# Adolescent cardiorespiratory fitness and risk of cancer in late adulthood: A nationwide sibling-controlled cohort study in Sweden

## TL;DR

Higher cardiorespiratory fitness in adolescence is linked to lower cancer mortality in adulthood, but some cancer diagnoses may be influenced by other factors.

## Contribution

This study uses sibling comparisons to address unobserved familial confounding in the link between adolescent fitness and cancer risk.

## Key findings

- Higher adolescent cardiorespiratory fitness is associated with lower overall cancer mortality in late adulthood.
- The association with prostate and skin cancer diagnoses appears to be influenced by unobserved familial factors.
- Some cancer risks (e.g., kidney, stomach) decrease after accounting for shared familial factors.

## Abstract

Cardiorespiratory fitness has been linked to both lower and higher risks of cancer, but the evidence comes from observational analysis which may be influenced by unobserved confounders and bias processes. We aimed to examine the associations between adolescent cardiorespiratory fitness and risk of cancer in late adulthood while addressing the unknown influence of unobserved familial confounders and diagnostic bias processes.

We conducted a sibling-controlled cohort study with registry linkage based on all Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 and who completed standardized cardiorespiratory fitness testing. The outcomes were overall cancer diagnosis and cancer mortality, and 14 site-specific cancers (diagnosis or death), ascertained using the National Patient Register and Cause of Death Register until 31 December 2023. A total of 1,124,049 men, including 477,453 full siblings, with a mean age of 18.3 years at baseline, were followed until a median (maximum) age of 55.9 (73.5) years, during which 98,410 were diagnosed with cancer and 16,789 died from cancer (41,293 and 6,908 among full siblings respectively). In cohort analysis, individuals in the highest quartile of fitness had a lower risk of overall cancer mortality (adjusted hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.67, 0.76; P < 0.001) compared to the lowest quartile, corresponding to a standardized cumulative incidence (1-Survival) difference of −0.85 (95% CI [−1.00, −0.71]) percentage points at 65 years of age. Individuals in the highest quartile of fitness also had lower risks (HRs ranging from 0.81 to 0.49, incidence differences ranging from −0.13 to −0.32 percentage points; P < 0.001 for all) of rectum, head and neck, bladder, stomach, pancreas, colon, kidney, liver, bile ducts, and gallbladder, esophagus, and lung cancer. Yet, individuals in the highest quartile of fitness had higher risks of prostate (HR: 1.10, 95% CI [1.05, 1.16]; P < 0.001, incidence difference: 0.48 percentage points, 95% CI [0.23, 0.73]) and skin cancer (e.g., non-melanoma HR: 1.44, 95% CI [1.38, 1.50]; P < 0.001, incidence difference: 1.84 percentage points, 95% CI [1.62, 2.05]). Individuals in the highest quartile of fitness had a higher risk of overall cancer diagnosis (HR: 1.08, 95% CI [1.06, 1.11]; P < 0.001, incidence difference: 1.32 percentage points, 95% CI [0.94, 1.70]), results driven by prostate and skin cancer being the most common types of cancer. When comparing full siblings, and thereby controlling for unobserved shared confounders, the lower risk of overall cancer mortality remained (HR: 0.78, 95% CI [0.68, 0.89]; P < 0.001, incidence difference: −0.61 percentage points, 95% CI [−0.93, −0.28]), while the excess risk of prostate (HR: 1.01, 95% CI [0.90, 1.13]; P = 0867, incidence difference: 0.05 percentage points, 95% CI [−0.50, 0.60]), skin (e.g., non-melanoma HR: 1.09, 95% CI [0.99, 1.20]; P = 0.097, incidence difference: 0.40 percentage points, 95% CI [−0.07, 0.87]), and overall cancer diagnosis (HR: 1.00, 95% CI [0.95, 1.06]; P = 0.921, incidence difference: 0.04 percentage points, 95% CI [−0.80, 0.88]) attenuated to the null. For other site-specific cancers, sibling comparisons results varied, with more attenuation for melanoma, kidney, stomach, bladder, pancreas, and liver, bile ducts, and gallbladder cancer, while associations with lung, colon, head and neck, and esophagus cancer seemed to attenuate less. The findings were confirmed through an extensive set of sensitivity analyses. The main limitations of this study include the lack of inclusion of female participants, lack of data on other risk factors such as smoking, alcohol consumption, and physical activity, and only adjustment for the unobserved confounders which are shared between full siblings.

Higher levels of adolescent cardiorespiratory fitness were associated with lower overall cancer mortality in late adulthood, a finding that persisted in sibling comparisons. However, the influence of unobserved familial confounding appeared to vary by cancer type and be more pronounced for cancer diagnoses than for mortality. This may suggest a need for robust causal methods to triangulate results, rather than relying on correlations alone, to better inform public health efforts.

High cardiorespiratory fitness, a measure of regular physical activity and linked to genetics, has been associated with reduced cancer risk.

Improving fitness in young people is a growing public health focus.

Existing studies may have limitations, such as not fully accounting for other factors, such as participation in cancer screening and other health behaviors that may be more common in individuals with higher fitness levels.

We studied over 1.1 million young men, including nearly 500,000 full brothers, using data from fitness tests at military conscription (around age 18) linked to Swedish healthcare and death registries to track cancer diagnoses and deaths in adulthood.

We found that high cardiorespiratory fitness in adolescence was associated with lower overall cancer-related deaths. This link remained even after accounting for factors shared between siblings, such as genetics, shared environment, and health-seeking behaviors such as participation in cancer screening.

We also found varying confounding by specific cancer sites, where associations between cardiorespiratory fitness and increased diagnoses of prostate and skin cancer appeared to be driven by other factors, as they were not observed when comparing full siblings. Associations between high cardiorespiratory fitness and lower risks of kidney, stomach, bladder, pancreas, and liver, bile ducts, and gallbladder cancer also became smaller after accounting for factors shared between siblings.

If supported by further causal analyses, our study suggests that while high adolescent cardiorespiratory fitness might protect against certain cancers, other associations might be driven by unmeasured factors or biases.

Our findings could highlight the importance of well-designed research when studying cardiorespiratory fitness and cancer risk for an accurate appreciation of potential public health benefits.

Our study did not include female participants, was not able to account for certain relevant risk factors for cancer such as smoking, alcohol, and physical activity, and only accounted for the unobserved confounders that are shared between full siblings. These limitations should be addressed in future studies to expand upon our results.

Using military conscription data from more than 1.1 million young men and a sibling-controlled cohort, Marcel Ballin and colleagues examine the association between cardiorespiratory fitness in adolescence and cancer risk in late adulthood.