Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2−) metastatic breast cancer (MBC). However, optimal therapy after CDK4/6 inhibitors is unknown. This review provides an update on recent understanding of potential resistance mechanisms to CDK4/6 inhibitors and therapeutic strategies. CDK4/6 inhibitors are broadly effective for HR+/HER2− MBC. However, intrinsic and acquired resistance is inevitable. Although there are no established clinical predictors of response aside from ER positivity, several cell cycle-specific and non-specific mechanisms have emerged as potential resistance biomarkers and therapeutic targets in recent studies. Examples include loss of function mutations in RB1 or FAT1, overexpression or amplification of CDK6 and CCNE1, alterations of FGFR, and PI3K/mTOR-mediated CDK2 activation. Biomarker studies and clinical trials targeting CDK4/6 inhibitor resistance are critical to improve treatments for HR+/HER2− MBC.