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  • Review Article
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The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment

Nature Reviews Clinical Oncology volume 21, pages 89–105 (2024)Cite this article

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Abstract

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.

Key points

  • 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

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Fig. 1: Mechanism of action of CDK4/6 inhibitors.
Fig. 2: Mechanisms of resistance to CDK4/6 inhibition.

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  1. Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK

    Laura Morrison & Nicholas C. Turner

  2. Breast Unit, The Royal Marsden Hospital, London, UK

    Laura Morrison & Nicholas C. Turner

  3. German Breast Group, Goethe University, Frankfurt, Germany

    Sibylle Loibl

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L.M. and N.C.T. researched data for the manuscript and L.M. wrote the manuscript. All authors made a substantial contribution to discussions of content and edited and/or reviewed the manuscript prior to submission.

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L.M. and S.L. declare no competing interests. N.C.T. has acted as an adviser to Astra Zeneca, Exact Sciences, Gilead, GlaxoSmithKline, Guardant, Inivata, Lilly, Novartis, Pfizer, Relay therapeutics, Repare therapeutics, Roche/Genentech and Zentalis, and has received research funding from Astra Zeneca, Guardant Health, Inivata, Invitae, Merck Sharpe and Dohme, Natera, Personalis, Pfizer and Roche/Genentech.

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Morrison, L., Loibl, S. & Turner, N.C. The CDK4/6 inhibitor revolution — a game-changing era for breast cancer treatment. Nat Rev Clin Oncol 21, 89–105 (2024). https://doi.org/10.1038/s41571-023-00840-4

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