Abstract C102: Interactions of a polygenic risk score and modifiable lifestyle factors for breast cancer in the Multiethnic Cohort

Abstract Purpose: A polygenic risk score (PRS) has demonstrated great potential in stratifying breast cancer risk in non-African ancestry populations. Several modifiable lifestyle risk factors have been identified for breast cancer, although little is known regarding their effects among women with varying genetic risk. Methods: In the Multiethnic Cohort (MEC), we conducted a nested case-control study of 3,229 breast cancer cases and 3,921 controls from five major racial/ethnic groups (White, African American, Latino, Japanese American, and Native Hawaiian). We examined a PRS of 313 variants in association with breast cancer risk and evaluated the interaction with selected modifiable lifestyle factors on the risk of breast cancer. The modifiable lifestyle factors examined included body mass index (BMI), physical activity, smoking, alcohol consumption, and five diet quality indexes, such as the Healthy Eating Index (HEI)-2010, the Alternative Healthy Eating Index (AHEI)-2010, the alternate Mediterranean Diet score (aMED), the Dietary Approaches to Stop Hypertension score (DASH), and the Dietary Inflammatory Index (DII). Results: The 313-variant PRS was strongly associated with breast cancer risk across the five racial/ethnic groups, with per standard deviation (SD) odds ratios (OR) of 2.07 (95% CI=1.63-2.63) in Native Hawaiian, 1.72 (95% CI=1.54-1.92) in White, 1.56 (95% CI=1.36-1.77) in Latina, 1.45 (95% CI=1.31-1.60) in Japanese American, and 1.32 (95% CI=1.20-1.44) in African American women. For the lifestyle factors, BMI (OR=0.84, 95% CI=0.75-0.93, for <25 vs. ≥ 25 kg/m2) and alcohol consumption (OR=1.14, 95% CI=1.02-1.26 for drinkers vs. non-drinkers) were significantly associated with breast cancer risk. We also observed a suggestive positive association for smoking (OR=1.14, 95% CI=0.98-1.32 for current vs. never/past smokers) and a suggestive inverse association for AHEI-2010 (OR=0.96, 95%CI=0.91-1.01 per SD increment). No association was observed for physical activity or other dietary indexes. We found that the association of BMI and AHEI-2010 with breast cancer risk depended on PRS. Specifically, among women with above-average genetic risk (50-100% of PRS), the OR of breast cancer was 0.77 (95% CI=0.66-0.88) for women with a BMI <25 kg/m2 (vs. BMI³25 kg/m2), while among women with below-average genetic risk (0-50% of PRS) the OR was 0.96 (95%CI=0.81-1.14, P-heterogeneity=0.04). In contrast, a significant inverse association of AHEI-2010 (per SD) with breast cancer risk was only observed in women with below-average genetic risk (OR=0.90, 95%=0.83-0.97) but not among women with above-average genetic risk (OR=1.00, 95%CI=0.94-1.08, P-heterogeneity=0.04). Conclusions: In line with previous reports, the 313-variant PRS was effective in stratifying breast cancer risk, with diminished transferability for women of African ancestry. Our findings also suggest that maintaining a healthy BMI may offset the genetic risk of breast cancer, while adhering to a healthy dietary pattern may further reduce risk for women with lower genetic risk. Citation Format: Alisha Chou, Fei Chen, Peggy Wan, Xin Sheng, Song-Yi Park, Daniel O. Stram, Lynne R. Wilkens, Loic Le Marchand, Christopher A. Haiman. Interactions of a polygenic risk score and modifiable lifestyle factors for breast cancer in the Multiethnic Cohort [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C102.