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 ≥60 years) and body mass index (BMI) (<25 and ≥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 ≥60 years and those with BMI ≥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.

What is already known on this topic

Higher cardiorespiratory fitness (CRF) is associated with a lower risk of breast cancer.

Polygenic risk scores identify women at elevated inherited risk of breast cancer.

It remains unclear whether higher CRF can mitigate the impact of genetic susceptibility on breast cancer risk.

What this study adds

Higher CRF was associated with lower breast cancer incidence in postmenopausal women.

Higher CRF attenuated excess breast cancer risk associated with high polygenic risk on the additive scale.

This attenuation was particularly evident among women aged ≥60 years and those with overweight or obesity.

How this study might affect research, practice or policy

Improving CRF may help reduce breast cancer risk among postmenopausal women at elevated genetic risk.

CRF assessment may support risk stratification and personalised prevention strategies.

Promoting fitness-enhancing behaviours may complement genetic risk assessment in breast cancer prevention.

The authors have declared no competing interest.

This study was financially supported by the National Natural Science Foundation of China (No. 32371228), the Key Research and Development Program of Shaanxi Province (No. 2025SF-YBXM-367), Fundamental Research Funds of Xi'an Jiaotong University (xtr052023011).

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This research was conducted using the UK Biobank Resource under application number 185057. UK Biobank received ethical approval from the North West Multi-centre Research Ethics Committee (REC reference: 11/NW/0382), and all participants provided written informed consent.

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