Therapy After Cyclin-Dependent Kinase Inhibition in Metastatic
Hormone Receptor-Positive Breast Cancer: Resistance
Mechanisms and Novel Treatment Strategies
https://acsjournals.onlinelibrary.wi...02/cncr.32931c
Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast
cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive
tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently
become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progres-
sion and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance
remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo
and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical chal-
lenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector
retinoblastoma protein(pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways,
in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6
inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of
CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.
Cancer 2020;0:1-17. © 2020 American Cancer Society.