Precision Post-CDK4/6i Management: Molecular Stratification Redefines Second-Line Therapy in HR+ Advanced Breast Cancer

Introduction: The Post-CDK4/6i Clinical Dilemma

The treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) has been revolutionized by the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET). This combination is now the firmly established first-line standard of care, significantly extending progression-free survival (PFS) and, in many cases, overall survival. However, virtually all patients eventually develop resistance to these agents. Determining the optimal subsequent line of therapy remains one of the most significant challenges in clinical oncology.

Historically, the transition after CDK4/6i progression involved switching the endocrine backbone (e.g., from an aromatase inhibitor to fulvestrant) or moving to cytotoxic chemotherapy. Recently, several new strategies have emerged, including novel oral selective estrogen receptor degraders (SERDs), PI3K/AKT/mTOR pathway inhibitors, and the continuation of CDK4/6 inhibition beyond progression. Despite a growing number of randomized controlled trials (RCTs), the absence of head-to-head comparisons between these diverse strategies has left clinicians with a complex decision-making matrix. The recent systematic review and network meta-analysis (NMA) by Escudero et al. provides a much-needed evidence-based framework for navigating this therapeutic crossroad through the lens of molecular stratification.