Evaluation of Homologous Recombination Deficiency (HRD) in Gastric Cancer: Real-World Prevalence and Outcomes with First-Line (1L) Platinum-Based Therapy

Background
Metastatic gastric and gastroesophageal junction cancers (GC/GEJ) have poor outcomes with limited predictive biomarkers to guide first- line (1L) therapy. HRD predicts sensitivity to platinum chemotherapy and PARP inhibition in several malignancies, but its clinical relevance is not well defined in GC/GEJ. We evaluated the association between HRD alterations, genomic context, and clinical outcomes following 1L platinum-based therapy (PBT) in metastatic GC/GEJ.

Methods
We queried the de-identified Tempus multimodal database using the Tempus Lens Platform to analyze a cohort of patients with advanced GC/GEJ. All patients had DNA (xT, 648 gene DNA-seq panel) and/or RNA sequencing (xR, whole transcriptome RNA-seq). Patients were classified as HRD-altered (HRD-alt) if they harbored pathogenic or likely pathogenic germline or somatic alterations in at least one of 23 predefined HRD-associated genes; all others were classified as HRD wild-type (HRD-wt). Tumor mutational burden (TMB-H, ≥ 10 mut/Mb) and microsatellite instability (MSI) were assessed. Real-world (rw) overall survival (rwOS) was estimated using Kaplan–Meier methods. Ηazard ratios (HRs) from Cox-proportional hazards models were adjusted for relevant clinical and molecular covariates at a significance level of p < 0.05.

Results
Among 1,066 eligible patients, 257 (24%) were HRD-alt and 809 (76%) were HRD-wt. HRD-alt tumors were associated with TMB-H (21% vs 5.9%, p< 0.001) and MSI-high status (12% vs 1.2%, p< 0.001). Median OS was longer in HRD-alt compared with HRD-wt patients (15 vs 12 months, HR:0.79, p = 0.033). Notably, HRD-alt tumors were strongly enriched for ERBB2 alterations compared to HRD-wt tumors (30% vs 8.8%, p< 0.001), predominantly driven by amplification (86%). Further stratification by HRD and ERBB2 status showed reduced HRs for rwOS in HRD-alt only (HR 0.78; 95%, p = 0.034), dual ERBB2/HRD-alt tumors (HR 0.63; 95% CI, 0.45–0.88, p = 0.006), and ERBB2-alt only (HR 0.52; 95% CI, 0.36–0.76, p < 0.001) compared to the wt/wt group. ERBB2-alt tumors demonstrated distinct co- mutation patterns enriched for cell-cycle and proliferative genes (CCNE1, TOP2A), whereas ERBB2–wt tumors more frequently harbored KRAS, ARID1A, and CDH1 alterations.

**Conclusions
**In this large rw-cohort of metastatic GC/GEJ, HRD alterations identified a biologically distinct subgroup with improved OS and greater durability on 1L PBT. HRD status was associated with ERBB2 amplification, and the HRD/ERBB2 status was associated with improved survival. These findings support HRD as a clinically relevant biomarker in GC/GEJ and justify prospective evaluation of HRD-informed treatment strategies.