Current Management of Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in a Changing Landscape

Over the past three decades, the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has undergone a remarkable transformation. Once associated with poor outcomes and a median survival of <2 years in the metastatic setting, HER2-positive metastatic breast cancer is at present increasingly managed for years, with long-term survival beyond 5 years becoming common. Parallel advances in early-stage therapy have substantially reduced recurrence rates and altered the clinical landscape of metastatic disease, with a growing proportion of patients currently presenting with de novo metastatic disease rather than relapse after prior HER2-directed treatment. These improvements have been driven by successive generations of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. Most recently, trastuzumab deruxtecan (T-DXd) has demonstrated unprecedented efficacy and is rapidly moving earlier in treatment algorithms across both metastatic and curative-intent settings. This shift raises important questions regarding optimal sequencing, toxicity management—particularly for interstitial lung disease—and the downstream implications for other HER2-directed therapies. In this review, we summarize the evolution of HER2-targeted therapy and discuss strategies for managing HER2-positive breast cancer across disease stages in the era of earlier treatment with T-DXd.