Abstract A129: Understanding risk factors for non-endometrioid tumors, a comprehensive analysis of the Epidemiology of Endometrial Cancer Consortium (E2C2)

Abstract Introduction Endometrial cancer (EC) incidence and mortality are rising, particularly for aggressive (non-endometrioid) subtypes. More than half of patients diagnosed with these tumors die within 5 years of their diagnosis. Black women are over two-fold more likely to be diagnosed with these tumors than White women, which may, in part, explain the two-fold higher mortality. The American Cancer Society recommends that all women be informed of the risks and symptoms of endometrial cancer upon reaching menopause. Designing educational efforts to combat aggressive tumor subtypes requires risk factor knowledge. However, identifying risk factors for non-endometrioid tumors is challenging to study in any single population due to their relative rarity. Methods We included 28,259 incident EC cases (2,986 non-endometrioid) and 53,179 cancer-free controls from 29 studies in the Epidemiology of Endometrial Cancer Consortium (E2C2) (10.8% Black, 80.1% White, 7.3% Asian, 1.2% ‘other’). We used multivariable logistic regression adjusted age, sex, race, date of diagnosis to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to compare associations of EC risk factor by tumor histologic subtype (endometrioid, non-endometrioid). We stratified associations by race. Results BMI, diabetes, and hypertension were positively associated with both non-endometrioid and endometrioid subtypes, while age at menarche, parity, age at first birth, smoking, and oral contraceptive use were inversely associated. Although BMI was the strongest risk factor for both non-endometrioid (OR35+ vs <25= 2.40; 95% CI: 2.07, 2.80) and endometrioid tumors (OR35+ vs <25=4.63; 95% CI: 4.33, 4.95), the association was notably weaker for non-endometrioid tumors (Phet<0.01). Similarly, parity was less strongly associated with non-endometrioid tumors (non-endometrioid OR4+ vs 0= 0.77; 95% CI: 0.65, 0.92; endometrioid: OR4+ vs 0= 0.51; 95% CI: 0.46, 0.55, Phet<0.01). We observed an unexpected inverse association of PMH use with non-endometrioid tumors (OR= 0.81; 95% CI: 0.73, 0.89), while PMH was positively associated with endometrioid tumors (OR= 1.29; 95% CI: 1.23, 1.34, Phet<0.01). Associations between the remaining factors were consistent across tumor subtypes (all Phet>0.20). In race-stratified analysis, BMI and PMH use were more strongly associated with non-endometrioid tumors in Black than White women, while the diabetes association was stronger in White than Black women (all Phet<0.05). Conclusions To our knowledge, this is the largest, most racially diverse study of risk factors for non-endometrioid tumors. Some key risk factors have pronounced differences by histologic subtype and were weaker for non-endometrioid tumors. The unexpected inverse association between PMH and non-endometrioid subtype requires confirmation and should be interpreted cautiously. For three important risk factors we saw substantial differences in associations between Black and White women. Our findings have important implications for designing educational interventions, particularly in Black women. Citation Format: Noah C. Peeri, Peng Wang, Kimberly Bertrand, Immaculata De Vivo, Lucio Miele, Renhua Na, Veronica Wendy. Setiawan, Mengmeng Du. Understanding risk factors for non-endometrioid tumors, a comprehensive analysis of the Epidemiology of Endometrial Cancer Consortium (E2C2) [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A129.