In an observational cohort study published in JAMA Network Open, Bodelon et al examined whether inherited susceptibility to excess body weight influences long-term survival among breast cancer survivors. Using a polygenic score for body mass index (BMI), the investigators sought to determine whether a genetic predisposition to higher body weight contributes to mortality risk independent of measured BMI and whether modifiable behaviors such as walking might mitigate this inherited risk.
Study Details
The analysis was conducted as part of the Cancer Prevention Study–II Nutrition Cohort, in which participants from 21 U.S. states completed baseline surveys between 1992 and 1993 and were followed with biennial questionnaires beginning in 1997. The analytical population consisted of 4,177 women who were diagnosed with a first primary, nonmetastatic breast cancer between 1992 and 2017, had available genetic data, and were postmenopausal at diagnosis. Analyses were restricted to women of genetically determined European ancestry. Median age at diagnosis was 71.5 years (interquartile range [IQR] = 66.3–76.7 years).
Information on demographic factors, lifestyle behaviors, and clinical characteristics was obtained from surveys and medical records. BMI was calculated from self-reported height and weight closest to the time of diagnosis. Physical activity was assessed by self-reported hours of walking per week.
Participants were followed from diagnosis until death or December 31, 2020. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) for all-cause mortality, as well as breast cancer–specific and cardiovascular disease–specific mortality, in relation to a polygenic score for body mass index (BMI-PGS). The investigators also conducted mediation analyses to assess the extent to which BMI explained associations between BMI-PGS and mortality, and spline models were used to estimate the amount of walking needed to offset genetic risk.
Key Findings
During a median follow-up of 14.5 years (IQR = 9.7–19.7 years), 2,114 women (50.6%) died, with 16.8% of deaths attributed to breast cancer and 18.9% to cardiovascular disease. Women in the highest tertile of the BMI-PGS were more likely to have obesity at diagnosis compared with those in the lowest tertile, but substantial overlap in BMI categories was observed across genetic risk groups.
An increase of one standard deviation in the BMI-PGS was associated with a 7% higher risk of all-cause mortality (HR = 1.07; 95% confidence interval [CI] = 1.02–1.12), and women in the highest tertile had a 15% increased risk of all-cause mortality compared with those in the lowest tertile. The 10-year cumulative mortality rate was 23.1% (95% CI = 20.9%–25.4%) in the highest tertile vs 18.6% (95% CI = 16.5%–20.7%) in the lowest. Associations with breast cancer–specific and cardiovascular mortality were similar in magnitude but did not reach statistical significance.
A longer time spent walking was associated with reduced mortality, regardless of genetic predisposition, although women with higher genetic risk required more walking to achieve a mortality risk comparable to those with lower genetic risk. Those in the highest BMI-PGS tertile needed to walk approximately 2.9 hours per week—about 1.7 hours more than women in the lowest tertile—to reach a similar risk level.
The authors concluded: “In this cohort of nonmetastatic [breast cancer] 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.”
Clara Bodelon, PhD, MD, of the Department of Population Science, American Cancer Society, Atlanta, Georgia, is the corresponding author for the JAMA Network Open article.
DISCLOSURE: The study was funded by The American Cancer Society. For full disclosures of the study authors, visit jamanetwork.com.
