S654 Metabolic and Inflammatory Risk Factors for Early-Onset Colorectal Cancer: A US Case-Control Study

Introduction: Colorectal cancer (CRC) incidence in adults under 50 has risen sharply, suggesting a shift in epidemiology. Identifying risk factors may improve early detection and guide screening efforts. This aims to identify clinical and metabolic predictors of early-onset colorectal cancer (EOCRC) in a real-world U.S. population. Methods: A retrospective case-control study was performed using TriNetX, a federated EHR database from 80+ U.S. healthcare institutions. Adults aged 30–49 with first-time CRC (ICD-10 C18–C20) between 2010–2023 were identified. Exclusions: prior malignancy, hereditary CRC syndromes (e.g., Lynch, FAP), inflammatory polyposis, or colectomy before diagnosis. Each case was matched 1:2 to cancer-free controls based on age (±2 years), sex, and year of encounter. Predictors (within 2 years before diagnosis): obesity (E66), type 2 diabetes (E11), IBD (K50, K51), metabolic syndrome (E88.81), tobacco use (F17, Z72.0), physical inactivity (Z72.3), and family history of GI malignancy (Z80.0). Multivariable conditional logistic regression was used; AUC evaluated model performance. Multiple imputation addressed missing BMI and HbA1c data. Results: 3,217 EOCRC cases were matched with 6,434 controls (N = 9,651). Mean age: 43.2; 52% male. EOCRC patients had higher prevalence of: (1) Obesity: 48.3% vs 29.1% (2) Diabetes: 32.5% vs 18.7% (3) Metabolic syndrome: 22.9% vs 12.8% (4) IBD: 9.7% vs 3.3% (5) Family history: 12.6% vs 5.1% (6) Inactivity: 18.4% vs 10.2% (all P < 0.01). Independent predictors: (1) IBD: odds ratio (OR) 2.43 (95% CI: 1.99–2.96) (2) Obesity: OR 2.08 (1.88–2.31) (3) Family history: OR 2.41 (2.02–2.87) (4) Metabolic syndrome: OR 1.77 (1.48–2.13) (5) Diabetes: OR 1.59 (1.36–1.85) (6) Smoking: OR 1.42 (1.22–1.67). Model AUC was 0.81. Subgroup analysis revealed stronger associations in African American and Hispanic patients, and in those without prior CRC screening. Sensitivity analysis using Firth’s correction confirmed robustness. Conclusion: EOCRC is associated with metabolic, inflammatory, and behavioral risk factors. These findings support EOCRC as a distinct entity and highlight the need for risk-based screening strategies for individuals under 50.