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 O2⋅min-1⋅kg-1 total-body mass and ml O2⋅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 O2⋅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 O2⋅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.

Unraveling the link between cardiorespiratory fitness and cancer: a state-of-the-art review

“…The associations were similar across race categories [77]. Watts and colleagues [73] recently showed that a one-MET increase in CRF was associated with a 4% reduction in breast cancer (HR = 0.96, 95% CI, 0.92-0.99), but the association was significantly attenuated on adjustment for BMI.…”

“…Ekblom-Bak and colleagues [72] in a 2023 prospective cohort analysis of ~ 180,000 Swedish men showed that higher CRF levels were associated with a lower risk of lung cancer mortality (HR = 0.41, 95% CI, 0.17-0.99) comparing the highest (> 13 METs) vs. lowest CRF (≤ 7 METs) categories; there was no strong evidence of an association for lung cancer incidence [72]. Watts and colleagues [73] in their recent 2024 evaluation of the UK Biobank comprising 72,572 participants showed no evidence of an association between CRF and lung cancer risk. All studies reviewed accounted for smoking status in their analyses.…”

“…There was no strong evidence of an association for colon cancer mortality [72]. Watts and colleagues [73] in their 2024 evaluation of the UK Biobank showed that a one-MET increase in CRF was associated with a 6% reduction in colorectal cancer (HR = 0.94, 95% CI, 0.90-0.99), but the association was significantly attenuated on adjustment for BMI.…”

“…Watts and colleagues [73] in their 2024 evaluation of the UK Biobank showed that a one-MET increase in CRF was associated with a 19% reduction in endometrial cancer (HR = 0.81, 95% CI, 0.73-0.89); the association was attenuated on adjustment for BMI.…”

“…We identified only one study that met the criteria. Watts and colleagues [73] employed the UK Biobank and independent genome-wide association study (GWAS) data from international consortia to explore the observational and genetic associations between CRF and several site-specific cancers. The genetic instrument employed for CRF included 14 fitness and 149 fitness and resting heart rate (RHR) genome-wide significant variants [73].…”