop resistance to these medications. In this review, we summarize several mechanisms of resistance to HER2-targeted treatments. Understanding how the tumors grow despite these therapies could allow us to develop better treatment strategies to continue to improve patient outcomes. ABSTRACT: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.