Clinical Application of CDK4/6Inhibitorsin Breast Cancer: Current Evidence,Resistance, and Future Di

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Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer by converting endocrine therapy into a more durable strategy of combined estrogenreceptor and cell-cycle suppression. Palbociclib, ribociclib, and abemaciclib are establishedtreatments in advanced disease, while dalpiciclib has generated phase III evidence in predominantlyChinese populations. The clinical scope of the class has expanded from first- and later-linemetastatic treatment to adjuvant therapy for selected patients with early-stage disease. Abemaciclibhas produced sustained invasive disease-free survival and a statistically significant overall-survival benefit in node-positive, high-risk early breast cancer, whereas ribociclib has reduced recurrenceacross a broader stage II–III population. By contrast, adjuvant palbociclib trials were negative, demonstrating that efficacy in advanced disease cannot automatically be extrapolated as a class effect in the curative setting. More recent data have extended CDK4/6 inhibition to maintenancetherapy for HR+/HER2+ advanced breast cancer and have refined strategies after prior CDK4/6exposure through estrogen-receptor degraders and PI3K/AKT/mTOR-pathway inhibition. Nevertheless, intrinsic and acquired resistance involving RB1 loss, cyclin E–CDK2 activation, growth-factor signaling, and estrogen-receptor evolution remains a major limitation. Treatment selection therefore requires integration of disease tempo, previous endocrine exposure, molecular findings, comorbidity, toxicity susceptibility, access, and patient preference. This reviewsummarizes the biological basis, pivotal clinical evidence, resistance mechanisms, safetymanagement, and emerging precision approaches for CDK4/6 inhibitors in breast cancer. It emphasizes that the future value of these agents will depend less on indiscriminate expansionandmore on their use in the appropriate patient, at the appropriate time, and within a biologicallycoherent treatment sequence.

• 1N420Y03B4151-9092.pdf