CDK4/6 inhibition in hormone receptor-positive/HER2-negative breast cancer: Biological and clinical aspects

A dysregulated cell division, one of the key hallmarks of cancer, results in uncontrolled cellular proliferation. This aberrant process, mediated by a dysregulated cell-cycle machinery and overactivation of cyclin-dependent kinase (CDK) 4 and 6, can potentially promote tumorigenesis. The clinical application of CDK 4/6 inhibitors, developed to inhibit cell-cycle progression, in the treatment regimens of breast cancer (BC) patients is expanding. Currently, three agents, ribociclib, palbociclib, and abemaciclib, are approved for treating patients with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. In addition, abemaciclib is FDA and EMA-approved for patients with hormone receptor-positive HER2-negative, node-positive, early BC at high risk of recurrence. Emerging data suggest potential anti-tumor effects beyond cell cycle arrest, providing novel insights into the agent's mechanisms of action. As a result, a broader application of the CDK4/6 inhibitors in patients with cancer is achieved, contributing to enhanced optimized treatment in the adjuvant and neoadjuvant settings. Herein, the immunomodulatory activities of CDK4/6 inhibitors, their impact on the cell's metabolic state, and the effect on the decision of the cell to undergo quiescence or senescence are discussed. Moreover, this review provides an update on clinical trial outcomes and the differences in the underlying mechanisms between the distinct CDK4/6 inhibitors.