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

Abstract

Background: The association of fitness with cancer risk is not clear.

Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.

Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O₂⋅min^-1⋅kg^-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), 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, a 0.5 SD increase in genetically predicted O₂⋅min^-1⋅kg^-1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.

Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

Fig. 1. Associations of cardiorespiratory respiratory fitness and incident cancer risk without and with body fat adjustment.

HRs and 95% CIs estimated using Cox regression models adjusted for age, sex, self-reported racial/ethnic group, Townsend index of deprivation, education, employment status, smoking status, alcohol consumption, red and processed meat consumption, fish consumption, fruit and vegetable consumption, salt consumption, diabetes status, hypertension, medication use (beta blockers, calcium channel blockers, ACE inhibitors, diuretics, bronchodilators, lipid-lowering agents, iron deficiency agents, non-steroidal anti-inflammatory drugs, metformin). Female reproductive cancers (breast, endometrial, and ovarian) were additionally adjusted for age at menarche, age at menopause, parity, hormone replacement therapy usage, and oral contraceptives. Associations with and without adjustment for either continuous BMI (for models with VO₂max scaled by total-body mass) or fat mass (for models with VO₂max scaled by fat-free mass). ACE Angiotensin-converting enzyme, BMI body mass index, CI confidence interval, HR hazard ratio.

Fig. 2. Sex-stratified associations of cardiorespiratory respiratory fitness and incident cancer risk without and with body fat adjustment.

HRs and 95% CIs estimated using Cox regression models adjusted for age, sex, self-reported racial/ethnic group, Townsend index of deprivation, education, employment status, smoking status, alcohol consumption, red and processed meat consumption, fish consumption, fruit and vegetable consumption, salt consumption, diabetes status, hypertension, medication use (beta blockers, calcium channel blockers, ACE inhibitors, diuretics, bronchodilators, lipid-lowering agents, iron deficiency agents, non-steroidal anti-inflammatory drugs, metformin). Associations with and without adjustment for either continuous BMI (for models with VO₂max scaled by total-body mass) or fat mass (for models with VO₂max scaled by fat-free mass). ACE Angiotensin-converting enzyme, BMI body mass index, CI confidence interval, HR hazard ratio.

Fig. 3. Associations of genetically predicted cardiorespiratory respiratory fitness and cancer risk.

Associations were estimated using the inverse variance weighted method. CI confidence interval, ER estrogen receptor, OR odds ratio.