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Assessing mifepristone's effects on endometrial tissue in women with BRCA mutations: A randomised clinical trial

ABSTRACT: Background: The endometrium, regulated by steroid hormones, is particularly susceptible to disease under imbalanced hormonal conditions. Progesterone regulates cell growth differently across tissues, acting as a pro-tumorigenic agent in the breast while serving as a tumor suppressor in the endometrium by countering the effects of oestradiol. Progesterone receptor modulators like mifepristone may prevent breast cancer formation but raise concerns about unopposed oestradiol exposure in the endometrium. This study examines mifepristone’s impact on the endometrium, particularly its potential link to endometrial carcinogenesis in BRCA mutation carriers, who have DNA repair and replication vulnerabilities. Methods: This study was part of a randomised, double-blind, placebo-controlled trial in which pre-menopausal women carrying BRCA1 or BRCA2 mutations were assigned to a three-month treatment with either mifepristone (50 mg) or a non-hormonal comparator (TrioB) every second day. Endometrial biopsies were collected pre- and post- treatment, processed, and analysed for changes in endometrial thickness, cellular composition, methylation patterns, and gene expression profiles. Compliance and safety monitoring were rigorously maintained. Results: Mifepristone treatment led to amenorrhea in all treated participants, consistent with its inhibition of ovulation. Ultrasound showed a non-significant increase in endometrial thickness post-treatment. Cellular analysis indicated a shift in composition, with a reduction in epithelial cells and an increase in fibroblast levels, suggesting that endometrial thickening may primarily reflect stromal expansion rather than epithelial proliferation. This distinction is clinically important, as epithelial proliferation is more closely associated with carcinogenesis. DNA methylation analysis revealed no significant alterations in the TCGA-EC methylation index, and gene expression profiling showed no significant elevation in carcinogenesis-related genes. Conclusions: Mifepristone treatment in BRCA mutation carriers does not significantly impact methylation or gene expression profiles associated with endometrial carcinogenesis. The findings support from the safety of short-term mifepristone use in this population, although long-time safety of mifepristone use in BRCA mutation carriers will be needed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283656 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:The development of non-invasive primary cancer preventive measures in humans require a thorough understanding of the initial cancer-driving molecular mechanisms. High grade serous extra-uterine M llerian cancers (HGSEMC; formerly classified as ovarian/tubal/peritoneal cancer) present at a very late stage and less than 40% of women survive 5 years. Although the recent TCGA initiatives revealed key molecular changes in established cancers, very little is known about the initial molecular alterations in cancer development. Analysis of normal tissue at extensively high risk prior to the development of any microscopic alterations is critical. BRCA1/2 mutation carriers have an up to 30 40 fold increased risk to develop ovarian cancer, preferentially HGSEMC. Despite a plethora of evidence linking mutations in BRCA1 or BRCA2 to cancer development the core components such as organ specificity (i.e. to breast and Fallopian Tube) are still missing. The Fallopian Tube of BRCA mutation carriers offers a unique opportunity to study carcinogenesis because these cancers originate only from the distal (i.e. fimbrial) end of the Fallopian Tube (which is in close proximity to the ovary), and not from the proximal end (which is close to the uterus). The ovary which is in extreme close proximity to the fimbriae provides an excellent soil for cancer cells which are likely shed from the fimbriae and once the cancer has been discovered the big bulk of tumour is usually present on the ovary and hence the majority of HGSEMC are also referred to as ovarian cancer . To study the earliest steps of human carcinogenesis we performed epigenome-wide DNA methylation (DNAme) analyses (using the Illumina 450k DNA methylation bead-array assay assessing DNAme at ~480 000 CpG sites) in 215 microscopic normal Fallopian Tube samples of BRCA1/2 mutation carriers (n=56) and controls (n=59) who had their tubes/ovaries removed for prophylactic or other reasons, respectively (for 52 and 49 individuals respectively we analysed both fimbrial and proximal Fallopian Tubes). In order to adjust for any epigenetic effects which are not of immediate importance to the carcinogenic process, for each volunteer we analysed both the fimbrial (at risk) and the proximal (non at risk) portion of the tubes separately. Formalin fixed paraffin embedded (FFPE) tissue blocks were retrieved from UCL Biobank (NC09.13). Histopathological features of fimbrial and proximal section of Fallopian Tube from BRCA carriers and control cases were carefully examined. Cases negative for serous tubal intraepithelial carcinoma (STIC) lesions were chosen for DNA isolation to characterize pre-cancer epigenetic changes. For DNA isolation, a core of 3 x 0.6 mm was taken from each block representing fimbrial and proximal end of fallopian tubes from both BRCA carriers and matched control cases. The DNA was isolated using QIAamp(r) DNA FFPE Tissue Kit as per manufacturer's protocol with minor modifications (Dewaxing for 4 hours in xylene and proteinase digestion performed overnight, other procedures were as per the instructions). DNA was quantified using Nandrop and restored using the Infinium FFPE DNA Restore Kit and then 200 nanogram of DNA was bisulfite converted using the EZ DNA Methylation-Gold(tm) and subjected to methylation analysis on the Illumina Infinium Human Methylation450 BeadChip.

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Assessing mifepristone's effects on endometrial tissue in women with BRCA mutations: A randomised clinical trial

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