Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer 
cells may result in diversion away from a pathway to senescence and toward a 
more proliferative phenotype. Cancer cells may increase cyclin D-dependent 
activity through a variety of mechanisms. Therapeutic inhibition of CDKs in 
tumors to negate their evasion of growth suppressors has been identified as a 
key anticancer strategy. In this review, we outline the development of CDK 
inhibitory therapy in breast cancer, including the initial experience with the 
pan-CDK inhibitor flavopiridol and the next generation of oral highly selective 
CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and 
LY2835219 (abemaciclib). Data from phase I and II studies in estrogen 
receptor-positive (ER+) breast cancer demonstrate promising efficacy with 
manageable toxic effects, chiefly neutropenia. We discuss these studies and the 
phase III studies that are accruing or nearing completion. We describe the 
application of such therapy to other breast cancer settings, including 
HER2-positive breast cancer and the adjuvant treatment of early breast cancer. 
We also discuss potential concerns surrounding the combination of CDK inhibitors 
with chemotherapy and their effects on repair of double-strand DNA breaks in 
cancer cells. Oral highly selective CDK inhibitors show great promise in 
improving the outcomes of patients with ER+ breast cancer, although caution must 
apply to their combination with other agents and in the early breast cancer 
setting.