Claudin 18.2 testing in gastroesophageal and pancreatobiliary cancers: current status, clinical implications and challenges

Claudin (CLDN) 18.2 is a tight-junction protein predominantly expressed in normal gastric epithelium. Malignant transformation can disrupt epithelial cell polarity, resulting in the exposure and overexpression of CLDN18.2 on tumor cell surfaces. This characteristic makes CLDN18.2 a promising therapeutic target in subsets of patients with gastric and gastroesophageal junction (G/GEJ), and pancreatobiliary cancers. The recent approval by the US Food and Drug Administration (FDA) of the anti-CLDN18.2 monoclonal antibody zolbetuximab marks a significant advancement in the management of locally advanced, unresectable, or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma. The increasing adoption and ongoing clinical trials of CLDN18.2-targeted therapies in G/GEJ and pancreatobiliary cancers have intensified the demand for reliable diagnostic testing. These developments underscore the need for accurate, standardized assessment of CLDN18.2 expression to inform patient selection and treatment planning. This review examines the current status, clinical implications, and challenges of CLDN18.2 testing in G/GEJ, as well as its expanding application in pancreatobiliary cancers. Multiple CLDN18.2 antibody clones and immunohistochemical staining platforms are currently utilized across clinical laboratories, each demonstrating variable accuracy, sensitivity, and specificity in detecting CLDN18.2 expression. Furthermore, CLDN18.2 expression is frequently heterogeneous within these cancers. Optimizing the clinical utility of CLDN18.2 testing requires rigorous attention to pre-analytic factors, such as tissue handling, fixation, and selection of representative tumor samples; analytic factors, including assay validation, antibody selection, and consistency in staining procedures; and post-analytic factors, such as scoring methods and clear cutoff criteria for interpretation. Each of these elements critically influences assay performance and reliability. Careful selection and evaluation of tumor samples, particularly in small biopsies or cytology specimens, are essential to ensure accurate assessment. Standardization of all aspects of CLDN18.2 immunohistochemistry, from specimen preparation to interpretation, is necessary to achieve accurate, reproducible, and clinically meaningful results that guide therapeutic decisions for patients with G/GEJ and pancreatobiliary cancers.