Genomic landscape study of esophago-gastric adenocarcinoma (EGAC) in young patients under the age of 30 years.

480 Background: Despite recent advances in treatment of EGAC, prognosis continues to be poor with reported 5-year survival of less than 30%. EGAC is more frequently diagnosed at an old age with the median age at diagnosis around 65 years. However, approximately 10% of EGAC are diagnosed at a younger age of less than 50 years and those patients present with more advanced stages resulting in worse prognosis. Our study investigated the genomic landscape of EGAC diagnosed under the age of 30 years to better understand the characteristics of EGAC occurring in very young population. Methods: 8,001 cases of clinically advanced EGAC who underwent comprehensive genomic profiling (CGP) from 2012 to 2024 were included in the study. Patients aged less than 30 years were classified as ‘EGAC-young’ and patients aged 50 and older were classified as ‘EGAC-old’. All classes of genomic alterations (GA), microsatellite instability high (MSI-high) status, tumor mutation burden (TMB), genomic ancestry, genomic signature, and homologous recombination defect signature (HRDSig) were determined from the sequencing data. PD-L1 was measured by IHC using the Dako 22C3 tumor proportional score (TPS) system. Comparisons utilized the Fisher Exact method with the Benjamini-Hochberg adjustment to reduce the false discovery rate. Results: Out of 8,001 cases, 7389 (92.4%) were classified as ‘EGAC-old’ and 26 (0.3%) as ‘EGAC-young’. Both groups had a higher frequency of male patients but there was no significant difference between the two groups (86.4% vs 76.9%; NS). Median GA per tumor was 6 in both groups. The ‘EGAC-old’ featured a significantly higher frequency of EUR ancestry (92.0% vs 73.1%; P=0.026). There were no significant differences in clinically important GA between both groups, including similar ERBB2 GA (21.2% vs 30.8%; NS) and FGFR3 GA (1.2% vs 7.7%; NS). There was a trend of more frequent GA of AKT2, CCNE1, and KEAP1 noted in ‘EGAC-young’ (0.9% vs 11.5%, 8.5% vs 26.9%, 1.3% vs 11.5%, respectively; P=0.071). MSI-high status was 3.1% in the ‘EGAC-old’ but not detected in the ‘EGAC-young’ (NS). The median TMB was higher in the ‘EGAC-old’ vs ‘EGAC young’ (3.8 mutations/Mb vs 1.9 mutations/Mb; P=.003). The frequencies of a positive HRDSig were similar in both groups (5.6% vs 8.0%; NS). There were no significant differences in COSMIC trinucleotide signatures. PD-L1 expression was identified in greater than 20% of the ‘EGAC-old’ but was not measured in the ‘EGAC-young’. Conclusions: Clinically advanced EGAC in young patients under the age of 30 years features a genomic landscape that differs from EGAC identified in older patients, including lower TMB and a trend of increased GA frequency of genes related to poor prognosis in other types of cancer. Further studies are warranted to utilize CGP findings in identifying potential implications for treatment and prognostication in these rare cases of EGAC occurring in very young patients.