LAUSR

BACKGROUND Whilst unopposed estrogen exposure is considered a major driver of endometrial carcinogenesis, chronic inflammation and insulin resistance/hyperinsulinemia are also major endometrial cancer risk factors. However, it is unclear whether diets with inflammatory or insulinemic potential are associated with risk of endometrial cancer. METHODS We followed 48,330 women from the Nurses' Health Study (NHS, 1984-2016) and 85,426 women from the Nurses' Health Study II (NHSII, 1989-2017). Using food frequency questionnaires, we calculated repeated measures of empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores, that characterize the potential of the whole diet to modulate circulating biomarkers of inflammation or C-peptide, respectively. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type I endometrial cancer risk. RESULTS We documented 1,462 type I endometrial cancer cases over 2,823,221 person-years of follow-up. In the pooled multivariable-adjusted analyses, women in the highest, compared with lowest quintiles were at higher risk of type I endometrial cancer (EDIP HRQ5vs.Q1 =1.46; 95% CI, 1.24-1.73, p-trend<.001; EDIH HRQ5vs.Q1 =1.58; 95% CI, 1.34-1.87, p-trend<.001). Additional adjustment for body mass index (BMI) attenuated the associations (EDIP HR, 1.03; 95% CI, 0.87-1.22; EDIH HR, 1.01; 95% CI, 0.85-1.21), and mediation analyses showed that BMI may explain 60.4% (37.4% -79.6%; p<.001) and 71.8% (41.0% -90.4%; p<.001) of the association of endometrial cancer with EDIP and EDIH, respectively. CONCLUSIONS In this large cohort study, higher dietary inflammatory and insulinemic potential were each associated with increased endometrial cancer incidence, and this association may be almost entirely mediated by adiposity.