Genetic Predisposition to Excess Body Weight and Survival in Women Diagnosed With Breast Cancer.

Importance: Excess body weight, which is associated with poor survival after breast cancer (BC) diagnosis, is a heritable trait. Objective: To investigate whether genetic predisposition to excess body weight is associated with the risk of mortality among BC survivors. Design, Setting, and Participants: This cohort study is part of the Cancer Prevention Study-II Nutrition Cohort, a large study in which participants responded to a survey in 1992 and to biennial follow-up surveys starting in 1997. The cohort includes adults residing in 21 US states. Women diagnosed with a first primary nonmetastatic BC between 1992 and 2017 with genetic data were included in this study. Analyses were restricted to postmenopausal women at the time of cancer diagnosis who had genetically determined European ancestry. Data analysis was conducted from July 2023 to July 2025. Exposure: A polygenic score for body mass index (BMI-PGS), computed using summary statistics from 941 single nucleotide variants reported in a meta-analysis of genome-wide association studies that included approximately 700 000 individuals. Main Outcomes and Measures: Deaths through 2020 were identified via linkage with the National Death Index. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for the association between BMI-PGS and all-cause mortality. Results: This analysis included 4177 women diagnosed with BC. The median (IQR) age at diagnosis was 71.5 (66.3-76.7) years. BC survivors with a BMI-PGS in the top tertile were more likely to have a BMI of 30 or greater (345 [24.8%]) compared with survivors in the lowest tertile (172 [12.4%]). During a median (IQR) follow-up time of 14.5 (9.7-19.7) years, 2114 BC survivors (50.6%) died. Compared with BC survivors in the lowest tertile of the BMI-PGS, those in the highest tertile had a 15% increased risk of all-cause mortality (HR, 1.15, 95% CI, 1.04-1.28). BC survivors with BMI-PGS in the highest tertile needed to walk approximately 1.7 hours per week more to be at a similar risk level as BC survivors in the lowest tertile of the BMI-PGS, which corresponds to approximately an extra 15 minutes of walking each day of the week. Conclusions and Relevance: In this cohort of nonmetastatic BC survivors, women who were genetically predisposed to having a higher BMI were at increased risk of all-cause mortality. Targeted lifestyle recommendations to mitigate their genetic predisposition should be considered to lower this risk.