Age-related germline landscape of endometrial cancer: Focus on early-onset cases.

10575 Background: Endometrial cancer (EC) has traditionally been associated with older age; however, recent trends indicate more cases in younger women. There is also a growing appreciation for germline drivers of EC, and these may be enriched in younger patients (pts). Given this, we sought to define germline pathogenic variants (gPV) in pts with EC by age. Methods: Pts with EC treated at our institution who underwent clinical tumor-normal sequencing from 12/2024-6/2021, inclusive of germline analysis of ≥76 genes, were identified. Clinical variables including age at diagnosis were collected. Logistic regression models evaluated associations between age at EC diagnosis and presence of gPV, biallelic loss, and Lynch syndrome (LS). Age categories were defined as early-onset (EC<50 years) and later-onset (EC ≥70 years) and were compared to those diagnosed ages 50-69 years. Appropriate statistical analysis had been performed. Results: Among 1625 pts with EC, median age at diagnosis was 63 (range 24-96) years. We observed differences in gPV rate across age groups, with 28/170 (16%) in early-onset EC, 152/1066 (14%) in EC diagnosed 50-69 years, and 36/389 (9%) in later-onset EC (p=0.016). Biallelic loss also exhibited differences by age groups with enrichment in early-onset EC (8.2% vs. 4.5% vs. 2.1% respectively, p=0.004). LS was enriched in early-onset EC, with 6.5% of patients diagnosed age <50 years having LS. Age was associated with gPV in univariate and multivariable (MV) logistic models, even after adjusting for ancestry and molecular subtype. Compared to those with EC diagnosed 50-69 years, early-onset EC was more likely to be exhibit biallelic loss (OR 3.34 95% CI 1.44-7.35) and be associated with LS (HR 3.49 95% CI 1.63-7.01) in MV models. In contrast, later-onset EC was less likely to be associated with gPV (OR 0.56 95% CI 0.37-0.83) and biallelic loss (OR 0.37 95% CI 0.15-0.82) in MV models. Among early-onset EC, 14/28 (50%) gPV were high penetrance and 14/28 (50%) exhibited biallelic loss. For late-onset EC, only 5/36 ( 14%) gPV had high penetrance with 8/36 (22%) showing biallelic loss. While the most common high-penetrant gPVs were MSH2 (n=5), MSH6 (n=3), and MLH1(n= 3) for the early-onset cohort, the later-onset cohort had gPV in BRCA2 (n=3), BRCA1 (n=1), and PALB2 (n=1). Among the 39 pts with LS and EC, the youngest pt ( MLH1 gPV) was diagnosed at 31 years, and the oldest pt ( PMS2 gPV) was diagnosed at 69 years. Heterogeneity was observed in the early-onset EC cohort. Rates of gPV were 8.9% and 19%, biallelic loss was 0% and 11%, and LS was 2.2% and 8% in those diagnosed <40 years and 40-49 years respectively, suggesting potentially different drivers of very early-onset EC. Conclusions: Rates of gPV, biallelic loss and LS differ across age groups for EC, with higher rates of highly penetrant genes that drive tumorigenesis enriched in younger pts. However, very early-onset EC may have different drivers and necessitates more research.