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<0.0001). Biomarkers of immunotherapy response were mixed: HRDsig+ tumors were less likely MSI-high (1.5% vs. 4.8%; p<0.0001), but more often TMB-high (≥10 mutations/Mb; 16.7% vs. 8.9%; p<0.0001). PD-L1 expression (TPS≥1%) trended higher (51.1% vs. 37.6%) but was not significant. HRDsig+ tumors were enriched for alterations in the DNA damage response pathway: BRCA1 (7.1% vs. 1.5%; p<0.0001), BRCA2 (14.7% vs. 2.2%; p<0.0001), PALB2 (5.9% vs. 0.8%; p<0.0001), ATM (6.2% vs. 4.2% p=0.007), and RAD21 (6.3% vs. 3.9%; p<0.0001). Genomic alterations in the cell cycle pathway were also more common: CDKN2A (35.5% vs. 27.6%), CDKN2B (20.7% vs. 12.4%), PTEN (15.6% vs. 5.8%) and MTAP (16.2% vs. 9.2%; all p<0.0001). Alterations in the growth factor receptor signaling pathway were less common: ERBB2 (11.4% vs. 19.3%; p<0.0001), EGFR (5.2% vs. 8.6%: p=0.0002), MET (3.5% vs. 5.4%; p=0.012), CDH1 (5.1% vs. 9.5%; p<0.0001) and KRAS (13.4% vs. 21.8%; p<0.0001). TP53 alterations were common in both but slightly lower in HRDsig+ tumors (74.0% vs. 77.8%; p=0.011). Conclusions: In this large cohort of advanced upper GI cancers, HRDsig+ tumors comprised a clinically meaningful subset. HRDsig+ tumors were enriched for alterations in the DNA damage response and cell cycle pathways, but harbored fewer alterations in the growth factor signaling pathway, suggesting distinct mechanisms of carcinogenesis. These findings highlight HRDsig as a promising biomarker for therapeutic stratification and support further evaluation of PARP inhibitors in upper GI cancers through biomarker-driven clinical trials. HRDsig+ tumors HRDsig- tumors Enriched genetic alterations BRCA1, BRCA2, PALB2, ATM, RAD21, CDKN2A, CDKN2B, PTEN, MTAP ERBB2, EGFR, MET, CDH1, KRAS, TP53 Biomarkers for immunotherapy More likely TMB-high More likely MSI-high