Differential benefit of adjuvant everolimus according to endocrine therapy backbone in the randomized UNIRAD trial

TL;DR

The UNIRAD trial found that adding everolimus to tamoxifen may improve outcomes for high-risk premenopausal breast cancer patients.

Contribution

The study suggests that everolimus may provide additional benefit when combined with tamoxifen in premenopausal patients.

Findings

Premenopausal patients treated with tamoxifen and everolimus showed improved 3-year disease-free survival.

Early discontinuation of treatment was less frequent in tamoxifen-treated patients.

Tamoxifen alone may be suboptimal for high-risk premenopausal breast cancer patients.

Abstract

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.

We randomly assigned 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 pre-specified. Post hoc analyses were carried out according to menopausal status and age. Treatment adherence was also analyzed.

We observed a limited trend toward more favorable prognostic features in tamoxifen-treated patients, with more frequent estrogen receptor-positive/progesterone receptor-positive tumors (88.5% versus 84.1%, P = 0.026) and less frequent pN2-positive status (39.8% versus 46.0%, P = 0.032). In premenopausal women, we observed a numerical benefit of everolimus: 3-year disease-free survival was 86% in the placebo group and 90% in the everolimus group (hazard ratio 0.76, 95% confidence interval 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 (hazard ratio 0.54, 95% confidence interval 0.28-1.02). Early discontinuation of either everolimus or placebo was less frequent in the tamoxifen group than in the aromatase inhibitor group: 48.0% versus 56.9% (P = 0.028).

The present post hoc analyses generate hypotheses regarding the interaction between menopausal status, tamoxifen, and everolimus in patients with high-risk, ER-positive, human epidermal growth factor receptor type 2-negative early breast cancer. They suggest that tamoxifen alone is an underpowered endocrine treatment in high-risk premenopausal patients.

Graphical abstract

•In the UNIRAD trial, a benefit of everolimus when added to tamoxifen in high-risk early luminal breast cancer was suggested.•This trend was most pronounced in premenopausal patients (3-year DFS: 84% versus 91%, hazard ratio 0.54).•Early discontinuation was less common in patients treated with tamoxifen.•Tamoxifen alone may be a suboptimal adjuvant therapy in premenopausal women with high-risk early luminal breast cancer.

In the UNIRAD trial, a benefit of everolimus when added to tamoxifen in high-risk early luminal breast cancer was suggested.

This trend was most pronounced in premenopausal patients (3-year DFS: 84% versus 91%, hazard ratio 0.54).

Early discontinuation was less common in patients treated with tamoxifen.

Tamoxifen alone may be a suboptimal adjuvant therapy in premenopausal women with high-risk early luminal breast cancer.

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