Hyperinsulinemic and Pro-Inflammatory Dietary Patterns and Metabolomic Profiles Are Associated with Increased Risk of Total and Site-Specific Cancers among Postmenopausal Women

**Background:** Hyperinsulinemia and chronic inflammation are proposed mechanisms driving cancer risk. Dietary patterns that promote these states may serve as modifiable risk factors for cancer prevention. The Empirical Dietary Index for Hyperinsulinemia (EDIH) and Empirical Dietary Inflammatory Pattern (EDIP) are data-driven dietary indices that predict the diet's potential to contribute to insulin hypersecretion and chronic systemic inflammation, respectively. This study evaluated associations of EDIH, EDIP, and the Healthy Eating Index-2015 (HEI-2015) with total and site-specific cancer risk among postmenopausal women, and characterized the plasma metabolomics profiles of each dietary pattern.

**Methods:** The study included 112,468 postmenopausal women aged 50–79 years from the Women's Health Initiative (WHI), enrolled between 1993 and 1998. Dietary data were collected via baseline self-administered food frequency questionnaires representing intake in the preceding three months. EDIH, EDIP, and HEI-2015 scores were calculated and adjusted for total energy intake using the residual method. Incident cancers were adjudicated through medical records and pathology reports. Multivariable-adjusted Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for cancer risk across quintiles of dietary scores, with the lowest quintile as reference. For the metabolomics aim, plasma metabolites from 2,306 participants were measured using targeted LC-MS/MS, and metabolomics profile scores for each dietary pattern were derived using elastic-net regression with leave-one-out cross-validation.

**Key Results:** Over a median of 17.8 years of follow-up, 18,768 incident invasive cancers were adjudicated. Higher EDIH and EDIP scores were associated with greater total cancer risk, and higher HEI-2015 with lower risk: HR Q5vsQ1 (95% CI): EDIH, 1.10 (1.04–1.15); EDIP, 1.08 (1.02–1.15); HEI-2015, 0.93 (0.89–0.98). The multivariable-adjusted incidence rate difference (Q5 vs Q1) for total cancer was +52 (EDIH), +41 (EDIP), and −49 (HEI-2015) per 100,000 person-years. All three indices were associated with colorectal cancer risk. EDIH and EDIP were associated with endometrial cancer risk (EDIH HR Q5vsQ1: 1.63, 1.16–2.30) and breast cancer risk (EDIH HR Q5vsQ1: 1.19, 1.07–1.32). EDIH was further associated with luminal B, ER-negative, and triple-negative breast cancer subtypes. EDIH was also associated with higher risk of intestinal polyps (HR Q5vsQ1: 1.23, 1.15–1.32). The HEI-2015 metabolomics profile score was associated with lower lung cancer risk (HR per 1 SD: 0.46, 0.24–0.90). Additional adjustment for BMI and type 2 diabetes attenuated the endometrial cancer associations but did not materially change other results.

**Clinical Implications:** This large prospective study demonstrates that dietary patterns contributing to hyperinsulinemia and inflammation are associated with greater risk of total and several site-specific cancers among postmenopausal women, while higher overall dietary quality is associated with lower risk. The findings suggest that EDIH and EDIP may identify cancer risk beyond traditional dietary quality indices, particularly for breast cancer subtypes and endometrial cancer. The metabolomics profiles provide mechanistic insights linking specific dietary components to cancer risk through pathways involving cholesteryl esters, amino acids, and alkaloids. These results support testing of dietary interventions targeting insulin and inflammation pathways in clinical trials for cancer prevention among postmenopausal women.