Project Funding Details

There are currently few management options that reduce breast cancer risk for BRCA1 and BRCA2 mutation carriers. Safe and effective prevention strategies beyond prophylactic mastectomy are urgently required. We previously discovered an abnormal population of 'progenitor' cells (the descendants of stem cells) in breast tissue from BRCA1 mutation carriers, suggesting they are the culprits that give rise to breast cancer. Recently, we discovered a key messenger, called RANKL, which activates progenitors and demonstrated that inhibition of RANKL switches them off. Notably, we also found that RANK (the target of RANKL) is present much more frequently (4-fold) in BRCA1 tumours. These findings raise the very real prospect that targeting RANKL might represent a novel breast cancer prevention strategy for BRCA1 mutation carriers, and possibly other high-risk women. Denosumab is an anti-RANKL drug approved in the clinic to treat bone metastases. Our findings suggest that it might have a ‘repurpose use’ for breast cancer prevention. Our goal is to pilot denosumab therapy in healthy BRCA1 and BRCA2 gene carriers, to determine whether RANKL inhibition switches off proliferative activity in breast tissue and modifies breast density (a marker of risk), as determined by MRI, and to ensure it is tolerable and safe. The BRCA-D study will recruit women planning prophylactic mastectomy (or who agree to undergo paired biopsies). Women will receive 4 doses of denosumab over 3 months. This study will provide proof-of-principle findings essential for enabling progression to an international randomised phase 3 prevention study, with long-term ramifications for improving clinical outcome.