Cardiorespiratory fitness, polygenic risk, and breast cancer in postmenopausal women: a prospective cohort study

BackgroundAlthough higher cardiorespiratory fitness (CRF) has been associated with lower breast cancer risk, whether CRF modifies the association between polygenic risk and breast cancer remains unclear. We examined the joint associations of cardiorespiratory fitness (CRF) and polygenic risk with incident breast cancer and whether higher CRF is associated with attenuation of excess breast cancer risk conferred by high polygenic risk in postmenopausal women. MethodsThis prospective cohort study included postmenopausal women from the UK Biobank. CRF was estimated using a submaximal cycle ergometer test, and genetic susceptibility was assessed using a breast cancer polygenic risk score (PRS). Associations of CRF and PRS with incident breast cancer were examined using Cox proportional hazards models with attained age as the underlying time scale. Analyses were conducted overall and stratified by age (40-59 and [&ge;]60 years) and body mass index (BMI) (<25 and [&ge;]25 kg/m2). Multiplicative and additive interactions were evaluated, with additive interaction assessed using the relative excess risk due to interaction (RERI). ResultsDuring a median follow-up of 10.7 years, 500 incident breast cancer cases were identified among 13,907 postmenopausal women. Higher CRF was associated with a lower incidence of breast cancer in a dose-response manner, whereas higher PRS was associated with progressively higher risk of incident breast cancer. Although multiplicative interaction was not significant, higher CRF was associated with attenuation of excess breast cancer risk conferred by high polygenic risk on the additive scale (RERI -0.88, 95% CI -1.57 to -0.18). This attenuation was particularly evident among women aged [&ge;]60 years and those with BMI [&ge;]25 kg/m2. ConclusionsHigher CRF was associated with a lower breast cancer risk and attenuation of excess breast cancer risk conferred by high polygenic risk, particularly among postmenopausal women at elevated baseline risk. These findings support further investigation of CRF as a potentially modifiable factor among women with elevated polygenic risk.