Molecular characteristics of early-onset versus average-onset gastroesophageal adenocarcinoma.

496 Background: Incidence of early-onset gastroesophageal adenocarcinoma (eoGEA, ages &lt;50 years) has been increasing in the United States since the 1990s, the etiology of which is still unclear, and limited data exists on molecular drivers. This study evaluates somatic and germline profiles in eoGEA compared to average-onset GEA (aoGEA, ages≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of GEA (esophageal, gastroesophageal junction and gastric adenocarcinomas) patients who underwent somatic NGS testing via the Tempus xT assay (595-648 gene DNA panel) from 12/2017 to 07/2024. This assay assesses somatic tumor mutations (including SNVs, Indels, CNVs, and select SVs), MSI, TMB, and incidentally detected germline SNVs and small indels in matched normal tissue. Clinical characteristics and immunotherapy markers were compared between eoGEA and aoGEA by Wilcoxon Rank Sum or Chi-squared test. Somatic and germline mutations were compared between two age groups with false discovery rate adjustments. Results: We compared the demographic, clinical, and molecular features of a total of 5863 patients with eoGEA (n=785, median age 43) and aoGEA (n=5078, median age 68). Over 80% of patients were diagnosed with stage IV disease. The eoGEA group had a higher proportion of females, non-white, and Hispanic or Latino patients compared to the aoGEA group (p&lt;0.001). Prevalence of MSI-H/ dMMR, and TMB-H was lower in eoGEA vs aoGEA (p&lt;0.001), while PD-L1 expression was similar. Prevalence of somatic CDH1 , CDKN2A , and TP53 SNVs, and FGFR2 and KRAS CNAs were higher in eoGEA vs aoGEA (q&lt;0.001). In a subset of 3286 patients with tumor/normal match testing (eoGEA=464 and aoGEA=2822), eoGEA also had a higher prevalence of germline CDH1 mutations (q&lt;0.001). Conclusions: eoGEA has a unique somatic and germline mutation profile compared to aoGEA; further study evaluating the molecular landscape including epigenetic changes could shed light on underlying mechanisms responsible for the rising incidence of eoGEA. eoGEA (n=785) aoGEA (n=5078) p-value/q-value* Baseline characteristics Median age at diagnosis (IQR) 43 (38, 47) 68 (61,74) &lt;0.001 Gender: male 509 (65%) 3798 (75%) &lt;0.001 Race (white) 280 (69%) 2347 (80%) &lt;0.001 Ethnicity (not hispanic or latino) 206 (60%) 1768 (86% &lt;0.001 Stage IV 495 (85%) 2883 (81%) 0.073 Immunologic markers TMB ≥ 10 25 (3.2%) 519(10%) &lt;0.001 MSI-H 13 (1.7%) 261 (5.1%) &lt;0.001 dMMR 7 (2.2%) 120 (5.9%) 0.007 Somatic mutations profiles * CDH1 126 (16%) 334 (6.6%) &lt;0.001 TP53 515 (66%) 3764 (74%) &lt;0.001 CDKN2A 101 (13%) 1011 (20%) &lt;0.001 KRAS 92 (12%) 931 (18%) &lt;0.001 NOTCH1 12 (1.5%) 228 (4.5%) 0.002 Germline mutation profiles * eoGEA (N=464) aoGEA (N= 2,822) Overall prevalence 46 (9.9%) 207 (7.3%) </jats:tr