Evolving treatment paradigms after CDK4/6 inhibitors in advanced breast cancer

Summary Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment of hormone-receptor-positive, human epidermal growth factor receptor 2‑negative (HR+/HER2−) breast cancer, becoming the standard in first-line endocrine therapy (ET). However, evidence supporting the optimal sequencing post-CDK4/6i progression remains scarce. Liquid biopsy and comprehensive genomic profiling enable tracking of resistance and identifying actionable mutations like ESR1, PIK3CA, AKT or PTEN . So far, post-CDK4/6i therapies include PARP inhibitors, selective estrogen receptor degraders (SERDs), PI3K inhibitors, AKT inhibitors, mTOR inhibitors, chemotherapy, and antibody–drug conjugates (ADCs), while rechallenging CDK4/6 inhibitors also offers additional avenues for molecularly targeted care. This position paper emphasizes the importance of biomarker-driven, individualized treatment strategies, highlights the need for collaborative efforts to ensure broad access to innovative therapies, and provides guidance for clinical practice, paving the way for more precise and personalized care in HR+/HER2− advanced breast cancer.