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

## TL;DR

Women with a genetic predisposition to higher body weight face a 15% higher risk of death after breast cancer, but walking more can help reduce this risk.

## Contribution

This study shows that genetic predisposition to higher BMI increases mortality risk in breast cancer survivors, and suggests lifestyle interventions can mitigate this risk.

## Key findings

- Women in the top tertile of BMI polygenic score had a 15% higher mortality risk compared to those in the bottom tertile.
- Walking an additional 1.7 hours per week can reduce the mortality risk associated with a high BMI polygenic score.
- Genetic predisposition to higher BMI was linked to a higher prevalence of BMI ≥30 in breast cancer survivors.

## Abstract

Is genetic predisposition to excess body weight associated with increased risk of mortality in breast cancer survivors?

In this cohort study of 4177 breast cancer survivors, those with a polygenic score for body mass index in the top tertile had a 15% higher mortality risk compared with those in the bottom tertile of the score. A greater number of hours of walking per week was needed to mitigate the inherited susceptibility.

These results suggest that genetic predisposition to excess body weight is associated with increased risk of mortality among breast cancer survivors and personalized lifestyle recommendations that incorporate genetic predisposition should be considered.

This cohort study investigates whether there is an association between a genetic predisposition to a greater body mass index and mortality risk among US women who survived nonmetastatic breast cancer.

Excess body weight, which is associated with poor survival after breast cancer (BC) diagnosis, is a heritable trait.

To investigate whether genetic predisposition to excess body weight is associated with the risk of mortality among BC survivors.

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.

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.

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.

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.

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.