Abstract P036: Circulating osteoprotegerin levels and breast cancer risk among women with a BRCA1 mutation: A prospective study
Authors: Kim Shana J. , Zaman Tasnim , Uzelac Aleksandra , Sun Ping , Lubinski Jan , Narod Steven A. , Salmena Leonardo , Kotsopoulos Joanne 
Published: January 2023

Abstract
Background: Upregulation of the receptor activator of nuclear factor κB (RANK) pathway has been implicated in the pathogenesis of BRCA1-associated breast cancer, and pharmacologic inhibition of the RANK pathway has been shown to suppress BRCA1-mammary tumorigenesis in animal studies. Osteoprotegerin (OPG) is the endogenous decoy receptor for RANK-ligand (RANKL) that inhibits RANK/RANKL-signaling. Lower levels of circulating OPG have been reported among women with a BRCA1 pathogenic variant (mutation). Thus, it is of interest to evaluate the association between circulating OPG and breast cancer as a potential novel biomarker of risk. Objective: To prospectively investigate the association between circulating OPG levels and breast cancer risk among women with a BRCA1 mutation. Methods: Eligible women from an on-going longitudinal study with a biobanked blood sample were included and had a confirmed BRCA1 mutation, no previous history of cancer, and no preventive bilateral mastectomy. Self-reported biennial questionnaires collected detailed information on key risk factors, screening, surgery, and cancer incidence. Serum OPG (pg/ml) was quantified using an enzyme-linked immunosorbent assay (ELISA). The exposure was dichotomized into high vs. low OPG level using the median OPG value in the entire cohort (low: ≤79.2 vs. high: &gt;79.2 pg/ml) and continuously (per 10-unit increase). Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of breast cancer by OPG level. The multivariable model adjusted for age, breastfeeding, smoking history, and coffee consumption. Results: There was a total of 662 BRCA1 mutation included in this prospective analysis with a mean age of 40.3 years (SD 12.1). Over a mean follow-up of 5.6 years (range 0.0-11.9), 49 incident breast cancers were diagnosed. Among women with low OPG, there were 31 incident cases compared to 18 incident cases among women with high OPG. Women with high OPG levels had a lower risk of developing breast cancer (HR 0.57; 95% CI 0.32-1.04; P value 0.07) compared to those with low OPG levels. Breast cancer risk decreased by a factor of 0.91 for every 10-unit increase in circulating OPG concentration (95% CI 0.84-1.00; P value 0.04). Conclusion: These findings suggest an inverse association between OPG levels and breast cancer risk among women with a BRCA1 mutation. Pending validation, circulating OPG levels may improve current risk prediction models and enhance the identification of women at the highest threshold of cancer risk. This may offer more personalized risk management strategies, and a potential for pharmacologic inhibition of the RANKL-signaling pathway as a novel approach to cancer prevention for high-risk women.
Citation Format: Shana J. Kim, Tasnim Zaman, Aleksandra Uzelac, Ping Sun, Jan Lubinski, Steven A. Narod, Leonardo Salmena, Joanne Kotsopoulos. Circulating osteoprotegerin levels and breast cancer risk among women with a BRCA1 mutation: A prospective study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P036.