Therapeutic advances in HR+/HER2- advanced breast cancer after failure of CDK4/6 inhibitor therapy

Breast cancer represents the most frequently diagnosed malignancy in women, with the hormone receptor-positive/HER2-negative (HR+/HER2-) subtype being the most prevalent. For advanced HR+/HER2- breast cancer, the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy has become the established first-line standard, significantly prolonging both median progression-free survival (mPFS) and overall survival (OS). Nevertheless, the majority of patients eventually develop resistance, leading to disease progression. The underlying mechanisms of resistance are multifactorial, involving dysregulated cell cycle control, reprogramming of signaling pathways, and remodeling of the tumor microenvironment (TME). At present, there is no standardized treatment strategy for overcoming CDK4/6i resistance. This article systematically reviews current post-CDK4/6i therapeutic strategies, including next-generation endocrine therapies (e.g., oral SERDs), targeted agents directed at the PI3K/AKT/mTOR axis, AKT inhibitors, and antibody–drug conjugates (ADCs), and discusses potential future therapeutic directions.