Building consensus for a new approach to breast cancer prevention in women with a BRCA1 mutation

Introduction

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.

Current Prevention Options

Drugs currently recommended for the 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.

Role of Progesterone

We and others have identified progesterone as one of the key drivers for triple-negative breast cancer development.

Key Findings

• 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.
• Preliminary data point to progesterone receptor antagonists, such as mifepristone, as a promising class of drugs for primary prevention.

Challenges in Clinical Trials

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).

Limitations of Current Tools

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.

Development of DNA Methylation Markers

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.

Future Directions

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 aims to bring consensus among the scientific, patient, and regulatory/ethical communities regarding the design and conduct of an initial clinical trial.