Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study

ABSTRACT Importance The association of cardiorespiratory fitness with cancer risk is not clear. Objective To investigate whether fitness is associated with the risk of diagnosis of common cancers. Design, setting, and participants In observational analyses, we used multivariable-adjusted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 ( N =72,572). In secondary analyses, we used a two-sample Mendelian randomization (MR) framework, with genetically predicted fitness as an instrumental variable derived from UK Biobank study participants and genetic cancer data from international consortia. Odds ratios (ORs) were estimated using the inverse-variance weighted method. Relationships between fitness and cancer may be partially mediated by adiposity, and therefore associations were estimated with and without adjustment for adiposity. Exposures Estimated maximal cardiorespiratory fitness (ml O 2 ⋅min -1 ⋅kg -1 total-body mass and ml O 2 ⋅min -1 ⋅kg -1 fat-free mass). Main outcomes and measures Diagnosis of lung, colon, rectal, endometrial, female breast, and prostate cancer. MR analyses additionally included pancreatic and renal cancers. Results After a median of 11 years of follow-up, 4,290 cancers of interest were diagnosed. A 3.5 ml O 2 ⋅min - 1 ⋅kg - 1 total-body mass increase in fitness (approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR=0.81, 95% CI 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, higher levels of genetically predicted fitness were associated with a lower risk of breast cancer (OR per genetically predicted 0.5 SD increase in ml O 2 ⋅min - 1 ⋅kg - 1 fat-free mass=0.92, 95% CI 0.86-0.98), including estrogen receptor (ER)+ (0.91, 0.84-0.99) and ER-(0.88, 0.80-0.97) subtypes. After adjusting for body fat, both the observational and genetic associations were attenuated. Conclusions and relevance Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Aiming to increase fitness, including via changes in body composition, may be an effective strategy for cancer prevention. KEY POINTS Question: Is cardiorespiratory fitness associated with subsequent risk of cancer diagnosis? Findings: In a prospective cohort study of 73,000 cancer-free participants who completed a submaximal fitness test, we report that higher fitness levels were associated with lower risks of endometrial, colorectal, and breast cancer. Using two-sample Mendelian randomization methods we also found an inverse association with breast cancer. Associations were attenuated following adjustment for adiposity. Meaning: Higher fitness may be associated with reduced risk of certain cancer sites. Aiming to increase fitness, including via changes in body composition, may be an effective strategy for cancer prevention. The role of adiposity in mediating the relationship between fitness and cancer risk is not fully understood, and further research is needed to explore this complex relationship.