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


RECENT FINDINGS
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.
['Xi|Jing|J|', 'Ma|Cynthia X|CX|']
D001943:Breast Neoplasms D051358:Cyclin-Dependent Kinase 4 D051361:Cyclin-Dependent Kinase 6 D018450:Disease Progression D019008:Drug Resistance, Neoplasm D005260:Female D006801:Humans D009362:Neoplasm Metastasis D047428:Protein Kinase Inhibitors D018719:Receptor, ErbB-2 D011960:Receptors, Estrogen D058570:TOR Serine-Threonine Kinases
Endocrine therapy CDK4/6 inhibitor Metastatic breast cancer (MBC) Resistance mechanisms Biomarkers RB1 Clinical trials Abemaciclib Alpelisib Aromatase inhibitor Aurora kinase inhibitor CDK inhibitor ESR1 Estrogen receptor-positive (ER+) breast cancer Everolimus FGFR inhibitor Fulvestrant Hormone receptor-positive (HR+) and HER2-negative (HER2−) breast cancer PI3K inhibitor PIK3CA Palbociclib Ribociclib Selective estrogen receptor downregulator (SERD) Sequencing of therapy Targeted therapy mTOR inhibitor