Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study
Authors: Watts Eleanor L. , Gonzales Tomas I. , Strain Tessa , Saint-Maurice Pedro F. , Bishop D. Timothy , Chanock Stephen J. , Johansson Mattias , Keku Temitope O. , Le Marchand Loic , Moreno Victor , Newcomb Polly A. , Newton Christina C. , Pai Rish K. , Purdue Mark P. , Ulrich Cornelia M. , Smith-Byrne Karl , Van Guelpen Bethany ,   The PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Eeles Rosalind A. , Haiman Christopher A. , Kote-Jarai Zsofia , Schumacher Fredrick R. , Benlloch Sara , Olama Ali Amin Al , Muir Kenneth R. , Berndt Sonja I. , Conti David V. , Wiklund Fredrik , Chanock Stephen J. , Wang Ying , Tangen Catherine M. , Batra Jyotsna , Clements Judith A. ,   APCB BioResource (Australian Prostate Cancer BioResource), Grönberg Henrik , Pashayan Nora , Schleutker Johanna , Albanes Demetrius , Weinstein Stephanie J. , Wolk Alicja , West Catharine M. L. , Mucci Lorelei A. , Cancel-Tassin Géraldine , Koutros Stella , Sørensen Karina Dalsgaard , Grindedal Eli Marie , Neal David E. , Hamdy Freddie C. , Donovan Jenny L. , Travis Ruth C. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry S. , Lu Yong-Jie , Giles Graham G. , MacInnis Robert J. , Kibel Adam S. , Vega Ana , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Nielsen Sune F. , Brenner Hermann , Maier Christiane , Kim Jeri , John Esther M. , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Castelao Jose Esteban , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa , Pandha Hardev , Thibodeau Stephen N. , Hunter David J. , Kraft Peter , Blot William J. , Riboli Elio , Day Felix R. , Wijndaele Katrien , Wareham Nicholas J. , Matthews Charles E. , Moore Steven C. , Brage Soren 
Published: December 2023

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.