Primary Tumor Genomics and Patterns of Distant Recurrence in Resected Gastric Cancer.

Patients with gastric cancer face substantial risk of recurrence after surgical resection. Molecular profiling of primary tumors may improve risk stratification to guide postoperative management. To identify genomic features of primary gastric tumors associated with disease recurrence and patterns of metastatic spread. This single-center cohort study took place at an academic quaternary referral center and included patients who underwent curative-intent resection of gastric adenocarcinoma from 2010 to 2024. Patients were classified by recurrence status and pattern of metastatic spread. Patients with gastric cancer (stages I to III) who underwent a margin-negative resection and had genomic sequencing of their primary tumor were included. Primary analysis excluded patients who had no evidence of disease with less than 2 years of follow-up. These data were analyzed from June 2025 through March 2026. Primary tumor specimens were sequenced using a targeted panel of cancer-associated genes (MSK-IMPACT). Correlation of disease-free survival and patterns of metastatic spread (hematogenous, peritoneal, or lymphatic) with primary tumor genomic profile. Among 438 patients who underwent complete oncologic resection, 377 had sufficient clinical follow-up or developed recurrence (median [IQR] age, 64 [55-71] years; 113 female [30%] and 264 male [70%]). Recurrence was identified in 179 patients, whereas 198 patients had no evidence of disease. In a multivariable analysis, alterations in KRAS (hazard ratio [HR], 1.54; 95% CI, 1.04-2.28; P = .03) and PIK3CA (HR, 2.15; 95% CI, 1.25-3.69; P = .006) were independently associated with worse disease-free survival. Tumors of patients with hematogenous recurrence had greater chromosomal instability (fraction genome altered, 0.11 vs 0.03; P = .001), whole-genome duplication (47% vs 15%; P = .02), and more frequent alterations of genes modulating cell cycle regulation (39% vs 6%; P < .001) compared with peritoneal recurrence. Bone metastasis arose from more genomically stable primary tumors (fraction genome altered, 0.005 vs 0.114; P < .001) and tumors with Lauren diffuse-type histology (36% vs 3%; P < .001) compared with other sites of hematogenous spread. This study identifies genomic alterations associated with disease-free survival and patterns of recurrence after resection of gastric cancer. These clinicogenomic risk factors may personalize postoperative surveillance strategies and inform perioperative treatment decisions.