Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown advantages in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This study aimed to evaluate the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy (ET) in patients with HR+, HER2- early breast cancer. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) related to CDK4/6 inhibitors combined with ET. Literature conforming to the research content was identified according to the inclusion and exclusion criteria. The efficacy endpoints included invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) with adjuvant therapy. The efficacy endpoint of neoadjuvant therapy was complete cell cycle arrest (CCCA). The safety outcomes included the incidence of adverse events (AEs) and grade 3-4 hematological and non-hematological AEs. Data analysis was performed using Review Manager software (version 5.3). A statistical model (fixed-effects model or random-effects model) was selected based on the level of heterogeneity, and a sensitivity analysis was performed if strong heterogeneity existed. Subgroup analyses were performed based on the baseline patient characteristics. Nine articles (including six RCTs) were included in the study. In adjuvant therapy, compared with the control group, CDK4/6 inhibitors combined with ET showed no statistically significant difference in IDFS (hazard ratio = 0.83, 95% confidence interval (CI) = 0.64-1.08, P = 0.17) and DRFS (hazard ratio = 0.83, 95% CI = 0.52-1.31, P = 0.42). In neoadjuvant therapy, CDK4/6 inhibitors combined with ET significantly improved CCCA compared with the control group (odds ratio = 9.00, 95% CI = 5.42-14.96, P < 0.00001). In terms of safety, the combination treatment group had a significantly increased incidence of grade 3-4 hematological AEs in patients, especially grade 3-4 neutropenia (risk ratio (RR) = 63.90, 95% CI = 15.44-264.41, P < 0.00001) and grade 3-4 leukopenia (RR = 85.89, 95% CI = 19.12-385.77, P < 0.00001), with statistically significant differences. In patients with HR+, HER2- early breast cancer, the addition of CDK4/6 inhibitors may prolong IDFS and DRFS in adjuvant therapy, especially in high-risk patients. Further follow-up is needed to establish whether OS can be improved with CDK4/6 inhibitors plus ET. CDK4/6 inhibitors also showed effective anti-tumor proliferation activity in neoadjuvant therapy. Regular monitoring of routine blood tests in patients using CDK4/6 inhibitors is essential.
Keywords: CDK4/6 inhibitors; early breast cancer; endocrine therapy; randomized controlled trial.