RANK Ligand Inhibition: A Potential Chemoprevention Strategy for Women at High Genetic Risk of Breast Cancer

Women carrying BRCA1/2 mutations have an elevated lifetime risk of developing breast cancer of 40-60%. Risk management options for mutation carriers include intensive breast cancer screening with clinical breast exam, mammography, and breast MRI, risk-reducing surgeries such as prophylactic mastectomy. The prevalence of BRCA mutations in the USA is believed to be approximately 0.2%-0.3%, equating to ~400,000 females alone who are at high lifetime risk (~70%) of developing breast cancer. These tumors often arise at an early age, with the peak relative risk occurring before 40 years of age. Heightened community awareness, and coordinated efforts to identify BRCA1/2 mutation carriers, together with increased access to genetic testing has led to a growing number of healthy mutation carriers facing serious clinical management issues. Asymptomatic BRCA mutation carriers have few effective breast cancer prevention options beyond bilateral prophylactic mastectomy (BPM). Although BPM will reduce the risk of breast cancer, only about 20-25% of mutation carriers pursue this option. Potential breast cancer preventive strategies including selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, have been shown to reduce the risk of ER+ breast cancer in moderate- to high-risk women. Data for BRCA mutation carriers are inconclusive and patient uptake of tamoxifen for prevention has been poor. Thus, the identification of a safe, effective and acceptable prevention strategy (particularly for ER-negative breast cancer) remains a huge unmet area of need for the field. Receptor activator of nuclear factor kappa-B ligand (RANKL) is an osteoclast differentiation factor that is essential for the development and activation of osteoclasts. RANKL is secreted by progesterone receptor (PR)-positive epithelial cells in response to progesterone, and acts as a paracrine factor on the estrogen receptor (ER)/PR-negative progenitor cells through its receptor RANK. RANK is expressed in the luminal progenitor subset of cells and there is a significantly increased proportion of RANK-positive luminal progenitors in mammary tissue from BRCA1 mutation carriers when compared to BRCA1 WT controls. Furthermore, RANK and RANKL expressions are upregulated in BRCA1 breast tumors. In mouse models of Brca1-driven breast cancer, RANK signaling has been shown to promote mammary tumor formation and progression while inhibition of RANKL signaling reduces mammary tumorigenesis. These findings have formed the basis of an international, randomized, double blind, placebo-controlled, multi-center international phase 3 breast cancer prevention study evaluating the role of the RANKL inhibitor denosumab in preventing or delaying breast tumors in BRCA1 mutation carriers (‘BRCA-P’, ABCSG-50). BRCA-P will solely focus on BRCA1 mutation carriers since a role for the RANKL/RANK signaling pathway in BRCA2 mutation carriers is less well understood. To date, a role for RANKL inhibition has not been explored in Brca2-deficient mouse models. This is important, as positive results could inform the design of the BRCA-P prevention study by expanding the inclusion criteria to include BRCA2 mutation carriers. Recent observations suggest that the progesterone-RANK-OPG system may be deregulated in both BRCA1 and BRCA2 mutation carriers: mutation carriers were found to have higher levels of serum progesterone during the luteal phase of the menstrual cycle compared to non-carriers. Hence, the potential efficacy of RANKL inhibition in delaying tumor onset will be investigated in a Brca2-deficient mouse mammary tumor model. The positive findings can pave the way for the inclusion of BRCA2 carriers in the clinical trials.The overarching goal of this task order is to evaluate chemopreventive efficacy of RANKL inhibitor in a preclinical model of BRCA2 driven breast cancer.