Abstract 4959: The RANK-axis and breast cancer risk by hormone receptor subtype: Results from the EPIC cohort
Authors: Sarink Danja , Schock Helena , Johnson Theron , collaborators EPIC cohort , Kaaks Rudolf , Fortner Renee T. 
Published: July 2017

Background: Activation of the receptor activator of nuclear factor kappa-B (RANK)-axis promotes mammary tumor development in experimental models. Circulating concentrations of soluble RANK ligand (sRANKL) may influence breast cancer risk via RANK activation; this may be modulated by circulating concentrations of osteoprotegerin (OPG), the decoy receptor for RANKL. sRANKL and breast cancer risk in humans have not previously been investigated.

Methods: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1976 incident invasive breast cancer cases (estrogen receptor positive (ER+), n=1598), matched 1:1 to controls, were included in the analysis. Women were both pre- and postmenopausal at blood collection. Serum sRANKL was quantified using an enzyme-linked immunosorbent assay (ELISA). Serum OPG was quantified using an electrochemiluminescent assay. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using conditional logistic regression.

Results: Associations between sRANKL and breast cancer risk differed by tumor hormone receptor status (phet 0.05). Higher concentrations of sRANKL were suggestively associated with risk of ER+ breast cancer (top vs. bottom quintile OR 1.36 [0.99-1.87]; ptrend 0.31). While results considering the sRANKL/OPG ratio were similar to those for sRANKL alone for hormone receptor positive breast cancer, we saw a suggestive inverse association between the ratio and ER-PR- disease (5th vs. 1st quintile OR 0.60 [0.31-1.16]; ptrend 0.04).

Conclusions: This study provides the first prospective data on sRANKL and breast cancer risk, providing suggestive evidence of a possible association between sRANKL concentrations and breast cancer. High circulating levels sRANKL in the context of low OPG may represent novel risk markers for hormone receptor positive breast cancer.

Table 1.Circulating concentrations of sRANKL and breast cancer risk by hormone-receptor subtype: EPIC nested case-control studyQuintiles12345ptrend*phet*sRANKLER+/PR+Cases/Controls167/198203/183176/192160/157214/190OR (95% CI)ref.1.32 (0.97-1.81)1.12 (0.81-1.54)1.19 (0.85-1.65)1.36 (0.99-1.87)0.310.05ER-/PR-Cases/Controls52/5157/4047/5349/5646/51OR (95% CI)ref.1.58 (0.82-3.04)0.97 (0.51-1.84)0.83 (0.44-1.58)0.74 (0.39-1.40)0.08sRANKL/OPG RatioER+/PR+Cases/Controls146/177175/181186/178184/180224/199OR (95% CI)ref.1.19 (0.85-1.65)1.25 (0.90-1.75)1.22 (0.87-1.70)1.42 (1.01-1.98)0.220.02ER-/PR-Cases/Controls45/4146/4253/4760/6046/60OR (95% CI)ref.1.11 (0.56-2.17)1.09 (0.57-2.09)0.87 (0.45-1.68)0.60 (0.31-1.16)0.04* based on continuous log2-transformed values; Conditional logistic regression models adjusted for: ages at menarche (&lt;12, 13, 14, ≥15, missing), menopause (&lt;44, 44-47, 48-50, 51-52, 53-54, ≥55, missing), and first full-term pregnancy (no FTP, &lt;25, 25-30, ≥30, missing), and number of full-term pregnancies (0, 1, 2, ≥3, missing) and BMI (kg/m2, continuous).

Citation Format: Danja Sarink, Helena Schock, Theron Johnson, EPIC cohort collaborators, Rudolf Kaaks, Renee T. Fortner. The RANK-axis and breast cancer risk by hormone receptor subtype: Results from the EPIC cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4959. doi:10.1158/1538-7445.AM2017-4959