Comprehensive Profiling of Claudin 18.2 Immunohistochemical Expression in 564 Surgically Resected Gastric and Gastroesophageal Junction Adenocarcinomas.

Claudin-18 isoform 2 (CLDN18.2) is a novel therapeutic target for advanced, HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma positive for CLDN18.2 immunohistochemical (IHC) expression, defined as ≥75% tumor cells with moderate-to-strong membranous staining. Clinical studies for emerging CLDN18.2-targeted therapeutics have used less stringent enrollment criteria to test the efficacy of such therapies in patients with moderate-to-low CLDN18.2 IHC expression. Anticipating the advent of such treatments, this study aimed to provide a comprehensive survey of CLDN18.2 expression using a clinical-trial-validated CLDN18.2 monoclonal antibody in surgically resected gastric/GEJ adenocarcinomas and characterize CLDN18.2-positive carcinomas using both high- and low-expression thresholds. Crisp membranous CLDN18.2 staining was detected in 59% (335/564) carcinomas including 57% (164/286) gastric and 62% (171/278) GEJ adenocarcinomas. Most gastric (147/164, 90%) and GEJ (166/171, 97%) adenocarcinomas with staining demonstrated moderate or strong staining intensity. Using the high-expression threshold (≥75% tumor cells with moderate-to-strong staining), positive CLDN18.2 expression was observed in 20% (57/286) gastric and 27% (75/278) GEJ adenocarcinomas and associated with EBV status (p<0.001) and stage I gastric (p=0.02) but stage IV GEJ adenocarcinomas (p=0.03). Using a low-expression threshold (≥10% tumor cells with membranous staining), positive CLDN18.2 remained significantly associated with stage I (p=0.004) and showed an unadjusted association with improved disease-specific survival in gastric adenocarcinomas (p=0.045), which was not retained in multivariable analysis. Whole transcriptomic analysis showed concordance between IHC and CLDN18 mRNA expression. Transcriptomic alterations in CLDN18.2 IHC positive gastric adenocarcinomas included pathways in drug resistance and tumor invasion. In summary, our study presents a detailed characterization of the prevalence and distribution of CLDN18.2 IHC expression patterns. Our results show that 59% surgically resected gastric/GEJ adenocarcinomas exhibit CLDN18.2 staining. CLDN18.2 IHC positivity defined by both high- and low-expression thresholds may be associated with early stage in gastric carcinoma. These findings expand our recognition of patients who may benefit from CLDN18.2-targeted therapy.