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

Background: Hormone receptor-positive/HER2-negative (HR+/HER2−) early breast cancer (EBC) presents a persistent risk of relapse, even beyond 5 years, driving the need for adjuvant intensification strategies. This review analyzes the clinical evidence for CDK4/6 inhibitors (CDK4/6i) in the adjuvant setting. This evidence is then integrated with molecular findings to support the concept of the “carry-over” effect, which is 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, with consideration of the “carry-over” effect. Emerging biomarkers and the impact of financial toxicity are also described. Results: PALLAS did not demonstrate a clear on-treatment or post-treatment benefit, whereas PENELOPE-B suggested, at most, a transient early advantage that was not maintained with longer follow-up; therefore, neither trial provides convincing evidence of a durable “carry-over” effect. In contrast, monarchE (abemaciclib) and NATALEE (ribociclib) showed significant improvements in iDFS and, in the case of abemaciclib, 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 the “carry-over” effect should not be considered 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.