Association Between Daily Timing of Everolimus and Survival in High-Risk HR+/HER2- Early Breast Cancer: A Sub-Analysis of the UCBG-UNIRAD Trial.

In the UNIRAD phase III trial, evening intake of tamoxifen was previously associated with improved disease-free survival (DFS), while no timing effect was observed for aromatase inhibitors. This sub-study evaluated whether the timing of everolimus intake affects DFS in patients receiving adjuvant endocrine therapy (ET). A total of 1278 patients with high-risk HR+/HER2- early breast cancer were randomized to receive adjuvant ET with either placebo or everolimus. Patients prospectively recorded the timing of both ET and everolimus intake using four time slots: morning (06:00-11:59), afternoon (12:00-17:59), evening (18:00-23:59), and night (00:00-05:59). The relationship between intake timing and DFS was a pre-specified secondary endpoint. Timing data were available for 513 of 632 patients (81.2%) in the everolimus arm. After a median follow-up of 60.6 months, 15 local relapses, 55 metastases, and 36 deaths were reported. Overall, everolimus timing had no significant association with DFS (HR = 0.84, 95% CI 0.53-1.35, P = 0.4). However, a significant interaction was found between everolimus timing and ET type (P = 0.001). Among tamoxifen users, evening/night intake of everolimus significantly improved DFS compared to morning/afternoon intake (HR = 0.17, 95% CI 0.05-0.59, P = 0.005), independently of tamoxifen timing. No timing effect was observed in patients on aromatase inhibitors (HR = 1.56, P = 0.1). In multivariate analysis, evening/night everolimus with tamoxifen remained an independent predictor of improved DFS (HR = 0.13, P = 0.002). Evening or nighttime intake of everolimus may enhance the efficacy of tamoxifen-based adjuvant therapy in high-risk HR+/HER2- early breast cancer.