The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility

• Published in: Critical reviews in oncology/hematology 2023-12, Vol.192, p.104148-104148, Article 104148
• Main Authors: Antonarelli, Gabriele, Taurelli Salimbeni, Beatrice, Marra, Antonio, Esposito, Angela, Locatelli, Marzia Adelia, Trapani, Dario, Pescia, Carlo, Fusco, Nicola, Curigliano, Giuseppe, Criscitiello, Carmen
• Format: Article
• Language: English
• Subjects: Breast Cancer; Cyclin-Dependent Kinase inhibitors; Endocrine Resistance; Molecular Biomarkers
• ISSN: 1040-8428; 1879-0461
• DOI: 10.1016/j.critrevonc.2023.104148

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the “post-CDK4/6is” landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario. [Display omitted] •Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is)-based combinations represent the frontline therapy in Hormone Receptor positive, Human Epidermal Growth Factor 2 negative (HR+/HER2-) metastatic Breast Cancer (mBC).•Patients with HR+ /HER2- mBC eventually develop resistance to CDK4/6is-based combinations, with approximately 15–30 % displaying rapid progression.•Molecular biomarkers of intrinsic and acquired resistance to CDK4/6is-therapy are currently lacking in clinical practice and are eagerly awaited.