S18 Ep45: Advancing Targeted Therapy in HR+/HER2– Metastatic Breast Cancer: Integrating Next-Generation Endocrine and PAM-Pathway Strategies Into Practice

Individualizing treatment for hormone receptor-positive, HER2-negative metastatic breast cancer requires integrating molecular profiling with clinical assessment of disease progression. Genomic testing for PIK3CA and ESR1 mutations informs the selection of targeted therapies, including PI3K/AKT/mTOR inhibitors and next-generation oral selective estrogen receptor degraders (SERDs). While combination regimens like capivasertib or gedatolisib offer significant benefits in mutant populations, clinicians must balance these potent treatments against toxicity profiles and patient quality of life. Emerging strategies, such as serial ctDNA monitoring, enable the early detection of resistance mechanisms, though financial and administrative hurdles persist. For patients with aggressive disease or specific mutations like Y537S, combination therapy often proves superior to single-agent approaches. Future treatment algorithms will increasingly rely on multi-gene or epigenomic signatures to refine patient selection and optimize long-term outcomes.