Evolving Treatment Paradigms in Hormone Receptor-Positive, Human Epidermal Growth Factor 2-Negative Metastatic Breast Cancer.
Summary
The treatment paradigm for hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) has significantly evolved from sequential therapies to more personalized strategies. CDK4/6 inhibitors combined with endocrine therapy remain the first-line standard of care, consistently improving progression-free survival and, for some agents, overall survival. The emergence of antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan is reshaping the therapeutic landscape, including for HER2-low and HER2-ultralow disease. Metastasis-directed therapy is also considered for oligometastatic or oligoprogressive disease, requiring nuanced decision-making. Overall management now integrates tumor biology, therapeutic advances, and patient-defined goals of care.
Analysis
This review highlights significant advancements in the management of HR+/HER2- metastatic breast cancer, the most common subtype. The integration of CDK4/6 inhibitors and, more recently, antibody-drug conjugates (ADCs) has substantially improved therapeutic options and outcomes for patients. The identification of HER2-low and HER2-ultralow disease as targets for ADCs represents a crucial translational breakthrough, expanding the populations eligible for innovative treatments. This underscores the importance of precise molecular characterization and ongoing research to optimize therapy sequencing, manage resistance, and enhance quality of life, while ensuring equitable access to care.