BRCA1/2 and Effect of Mifepristone on the Breast

The Effect of a Progesterone Receptor Modulator on Breast Tissue in Women With BRCA-1 and -2 Mutations - a Placebo Controlled RCT.

Ovarian steroids, as well as their synthetic counterparts gestagens and estrogens have a role in breast cell proliferation and the development of breast cancer. Here, the effect of a progesterone receptor modulator, mifepristone, on cell proliferation in human breast tissue in vivo will be studied in women with BRCA-1 or -2 mutations. Our preliminary results implicate a possible protective effect of mifepristone in breast epithelium. The ability of mifepristone to block breast epithelial cell proliferation may prevent tumorigenesis and may also prove beneficial when used for contraceptive purposes and on other indications. The proposed project concerns a Randomized Controlled Trial on mifepristone versus placebo treatment of women with BRCA-1or -2 mutations with a high risk/incidence of breast cancer and ovarian cancer.

Study Overview

• Status: Completed
• Conditions: Women With Mutations in the Breast Cancer Susceptibility Genes BRCA1,2
• Intervention / Treatment: Drug: Mifepristone

Detailed Description

Objectives • Research objective To study the safety and effect of treatment with mifepristone, a progesterone receptor modulator, on epithelial cell proliferation in human breast tissue in women with BRCA-1 or -2 mutations prior to protective mastectomy.

Project description

• Hypothesis/ Theory Mifepristone treatment exerts an antiproliferative, protective effect on breast tissue in women with BRCA-1 or -2 mutations

Study Design Randomized, double blind, placebo controlled trial. Women will be recruited among patients with BRCA-1 or -2 mutations scheduled for prophylactic mastectomy. Included women will be randomized to a 3-month treatment with mifepristone, 50 mg (Mifegyne, Exelgyn, Paris, France) or placebo taken orally every second day. Breast biopsies will be obtained in the luteal phase prior to start of treatment and again during surgery.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 17176
    • Department of Woman and Child Health Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion criteria:

• Pre-menopausal women, >/= 18 years of age
• with good general health and
• regular menstrual cycles (25-35 days) who are willing and
• able to participate after giving informed consent.
• women having BRCA1/2 mutation and have decided to undergo risk reducing mastectomy

Exclusion criteria includes:

• Any hormonal treatment used within 2 months prior to study start and
• Any contraindication to mifepristone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mifepristone; treatment with oral mifepristone 50 mg every second day for 12 weeks in 30 women with BRCA 1 or 2 mutation	Drug: Mifepristone; Randomised controlled trial of Mifepristone and placebo comparator Triobe
Placebo Comparator: TrioBe; treatment with a quarter of a tablet of TrioBe every second day for 12 weeks	Drug: Mifepristone; Randomised controlled trial of Mifepristone and placebo comparator Triobe

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
epithelial cell proliferation in breast tissue	Changes from baseline after 12 weeks of mifepristone treatment in epithelial cell proliferation by measuring expression of genes specifically in the pathways involving apoptotic and cell proliferation by microarray study, including PTEN, Bcl-2 and Ki-67 along with steroid receptors.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital signs and safety lab analysis	Safety data includes vital signs, general- and gynecological-, incl breast - examinations, safety lab (hematology (blood status+CRP), kidney function (Na, K, krea) liver function (ASAT, ALAT, ALP, GT, bilirubin) , thyroid function (TSH,T3,T4), hormonal values FSH ,LH , PRL, SHBG, testosterone, E2 (sensitive) progesterone, urine dipstick and pregnancy test (prior to start). Endometrial histology will be investigated in biopsies obtained at baseline and at surgery. Women with BRCA-1/-2 mutations are followed according to the existing clinical routine with regard to ovarian cancer screening.	3 months
Side effects and Adverse Events	Side effects of mifepristone are mild and the only significant side effect reported in previous clinical trials with the same regimen has been mild flushes. All side effects and SAE/AE as well as any concomitant medication will be recoded by the participating patients in a dairy.	3 months
Endometrial effects	Bleeding patterns and endometrial morphologywill be studied. Endometrial histology and progesterone receptor modulator associated changes will be investigated in biopsies obtained at baseline and at surgery. Bleeding pattern will be registered during the study period by the participating women.	3 months
Ovarian effects	Women with BRCA-1/-2 mutations are followed according to the existing clinical routine with regard to ovarian cancer screening.	3 months
Breast symptom evaluation	Breast symptom evaluation will be registered at baseline and during the study by a breast symptom score.	3months

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Investigators: Principal Investigator: Kristina Gemzell Danielsson, Professor, Dept of Womens and Childrens Health Karolinska Institutet; Study Chair: Angelique Flöter Rådestad, MD PhD, Dept of Womens and Childrens Health, Karolinska Institutet

Publications and helpful links

General Publications

• Engman M, Skoog L, Soderqvist G, Gemzell-Danielsson K. The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology. Hum Reprod. 2008 Sep;23(9):2072-9. doi: 10.1093/humrep/den228. Epub 2008 Jun 24.
• Isern AE, Loman N, Malina J, Olsson H, Ringberg A. Histopathological findings and follow-up after prophylactic mastectomy and immediate breast reconstruction in 100 women from families with hereditary breast cancer. Eur J Surg Oncol. 2008 Oct;34(10):1148-54. doi: 10.1016/j.ejso.2008.03.002. Epub 2008 Apr 23.
• Kauff ND, Brogi E, Scheuer L, Pathak DR, Borgen PI, Hudis CA, Offit K, Robson ME. Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer. 2003 Apr 1;97(7):1601-8. doi: 10.1002/cncr.11225.
• Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science. 2006 Dec 1;314(5804):1467-70. doi: 10.1126/science.1130471.
• Bartlett TE, Evans I, Jones A, Barrett JE, Haran S, Reisel D, Papaikonomou K, Jones L, Herzog C, Pashayan N, Simoes BM, Clarke RB, Evans DG, Ghezelayagh TS, Ponandai-Srinivasan S, Boggavarapu NR, Lalitkumar PG, Howell SJ, Risques RA, Radestad AF, Dubeau L, Gemzell-Danielsson K, Widschwendter M. Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women. Genome Med. 2022 Jun 15;14(1):64. doi: 10.1186/s13073-022-01063-5. Erratum In: Genome Med. 2022 Jul 19;14(1):76.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: July 5, 2013
• First Submitted That Met QC Criteria: July 10, 2013
• First Posted (Estimate): July 12, 2013

Study Record Updates

• Last Update Posted (Actual): January 19, 2022
• Last Update Submitted That Met QC Criteria: January 15, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Abortifacient Agents; Luteolytic Agents; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Mifepristone
• Other Study ID Numbers: 2012-003703-35