Effect of HER2-Low Expression on the Efficacy of CDK4/6 Inhibitors in Breast Cancer: A Meta-Analysis

CDK4/6 inhibitors combined with endocrine therapy have become the standard first-line and second-line therapy for advanced HR+/HER2- breast cancer. This study aimed to evaluate the impact of HER2 low expression on the efficacy of breast cancer patients treated with CDK4/6 inhibitors. We systematically searched 4 major databases and important conference proceedings up to May 2025, and screened out studies that reported the progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in HR+/HER2-low breast cancer patients and HR+/HER2-zero breast cancer patients treated with CDK4/6 inhibitors. We calculated the pooled hazard ratio (HR) and its 95% confidence interval (CI). A total of 18 studies involving 8461 patients were finally included. Among them, HER2-low breast cancer patients accounted for 41.25% of the sample, and HER2-zero breast cancer patients accounted for 57.98% of the sample. The results showed that the progression-free survival (PFS) of HR+/HER2-low breast cancer patients treated with the combination of CDK4/6 inhibitors and endocrine therapy was significantly lower than that of HR+/HER2-zero breast cancer patients (HR = 1.19, 95% CI, 1.10-1.28, P < .0001). Further subgroup analysis indicated that among HER2-low patients, whether they received first-line treatment, subsequent treatment, or were treated with Ribociclib, their prognosis was worse. Analysis of OS showed no statistically significant difference between groups (HR = 1.00, 95% CI, 0.93-1.07, P = .93). Similarly, no significant differences were observed in ORR. In addition, no significant differences in the PFS were observed in HR+/HER2-low breast cancer patients, regardless of whether the HER2 status changed due to treatment, the presence of visceral metastases. In conclusion, among patients receiving CDK4/6 inhibitor combined with endocrine therapy, HER2-low status was associated with significantly shorter PFS but not with significant differences in OS or ORR. However, it is worth noting that most of these studies are retrospective and real-world studies, with limited adjustments for confounding factors, and the statistical power of testing may be insufficient.