Claudin 18.2 and Other Therapeutic Biomarkers in Gastric and Gastroesophageal Junction Adenocarcinomas

Biomarker-driven therapies have led to several recent advances in treating gastric and gastroesophageal junction (GEJ) cancers, but the overlap of these biomarkers remains unclear. We analyzed coexpression of Claudin 18.2 (CLDN18.2), HER2, PD-L1, and mismatch repair (MMR), focusing on CLDN18.2 staining extent and clinicopathologic correlations in gastric and GEJ adenocarcinomas. A total of 145 cases from 2023 to 2024 were identified from pathology archives. Following published clinical trial criteria, tumors were considered CLDN18.2-positive if ≥75% of tumor cells showed moderate-to-strong membranous staining. CLDN18.2 positivity was observed in 70 cases (48%) and was enriched in tumors with signet-ring-cell features ( P =0.0391, univariate; P =0.0113, multivariate). No significant correlation was found with other clinicopathologic features or HER2, PD-L1, or MMR status. The inclusion of CLDN18.2 increased the proportion of cases with at least one actionable biomarker to 92%. Among triple-negative (HER2-negative, PD-L1-negative, and MMR-proficient) tumors, CLDN18.2 was positive in 52% overall and 50% of cases with metastasis, suggesting its potential utility in expanding treatment options. CLDN18.2 appeared to demonstrate relatively low intratumoral heterogeneity, with most tumors (72%) demonstrating either no staining (<10% tumor cells staining) or diffuse staining (≥90% of tumor cells staining). Among tumors classified as CLDN18.2-positive on the above criteria, 84% displayed homogeneous positivity. Nevertheless, heterogeneous expression was observed in a small percentage of tumors (28% of all tumors), indicating that sampling-related misclassification remains a potential concern. Our study provides detailed insights into CLDN18.2 expression and sheds light on the biomarker landscape in gastric and GEJ cancers.