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

Objective: To examine the joint associations of cardiorespiratory fitness (CRF) and polygenic risk with incident breast cancer and whether higher CRF attenuates excess breast cancer risk associated with high polygenic risk in postmenopausal women. Methods: This 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 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). Results: During 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 breast cancer risk in a dose-response manner. Although multiplicative interaction was not significant, higher CRF attenuated excess risk associated with high polygenic risk on the additive scale (RERI -0.84, 95% CI -1.56 to -0.12). This attenuation was particularly evident among women aged [&ge;]60 years and those with BMI [&ge;]25 kg/m2. Conclusion: Higher CRF was associated with a lower breast cancer risk and attenuated excess breast cancer risk associated with high polygenic risk, particularly among postmenopausal women at elevated baseline risk, supporting a potential role for improving CRF in genetically informed breast cancer prevention.