Genomic landscape of homologous recombination deficiency signature in esophageal and gastric adenocarcinomas.

431 Background: Advanced upper gastrointestinal (GI) cancers are aggressive malignancies with poor prognosis, where chemotherapy and immunotherapy often provide limited benefit. Homologous recombination deficiency signature (HRDsig) has been found to predict PARP inhibitor sensitivity in ovarian, breast and lung cancers. However, the role of HRDsig and PARP inhibitor use in upper GI cancers has yet to be established. Methods: Hybrid capture-based genomic profiling was performed on 17,476 stage III-IV esophageal and gastric adenocarcinomas. Sequencing data were analyzed for genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), HRDsig, tobacco exposure signature, and genomic ancestry. PD-L1 expression was assessed by immunohistochemistry using Dako Tumor Proportion Score (TPS). Results: Of 17,476 cases, 977 (5.6%) were HRDsig+. Baseline sex (~75% male), age (median 66.5 years) and genomic ancestry (~75% European) were similar between HRDsig+ and HRDsig- tumors. HRDsig+ tumors more often exhibited the tobacco exposure signature (1.1% vs. 0.2%; p