Endocrine resistance in HR+/HER2− breast cancer: molecular mechanisms and emerging therapeutic strategies

Hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer accounts for the majority of breast cancers and remains highly dependent on endocrine therapy across both early and advanced disease settings. Although the incorporation of CDK4/6 inhibitors has substantially improved clinical outcomes, endocrine resistance, whether primary or secondary, ultimately limits durable disease control. Resistance arises through heterogeneous and evolving mechanisms, including ESR1 mutations and fusions, ER transcriptional reprogramming, activation of PI3K/AKT/mTOR and other bypass pathways, cell-cycle escape, epigenetic remodeling, and metabolic adaptation. These molecular insights are increasingly being translated into biomarker-guided therapeutic strategies, including next-generation oral selective estrogen receptor degraders, PROTAC ER degraders, and PI3K/AKT/mTOR inhibitors; antibody–drug conjugates are considered separately as antigen-directed options after endocrine resistance. Importantly, circulating tumor DNA monitoring of emerging ESR1 mutations provides an opportunity to identify molecular progression before radiographic progression and to support earlier treatment adaptation. This narrative review integrates recent mechanistic and clinical evidence on endocrine resistance in HR+/HER2− breast cancer, with emphasis on how resistance mechanisms and biomarkers can inform drug selection, treatment sequencing, and dynamic disease monitoring. A mechanism-guided approach may therefore help move clinical management from empiric treatment switching toward more individualized, biomarker-driven, whole-course care.