Periodic Reporting for period 1 - BRCA-PREVENT (Building consensus for a new approach to breast cancer prevention in women with a BRCA1 mutation)
Okres sprawozdawczy: 2023-09-01 do 2025-02-28
Women with germline mutations in the BRCA1 genes face a 40-fold increased risk of developing breast and ovarian cancer. As a result, and due to a lack of other options, many women with a BRCA1 mutation choose to undergo drastic risk reducing surgery (removal of both breasts, ovaries and Fallopian Tubes) when they are still very young. Drugs
currently recommended for prevention of breast cancer, such as tamoxifen or aromatase inhibitors, do not prevent those cancers with the poorest prognosis, such as triple negative breast cancer. Methods to prevent breast and ovarian cancers in these women are therefore a critical unmet medical need.
We and others have identified progesterone as one of the key drivers for triple negative breast cancer development. We have shown that progesterone is consistently elevated during the luteal phase of the menstrual cycle in BRCA1 mutation carriers compared to women without such a mutation, and preliminary data point to progesterone receptor antagonists, such as mifepristone, as a promising class of drugs for primary prevention.
Clinical trials of primary cancer prevention are extremely challenging due to the time-gap between the start of the cancer preventive treatment and the primary endpoints (i.e. cancer incidence and cancer death). Current tools do not predict the likelihood of future cancer development with sufficient accuracy to be used to determine the preventive efficacy of a new treatment. We have developed DNA methylation markers reflecting tissue age and cell type that are increased in cancer tissue as well as in normal tissue from women with a BRCA1 mutation and could be used to monitor preventive efficacy.
Clinical trials are now required to further investigate the use of antiprogestins for the prevention of breast and ovarian cancer. This ERC Proof of Concept grant aimed to bring consensus among the scientific, patient and regulatory/ethical communities regarding the design and conduct of an initial clinical trial.
currently recommended for prevention of breast cancer, such as tamoxifen or aromatase inhibitors, do not prevent those cancers with the poorest prognosis, such as triple negative breast cancer. Methods to prevent breast and ovarian cancers in these women are therefore a critical unmet medical need.
We and others have identified progesterone as one of the key drivers for triple negative breast cancer development. We have shown that progesterone is consistently elevated during the luteal phase of the menstrual cycle in BRCA1 mutation carriers compared to women without such a mutation, and preliminary data point to progesterone receptor antagonists, such as mifepristone, as a promising class of drugs for primary prevention.
Clinical trials of primary cancer prevention are extremely challenging due to the time-gap between the start of the cancer preventive treatment and the primary endpoints (i.e. cancer incidence and cancer death). Current tools do not predict the likelihood of future cancer development with sufficient accuracy to be used to determine the preventive efficacy of a new treatment. We have developed DNA methylation markers reflecting tissue age and cell type that are increased in cancer tissue as well as in normal tissue from women with a BRCA1 mutation and could be used to monitor preventive efficacy.
Clinical trials are now required to further investigate the use of antiprogestins for the prevention of breast and ovarian cancer. This ERC Proof of Concept grant aimed to bring consensus among the scientific, patient and regulatory/ethical communities regarding the design and conduct of an initial clinical trial.
The main achievement of the project was a two-day consensus conference following extensive consultation with more than 30 experts from a wide range of disciplines, including clinical medicine, surgery, clinical genetics, epidemiology, statistics, pathology, trial methodology, epigenetics, patient advocacy, ethics, and regulatory affairs. The meeting was held in Innsbruck in September 2024. Two manuscripts have been prepared following the conference. The first summarises the consensus of the group – which we named the International Mifepristone Breast Cancer Prevention (IMBCP) Group – and recommendations for further research. This paper articulates the scientific rationale, current state of the field, and a proposed implementation pathway for using mifepristone as a primary breast cancer prevention strategy in women with BRCA1 pathogenic variants. A key component of the approach is the use of epigenetic markers to monitor treatment efficacy - markers that can be assessed in breast biopsies or, more conveniently, in cervical or buccal samples. The second manuscript outlines the urgent need to give antiprogestins such as mifepristone the opportunity to be investigated as a non-surgical option for primary prevention.
Primary prevention of breast cancer would offer huge potential impacts to women at risk. In order to continue our work, the International Mifepristone Breast Cancer Prevention Group has subsequently also secured funding from the US-based RISE-UP for Breast Cancer initiative (https://riseup.ucsf.edu/ideas-implementation-i2i(odnośnik otworzy się w nowym oknie)).