The likely ‘cell-of-origin’ that leads to breast cancer in BRCA1 pathogenic variant carriers is a progenitor cell that expresses the receptor RANK ligand [RANK] and is highly proliferative and prone to DNA damage. It appears to be hyper-responsive to progesterone through paracrine signaling mediated by RANK ligand [RANKL] (Lim et al Nature Med, 2009; Nolan et al Nature Med 2016). These and other findings have led to the first international breast cancer prevention study for BRCA1 pathogenic variant carriers which aims to evaluate the RANKL inhibitor denosumab (whose safety profile is already well understood) as a breast cancer prevention drug (EudraCT: 2017-002505-35; NIH: NCT04711109).
BRCA-P is a randomised, double-blind, placebo controlled, phase 3 trial in adult women carrying a germline pathogenic variant in BRCA1. Eligible participants include women with a germline pathogenic variant in BRCA1, aged 25-55 years, unaffected by breast or ovarian cancer, not pregnant or currently trying to become pregnant, have not had preventive prophylactic mastectomy and are not currently taking a preventive medication like tamoxifen. In total, 2,918 subjects will be recruited including 300 from Australia.Women will be randomised (1:1 ratio) to receive either denosumab 120 mg or placebo via sub cutaneous administration every 6 months for 5 years. The study, is being led by the ABCSG (Austria) and is being conducted in Australia by Breast Cancer Trials (BCT) in collaboration with kConFab.
In addition to exploring denosumab as a breast cancer prevention drug, BRCA-P will also study the effect of denosumab on the incidence of ovarian and other cancers. This study will also determine its safety and tolerability, effect on bone health, immune subsets, circulating tumour DNA and describe patient reported outcomes.
The BRCA-P trial is actively recruiting participants. The recruitment target has not been reached.
We hope the results of the BRCA-P prevention study will provide a non-surgical option for cancer risk reduction in women with a germline BRCA1 pathogenic variant. This study will also pave the way for future prevention studies and will inform on the role of monitoring circulating tumour DNA and immune subsets, clinical examination and the psychological impact of these assessments.