After a CDK4/6 Inhibitor: State of the Art in Hormone Receptor–Positive Metastatic Breast Cancer
Jimmitti Teysir, Maxwell R. Lloyd, Samer Alkassis, Rena D. Callahan, Ricki Fairley, Seth A. Wander, Aditya Bardia, Komal Jhaveri
Abstract
CDK 4/6 inhibitors (CDK4/6i) remain part of the standard first-line treatment for patients with hormone receptor–positive metastatic breast cancer, offering demonstrable improvements in both progression-free survival and overall survival. However, resistance inevitably develops, and the optimal treatment sequencing after CDK4/6i progression remains undefined. Tumor heterogeneity and diverse resistance mechanisms—including alterations in ESR1 and PIK3CA —complicate treatment decisions in the post-CDK4/6i setting. Genomic profiling has helped to characterize these and other clinically relevant alterations, uncovering new avenues for therapeutic intervention. Building on these insights, a growing number of novel endocrine agents, phosphoinositide-3-kinase/AKT pathway–targeted therapies, and antibody-drug conjugates (ADCs) have demonstrated efficacy in biomarker-selected populations and are reshaping the treatment landscape beyond CDK4/6i progression. This chapter reviews current standards of care, emerging therapeutic options, and evolving combination strategies across biomarker-defined subgroups. We also highlight how ongoing clinical trials and advances in molecular profiling are informing personalized approaches to overcome endocrine resistance and improve patient outcomes.