Differential benefit of adjuvant everolimus according to endocrine therapy backbone in the randomized UNIRAD trial
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Background
The randomized, double-blind UNIRAD trial evaluating the addition of 2 years of everolimus to endocrine therapy in patients with high-risk, early luminal breast cancer failed to demonstrate a benefit. We report the subgroup analyses.
Patients and Methods
We randomized 1278 patients in a 1:1 ratio to receive 2 years of placebo or everolimus, added to endocrine therapy for up to 4 years after initiation. Randomization was stratified by endocrine therapy agent, prior adjuvant versus neoadjuvant therapy, progesterone receptor expression, and lymph node involvement. Subgroup analyses by each stratification factor were prespecified. Post hoc analyses were performed according to menopausal status and age. We also analyzed treatment adherence.
Results
We observed a limited trend toward more favorable prognostic features in tamoxifen-treated patients, with more frequent ER+/PR+ tumors (88.5% vs. 84.1%, p=0.026) and less frequent pN2+ status (39.8% vs. 46%, p=0.032). In premenopausal women, we observed a numerical benefit of everolimus: 3y-DFS was 86% in the placebo group and 90% in the everolimus group [HR=0.76 (95%CI: 0.43-1.34)]. In premenopausal patients treated with tamoxifen (n=153; 12.3%), we observed an even stronger trend in favor of everolimus as 3-year DFS was 84% in the placebo group and 91% in the everolimus group [HR=0.54 (95%CI: 0.28-1.02)]. Early discontinuation of either everolimus or placebo was less frequent in the tamoxifen group than in the AI group: 48.0% vs. 56.9% (p=0.028).
Conclusions
The present post-hoc analyses generate hypotheses regarding the interaction between menopausal status, tamoxifen and everolimus in patients with high-risk, ER-positive, HER2-negative early breast cancer. They suggest that tamoxifen alone is no longer the standard of care in high-risk premenopausal patients.
