Molecular characteristics and clinical outcomes of gastroesophageal cancer diagnosed at age 50 years

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.