Short-term hormonal modulation with mifepristone does not induce oncogenic changes in the endometrium of BRCA1/2 pathogenic variant carriers.

Progesterone receptor antagonists such as mifepristone have emerged as candidates for breast cancer prevention, particularly in high-risk populations such as BRCA1/2 pathogenic variant carriers. However, their impact on endometrial safety remains insufficiently characterized, raising concerns about unopposed oestrogen stimulation in the setting of impaired DNA repair. This study reports secondary outcomes evaluating short-term endometrial effects of mifepristone in this high-risk population. We previously conducted a randomized, double-blind, placebo-controlled trial (NCT01898312) involving 45 premenopausal women with BRCA1/2 pathogenic variants. Participants received mifepristone (50 mg every other day, n = 30) or a non-hormonal comparator (n = 15) for three months. Here we present secondary outcomes from the trial: Paired endometrial biopsies from a subset of 14 participants were analysed using transcriptomic, DNA methylation, and cell-type deconvolution methods. Statistical comparisons were performed using paired and unpaired Wilcoxon tests. Here we show that mifepristone induces amenorrhea in all treated participants without increasing epithelial cell proportions, the compartment most relevant to endometrial carcinogenesis. Multi-omics analyses reveal no molecular signatures consistent with oncogenic transformation. DNA methylation and gene expression indices associated with endometrial cancer remain stable after treatment, even after adjusting for age and cell composition. Short-term mifepristone exposure does not produce molecular changes linked to endometrial carcinogenesis in BRCA1/2 pathogenic variant carriers. These findings provide important safety data for the future development of progesterone receptor modulators in cancer prevention. Long-term studies are needed to confirm these observations.