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

## TL;DR

Short-term use of mifepristone in women with BRCA1/2 mutations does not cause harmful changes in the womb lining, suggesting it may be safe for breast cancer prevention.

## Contribution

The study provides new safety data showing mifepristone does not induce endometrial oncogenic changes in BRCA1/2 mutation carriers.

## Key findings

- Mifepristone caused amenorrhea without increasing epithelial cell proportions linked to cancer.
- Multi-omics analyses found no molecular signatures of oncogenic transformation in endometrial tissue.
- DNA methylation and gene expression related to endometrial cancer remained stable after treatment.

## Abstract

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.

Women who have inherited different versions (mutations) of the BRCA1 or BRCA2 gene are more likely to get breast cancer. Medicines that block the activity of the hormone progesterone, such as mifepristone, are being evaluated to determine whether they can be taken to prevent development of breast cancer. However, it is important to know what impact taking these medicines has on the lining of the womb (endometrium), because changes in the endometrium can result in development of cancer. We gave mifepristone or a placebo to women with mutations in BRCA1 or BRCA2 for three months and examined tissue samples from the womb. We found that mifepristone caused periods to stop but did not increase cell growth or result in changes usually seen when cancer develops. These results suggest that short-term use of mifepristone is safe for the womb, but longer studies are needed to evaluate longer term effects.

Widschwendter, Herzog et al. examine the short-term effects of mifepristone on the endometrium in women with BRCA1/2 mutations. Mifepristone does not cause molecular changes linked to endometrial cancer, providing important safety data for future cancer prevention strategies.