Evolving Treatment Paradigms in Hormone Receptor-Positive, Human Epidermal Growth Factor 2-Negative Metastatic Breast Cancer.

Abstract

Hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) represents the most common subtype of MBC and has undergone substantial therapeutic evolution. Treatment has shifted from sequential endocrine therapy (ET) and chemotherapy toward personalized strategies incorporating molecularly targeted agents and antibody-drug conjugates (ADCs), with increasing emphasis on quality of life and shared decision making. CDK4/6 inhibitors plus ET remain a first-line standard of care in high-resource settings, demonstrating consistently improved progression-free survival (PFS) and, for select agents, overall survival (OS). Management in special populations requires additional consideration of trial and real-world data, toxicity profiles, and patient preferences. Beyond ET, ADCs are reshaping the landscape. Trastuzumab deruxtecan expanded therapeutic utility across HER2-low and HER2-ultralow disease, whereas sacituzumab govitecan and datopotamab deruxtecan provide later-line options. As ADCs emerge as earlier therapies, questions regarding sequencing, cross-resistance, and toxicity remain central to clinical decision making. Metastasis-directed therapy (MDT) in oligometastatic and oligoprogressive breast cancer also requires nuanced decision making. Despite high local control rates with stereotactic body radiotherapy, randomized trials have not demonstrated consistent improvements in PFS or OS in unselected populations. Current evidence supports systemic therapy as the foundation of management, with MDT selectively considered for oligoprogression, symptom prevention, or within clinical trials. Ultimately, management of hormone receptor-positive/HER2-negative MBC requires dynamic integration of tumor biology, systemic therapy advances, and patient-defined goals of care. As therapeutic complexity increases, shared decision making and equitable access to evidence-based and supportive care services remain essential for delivering high-quality, individualized oncology care.