Abstract
Background – The incidence of gastroesophageal cancer diagnosed prior to 50 years (GEC < 50) is increasing. Assessment of the clinicopathologic and molecular characteristics of these cancers is limited currently.

Methods – This analysis utilized Tempus’ clinicogenomic database to compare patients with GEC aged <50 vs 50 + (GEC50+) at diagnosis who completed tumor molecular profiling between December 2017 and July 2024. The spectrum of biomarkers, somatic alterations, and germline alterations were compared between those with GEC < 50 and GEC50+ and a multivariate analysis was conducted to identify factors associated with longer survival.

Results – Among 5,863 GEC patients, 785 had GEC < 50. There were more females (35% vs 25%, p < 0.001) and fewer white patients (69% vs 80%, p < 0.001) with GEC < 50. Fewer GEC < 50 tumors had high tumor mutational burden (3.2% vs 10.2%, p < 0.001) or high microsatellite instability (MSI-H; 1.7% vs 5.1%, p < 0.001), but there was no difference in PD-L1 positivity (49% vs 51%, p = 0.3). Higher incidence of somatic CDH1 mutations was seen in GEC < 50 (16.1% vs 6.6%, q < 0.001), with lower incidence of TP53 (65.6% vs 74.1%), CDKN2A (12.5% vs 19.8%), and KRAS (11.7% vs 18.3%, p < 0.001 for all) alterations. The most significant germline difference was higher incidence of CDH1 (2.2% vs 0.3%, q = 0.001) and TP53 (0.6% vs 0%, q = 0.039) alterations among GEC < 50. Median survival for patients with metastatic disease was longer for GEC < 50 (11 vs 8.5 months, p = 0.002), and GEC < 50, ERBB2 amplification, and MSI-H were associated with superior survival.

Conclusions – Unique molecular and germline profiles were seen in GEC < 50, which may suggest differences in causal factors yet undiscovered.

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