Identification of possible mediators of the relationship between sex and cancer incidence: analysis of the EPIC-Europe study

Background: Cancer remains a leading cause of premature death globally and is expected to rise substantially in the coming decades. Men generally experience higher incidence rates of non-sex-specific cancers than women, an observation partly explained by behavioral risk factors such as tobacco use and dietary patterns. However, the extent to which these modifiable lifestyle factors mediate the relationship between sex and cancer risk remains unclear. Investigating their potential mediating effect is crucial, as it could clarify whether addressing these behaviors can substantially reduce the observed sex gap in cancer incidence or if other biological and environmental factors play a predominant role. Objectives: This study investigated whether adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines could help explain the difference in non-sex-specific cancer risk between men and women. We aimed to quantify how much of the observed sex disparity is mediated by modifiable behaviors—primarily smoking and lifestyle factors captured by the WCRF/AICR Score—in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: We analyzed baseline and follow-up data from 248,016 individuals recruited in several European countries, excluding participants from Greece, Norway, and Sweden for privacy reasons and from France due to female-only recruitment. Key demographic information, anthropometric measures, and lifestyle data (including diet, physical activity, and smoking habits) were collected at enrollment. We computed WCRF/AICR Scores based on adherence to dietary and lifestyle recommendations, then applied flexible parametric Royston–Parmar survival models to estimate sex-specific hazard ratios (HRs) for non-sex-specific cancer incidence. The first model adjusted for demographic factors (age, country, education, chronic disease), while the second added smoking status and WCRF/AICR Score as potential mediators. A formal mediation analysis, assuming no unmeasured confounding, was conducted to decompose the total effect of sex on cancer risk into direct and indirect components. Results: During a mean follow-up of approximately 14 years, women showed a markedly lower incidence of non-sex-specific cancers than men (HR: 0.54, 95% CI: 0.52–0.56) after adjusting for baseline age, education, chronic conditions, and country. Including smoking and the WCRF/AICR Score attenuated but did not eliminate the difference (HR: 0.67, 95% CI: 0.65–0.70). Mediation analysis revealed that these modifiable factors accounted for a significant fraction of the sex disparity, yet a residual gap persisted. Conclusions: These results suggest a combination of lifestyle behaviors and non-modifiable biological mechanisms likely underpins men’s excess risk. Thus, public health interventions aiming to reduce tobacco use and improve dietary and physical activity habits can mitigate a portion of the excess cancer burden among men. Nonetheless, even with these factors taken into account, men remained at higher risk than women, pointing to additional biological, genetic, or environmental influences that warrant further exploration. Future studies integrating repeated lifestyle assessments, biomarker data, and cancer site specific analyses may help clarify how sex interacts with modifiable risks to shape cancer incidence. By addressing these multifaceted contributors, more effective prevention strategies can be developed to reduce the overall cancer burden and narrow persistent sex disparities.