Plasma osteoprotegerin and breast cancer risk in BRCA1 and BRCA2 mutation carriers

// Lovisa Odén 1, 2 , Mohammad Akbari 1, 3 , Tasnim Zaman 1, 5 , Christian F. Singer 4 , Ping Sun 1 , Steven A. Narod 1, 3 , Leonardo Salmena 5, 6 , Joanne Kotsopoulos 1, 3 1 Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada, M5S 1B2 2 Karolinska Institutet, SE-171 77, Stockholm, Sweden 3 Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada, M5T 3M7 4 Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Spitalgasse 23, 1090 Wien, Vienna, Austria 5 Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle Toronto, ON, Canada, M5S 1A8 6 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, M5G 2M9 Correspondence to: Joanne Kotsopoulos, email: joanne.kotsopoulos@wchospital.ca Keywords: osteoprotegerin (OPG), BRCA1/2, chemoprevention, breast cancer, receptor activator of nuclear factor κB (RANKL) Received: September 02, 2016 Accepted: November 09, 2016 Published: November 22, 2016 ABSTRACT Emerging evidence suggests a role of receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) signaling in breast cancer development. Lower osteoprotegerin (OPG) levels, the endogenous decoy receptor for RANKL which competes with RANK for binding of RANKL, has been reported among BRCA mutation carriers. Whether low OPG levels contribute to the high breast cancer risk in this population is unknown. OPG concentrations were measured in plasma of 206 cancer-free BRCA mutation carriers using an enzyme-linked immunosorbent assay. Subjects were categorized as high vs. low based on the median of the entire cohort (95 ng/mL) and followed for a new diagnosis of breast cancer. Cumulative incidence by baseline plasma OPG concentration was estimated using Kaplan-Meier survival analysis. Cox proportional hazards models were used to estimate the adjusted hazard ratios for the association between plasma OPG and breast cancer risk. Over a mean follow-up period of 6.5 years (range 0.1–18.8 years), 18 incident breast cancer cases were observed. After ten years of follow-up, the cumulative incidence of breast cancer among women with low OPG was 21%, compared to 9% among women with high OPG ( P -log rank = 0.046). After multivariate adjustment, women with high plasma OPG had a significantly decreased risk of developing breast cancer, compared to women with low OPG (HR = 0.25; 95%CI 0.08–0.78; P = 0.02). These data suggest that low OPG levels are associated with an increased risk of BRCA -associated breast cancer. Targeting RANK signalling may represent a plausible, non-surgical prevention option for BRCA mutation carriers.