Triple Negative Breast Cancer in BRCA1 pathogenic variant carriers: Strategies for an individualised primary prevention approach utilising Progesterone Receptor Modulators

Women carrying a germline pathogenic variant (PV) of the BRCA1 gene are at an extremely high risk of developing triple negative breast cancer (TNBC) at a young age. Options to manage the TNBC risk for BRCA1 PV carriers remain scarce; the sole primary prevention strategy available is a risk reducing bilateral mastectomy. Recent evidence suggests that aberrant levels of progesterone in female BRCA1 PV carriers mediate at least part of the TNBC risk and preclinical studies have conclusively demonstrated that Progesterone Receptor Modulators (PRMs), such as mifepristone, significantly reduce the cancer risk. The efficacy of any medical primary preventive intervention in ultra-high-risk individuals should ideally be monitored by a robust and reliable parameter that reflects the actual risk. DNA methylation-based markers reflective of the proportion of at-risk cells and their replicative age are a promising strategy to capture field cancerization in the breast in real time. Here we summarize the current evidence in relation to the use of mifepristone for primary cancer prevention in women with a BRCA1 PV and provide suggestions as to how DNA methylation markers would enable a personalised prevention approach. A consensus workshop, held in Innsbruck in September 2024, began a community effort to work towards clinical trials of this novel approach. This group – the International Mifepristone Breast Cancer Prevention (IMBCP) Group – will now broaden its reach and continue to work towards ensuring that the necessary discussions take place, ultimately bringing about tangible change for women at the highest cancer risk.