Abstract 601: Early pregnancy serum sRANKL, OPG, and TRAIL and maternal breast cancer risk: Results from the Finnish Maternity Cohort
Authors: Sarink Danja , Johnson Theron , Surcel Helja-Marja , Kaaks Rudolf , Fortner Renée Turzanski 
Published: August 2019

Abstract
The Receptor Activator of Nuclear Factor kappa-B (RANK)-axis mediates structural changes in the breast during pregnancy in preparation for lactation, but is also implicated in breast tumor development. The RANK-axis includes RANK, its ligand (RANKL) and osteoprotegerin (OPG). OPG is the decoy receptor for RANKL and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL). Based results from experimental and epidemiologic studies, we hypothesized that relatively high serum concentrations of RANK-axis members in early pregnancy would be associated with higher risk of breast cancer in the mother, with differential effects in estrogen (ER)+ and progesterone receptor (PR)+ and ER-/PR- disease. A case-control study including 288 case-control sets (165 ER+/PR+, 79 ER-/PR-) was nested in the Finnish Maternity Cohort. Women eligible for this study donated a blood sample at age ≤40 years and ≤140 days gestation age (GA) in a primiparous term pregnancy; cases were diagnosed within 10 years of this pregnancy. Serum OPG and TRAIL were measured using an electrochemiluminescence assay, and sRANKL (soluble RANKL) using an enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using conditional logistic regression adjusted for GA at blood collection. Relatively high sRANKL concentrations were associated with higher risk of ER+/PR+ breast cancer (Tertile3vs.1, OR=2.08 [1.25-3.44]) (Table); this association was similar after adjustment for OPG levels. sRANKL concentrations were not associated with ER-/PR- disease, and we observed no associations for OPG and TRAIL. In line with previous studies in non-pregnant women, we provide the first evidence for an association between early pregnancy sRANKL and risk of breast cancer in the decade following pregnancy. Relatively high circulating sRANKL concentrations in early pregnancy may identify women at increased risk of breast cancer subsequent to pregnancy.
Table.Serum concentrations of sRANKL, OPG and TRAIL in early pregnancy and breast cancer risk by ER/PR subtype: results from the Finnish Maternity Cohort.Tertiles123ptrendaORlog2phetbsRANKL, cut points (pmol/L)≤ .00050.005 - 0.09&gt; 0.09Full populationCases/Controls86/18199/181103/180288/542OR (95% CI)Ref.1.27 (0.88-1.83)1.42 (0.99-2.06)0.051.14 (1.00-1.29)0.36ER+/PR+Cases/Controls43/11461/10361/93165/310OR (95% CI)Ref.1.76 (1.08-2.88)2.08 (1.25-3.44)0.031.21 (1.02-1.44)ER-/PR-Cases/Controls27/4624/5228/5379/151OR (95% CI)Ref.0.89 (0.45-1.76)1.03 (0.52-2.06)0.451.09 (0.87-1.36)OPG, cut points (pmol/L)≤ 6.946.94 - 8.62&gt; 8.62Full populationCases/Controls c83/16773/166104/166260/499OR (95% CI)Ref.0.85 (0.57-1.26)1.21 (0.82-1.79)0.641.10 (0.73-1.65)0.99ER+/PR+Cases/Controls53/9842/9756/94151/289OR (95% CI)Ref.0.77 (0.46-1.28)1.08 (0.65-1.82)0.991.00 (0.58-1.70)ER-/PR-Cases/Controls19/4523/4129/5171/137OR (95% CI)Ref.1.36 (0.61-3.03)1.29 (0.60-2.77)0.950.98 (0.45-2.12)TRAIL, cut points (pmol/L)≤ 0.400.40 - 1.07&gt; 1.07Full populationCases/Controls c93/16679/16688/166258/492OR (95% CI)Ref.0.86 (0.59-1.26)0.93 (0.65-1.34)0.620.93 (0.71-1.22)0.74ER+/PR+Cases/Controls54/9542/9655/98150/285OR (95% CI)Ref.0.73 (0.44-1.21)0.94 (0.59-1.51)0.930.99 (0.70-1.40)ER-/PR-Cases/Controls24/4727/4720/4270/134OR (95% CI)Ref.1.09 (0.55-2.16)0.91 (0.45-1.84)0.690.90 (0.55-1.53)a ptrend based on log2-transformed sRANKL and OPG concentrations; b pheterogeneity comparing ER+/PR+ to ER-/PR- subtypes, based on log2-transformed sRANKL concentrations (244 case-sets); c 28 case sets (OPG) and 30 case sets (TRAIL) missing concentrations due to equipment failure.
Citation Format: Danja Sarink, Theron Johnson, Helja-Marja Surcel, Rudolf Kaaks, Renée Turzanski Fortner. Early pregnancy serum sRANKL, OPG, and TRAIL and maternal breast cancer risk: Results from the Finnish Maternity Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 601.