Background and objective Genetic predisposition and menopausal hormone therapy (MHT) are established risk and preventive factors for colorectal cancer (CRC), respectively. We aimed to evaluate the joint associations of a polygenic risk score (PRS) and MHT on CRC risk for informing CRC prevention.

Methods We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent from 38 studies. MHT use was assessed as the use of any MHT, estrogen-only (E-only) or combined estrogen-progestogen (E+P) therapy at reference time. A PRS based on 141 genetic variants previously identified by genome-wide association studies of CRC was modelled as categorical variable in quartiles and also as per-standard deviation difference between PRS and minimum of PRS [(PRS-min(PRS))/SD(PRS)] (PRS.minsd). Multiplicative interaction between PRS and MHT was evaluated using standard logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI).

Results The use of any MHT as well as E+P and E-only were associated with reduced CRC risk (Odds ratio [OR] 0.70, 0.71, 0.65, respectively). PRS was associated with increased CRC risk, whether as continuous variable (PRS.minsd) (OR 1.53) or in quartiles (OR 1.49, 1.92, 2.87, respectively). We identified statistically significant negative multiplicative interaction (OR: 0.92; 95%CI: 0.87, 0.98) as well as negative additive interaction (RERI: -0.13; 95%CI: -0.15, -0.10) between PRS.minsd and any MHT use. Results were limited to additive interactions with PRS.minsd for E-only use (RERI: -0.14; 95%CI: -0.18, -0.11) and E+P use (RERI: -0.12; 95%CI: -0.16, -0.08). The magnitude of negative additive interactions increased with higher quartiles of PRS for all MHT variables and was consistently significant for the highest quartile compared to the lowest quartile of PRS for any MHT use (RERI: -0.78; 95%CI: -1.03, -0.52), E-only use (RERI: -0.78; 95%CI: -1.18, -0.39), and also E+P use (RERI: -0.53; 95%CI: -0.96, -0.10). Negative multiplicative interaction was also observed for higher PRS quartiles of all MHT variables but significant only for the highest quartile with E-only use (OR: 0.73; 95%CI: 0.55, 0.97). These negative interactions on both multiplicative and additive scales indicate that MHT has a relatively more protective effect on CRC risk for those women with larger PRS scores. For example, compared to women in the lowest PRS quartile with no MHT use, the risk of CRC for women in higher quartiles of PRS was more strongly reduced with MHT use (ORPRS.Q3+noMHT: 1.93 vs ORPRS.Q3+MHT: 1.38, OR MHT/noMHT in PRS.Q3: 0.71; ORPRS.Q4+noMHT: 2.81 vs ORPRS.Q4+MHT: 1.77, OR MHT/noMHT in PRS.Q4: 0.63).

Conclusions The protective effect of MHT use on the risk of CRC is stronger in women with higher genetic risk. Risk prediction models incorporating PRS may need to account for potential effect modification by non-genetic risk factors.

Citation Format: Yu Tian, Yi Lin, Andre E. Kim, Stephanie A. Bien, Polly A. Newcomb, Graham Casey, Elizabeth A. Platz, Loic Le Marchand, Peter T. Campbell, Hermann Brenner, Michael Hoffmeister, Feng Guo, Xuechen Chen, Marc J. Gunter, Niki Dimou, Stephen B. Gruber, Andrew T. Chan, Amit D. Joshi, Sonja I. Berndt, Emily White, Victor Moreno, Ross L. Prentice, Ulrike Peters, William Gauderman, Li Hsu, Jenny Chang-Claude. Association of polygenic risk score and menopausal hormone therapy for colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 818.