The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment

Cyclin-dependent kinase (CDK) 4/6 inhibition in combination with endocrine therapy is the standard-of-care treatment for patients with advanced-stage hormone receptor-positive, HER2 non-amplified (HR+HER2-) breast cancer. These agents can also be administered as adjuvant therapy to patients with higher-risk early stage disease. Nonetheless, the clinical success of these agents has created several challenges, such as how to address acquired resistance, identifying which patients are most likely to benefit from therapy prior to treatment, and understanding the optimal timing of administration and sequencing of these agents. In this Review, we describe the rationale for targeting CDK4/6 in patients with breast cancer, including a summary of updated clinical evidence and how this should inform clinical practice. We also discuss ongoing research efforts that are attempting to address the various challenges created by the widespread implementation of these agents. Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy have become the standard-of-care therapy for patients with advanced-stage hormone receptor-positive breast cancer. However, this success has created several challenges, such as the need to better understand resistance to these agents and develop novel therapies accordingly. Here, the authors provide an update on the clinical activity of the established CDK4/6 inhibitors along with a summary of ongoing research efforts attempting to address the new challenges created by the success of these agents. Cyclin-dependent kinase (CDK) 4/6 inhibitors inhibit the cell cycle, thus inducing cellular senescence and are increasingly being implicated in antitumour immunity.Three CDK4/6 inhibitors are currently used in routine clinical practice and have shown highly consistent progression-free survival results, although inconsistencies have emerged in their overall survival results.The toxicity profile varies between different CDK4/6 inhibitors, allowing a degree of treatment tailoring based on the needs of individual patients.The increased and earlier use of CDK4/6 inhibitors has resulted in a better understanding of the mechanisms of acquired resistance; potential treatment combinations that might overcome these mechanisms are being explored.Treatment selection after disease progression on a CDK4/6 inhibitor remains an area of active research and is likely to be influenced by the underlying mechanisms of resistance