The impact of menopausal status on the efficacy of adjuvant CDK4/6 inhibitors in hormone receptor-positive early breast cancer: a systematic review and meta-analysis of phase III clinical trials.

Adjuvant cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve outcomes in hormone receptor-positive (HR+), HER2-negative early breast cancer, though trial results have been heterogeneous. Menopausal status and endocrine therapy backbone may contribute to variability in treatment effect. We performed a meta-analysis evaluating whether menopausal status influences the efficacy of adjuvant CDK 4/6 inhibition. A systematic review of phase III randomized trials evaluating adjuvant CDK4/6i in HR+/HER2- early-stage breast cancer was conducted. Trial-level hazard ratios (HRs) and 95% confidence intervals (CIs) for iDFS and OS were extracted separately for pre-/peri-menopausal and postmenopausal subgroups. HRs were pooled using random-effects modelling (DerSimonian-Laird method) with inverse-variance modeling. Heterogeneity was assessed using I² statistics. A sensitivity analysis limited to approved CDK4/6i (ribociclib and abemaciclib) was performed. Four trials comprising 17,748 participants were included, of whom 45% were pre-/peri-menopausal and 55% were postmenopausal. Pooled iDFS HRs were 0.80 (95% CI 0.67-0.97, I²=64%) in pre-/peri-menopausal patients and 0.79 (95% CI 0.72-0.86, I²=0%) in postmenopausal patients. Pooled OS HRs were 1.02 (95% CI 0.67-1.54, I²=80%) in pre-/peri-menopausal and 0.89 (95% CI 0.78-1.03, I²=0%) in postmenopausal patients. No significant subgroup differences were observed for iDFS or OS. Compared to post-menopausal participants, those who were premenopausal had 3.0% fewer absolute iDFS events at 5-6 years. Sensitivity analyses yielded consistent findings. Efficacy of adjuvant CDK4/6 inhibition in HR+/HER2-negative early breast cancer does not appear to be influenced by menopausal status as defined in individual trials. Greater heterogeneity among pre-/peri-menopausal patients may reflect differences in endocrine therapy backbone, tumor characteristics and patient risk. Not applicable.