“Carry-Over” Effect of CDK4/6 Inhibitors in Adjuvant Therapy for Hormone Receptor (HR)-Positive/HER2-Negative Early Breast Cancer: Clinical Evidence and Molecular

Background: Hormone receptor-positive/HER2-negative (HR+/HER2−) early breast cancer (EBC) presents a persistent risk of relapse, even beyond 5 years, driving adjuvant intensification strategies. This review analyzes the clinical evidence for CDK4/6 inhibitors (CDK4/6i) in the adjuvant setting and integrates it with molecular findings to support the concept of the “carry-over” effect, understood as a lasting benefit that persists after the end of active treatment, reflected by a sustained separation of invasive disease-free survival (iDFS) curves during follow-up. Relevant sections: The main adjuvant trials in EBC are reviewed, considering the “carry-over” effect. Also, emerging biomarkers and the impact of financial toxicity are described. Results: PALLAS and PENELOPE-B (palbociclib) did not demonstrate an overall benefit in iDFS, with results potentially influenced by discontinuation, toxicity, and risk heterogeneity; however, translational analyses suggest a possible benefit in subgroups defined by biomarkers. In contrast, monarchE (abemaciclib) and NATALEE (ribociclib) showed significant improvements in iDFS, and in the case of abemaciclib, also a signal of benefit in overall survival, supporting the existence of a clinically relevant post-treatment effect. Conclusions: From a biological perspective, the review proposes that “carry-over” would not be a uniform class effect, but rather the result of a sequence of events modulated by pharmacological selectivity (CDK4 vs. CDK6 and additional targets), the induction of cellular senescence, and immunomodulatory effects that could favor the control of micrometastases. In addition, elements that influence interpretation and the need to optimize adherence and toxicity management to “materialize” the benefit in a potentially curable context are discussed.