Claudin 18.2 expression in gastroesophageal adenocarcinoma: biomarker overlap and association with clinical outcomes in a European cohort

BACKGROUND: Claudin 18.2 (CLDN18.2) is highly expressed in up to 40% of gastroesophageal adenocarcinomas (GEA) and represents an emerging therapeutic target for these tumors. However, its distribution across molecular subtypes and its prognostic and predictive roles remain insufficiently studied. METHODS: This ambispective, multicenter study included 563 patients with GEA diagnosed between 2019 and 2025 across 17 European institutions. Tumor samples were analyzed for CLDN18.2, human epidermal growth factor receptor 2 (HER2), mismatch repair, Epstein-Barr virus (EBV), and programmed death-ligand 1 [PD-L1; combined positive score (CPS)] using immunohistochemistry and/or in situ hybridization. Molecular alterations were characterized using next-generation sequencing. Associations between molecular features and clinical outcomes, such as overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS), were evaluated. RESULTS: High CLDN18.2 expression was observed in 48.3% of tumors, correlating with diffuse-type histology and peritoneal involvement (P < 0.01). Its prevalence varied across molecular subtypes: 33.9% in deficient mismatch repair, 62.5% in EBV-positive, 41.9% in HER2-positive tumors, and 47.2% in tumors with PD-L1 CPS ≥5. Among patients treated with first-line chemotherapy, CLDN18.2 status did not affect mPFS [hazard ratio (HR) 0.90; P = 0.50] or mOS (HR 1.06; P = 0.80). However, among HER2-positive patients, CLDN18.2-high tumors were associated with improved outcomes with HER2-targeted therapy (mPFS 17.0 versus 8.9 months, HR 0.42; P = 0.03; mOS 43.0 versus 23.0 months, HR 0.40; P = 0.07). By contrast, in patients with CLDN18.2-high tumors receiving an immunotherapy-based regimen (IO), there was a trend toward lower ORR (51% versus 64%; P = 0.15), shorter mPFS (8.9 versus 14.0 months; HR 1.47; P = 0.14), and reduced mOS (16.0 versus 43.0 months; HR 2.04; P = 0.052). Combined analyses of CLDN18.2 and PD-L1 showed poorer survival outcomes in CLDN18.2-high tumors across PD-L1 thresholds. CONCLUSIONS: CLDN18.2-high GEA was more prevalent than previously reported in pivotal trials and showed substantial overlap across molecular subtypes. It was associated with a greater benefit from HER2-targeted therapy but a trend toward poorer outcomes with IO, underscoring the need for biomarker-guided therapeutic strategies in GEA.