Concordance of claudin-18.2 expression in biopsy, resection, and recurrent specimens: implications for zolbetuximab therapy in pancreatic ductal adenocarcinoma

Claudin-18.2 is a promising therapeutic target for gastrointestinal cancer. However, its expression pattern in pancreatic ductal adenocarcinoma, especially the concordance between biopsy and resection specimens, is unknown. This study aimed to evaluate the consistency of claudin-18.2 positivity across different specimen types using the clinically validated antibody clone 43-14A employed in ongoing zolbetuximab trials. Immunohistochemical analysis for claudin-18 was conducted on 211 resected pancreatic cancer tissues, 133 matched preoperative biopsy samples, and 60 samples from recurrent lesions. Concordance rates were calculated based on a clinically relevant cutoff (≥75% of tumor cells with moderate-to-strong membranous staining). Receiver operating characteristic analysis was used to optimize the biopsy thresholds. Claudin-18.2 positivity was observed in 9.5% of the resection specimens. The concordance rates were 92.5% between biopsy and resection specimens and 83.3% between primary and recurrent lesions. Receiver operating characteristic analysis suggested that a lower cutoff (20%) in biopsy samples achieved 100% sensitivity for detecting positive cases. While overall claudin-18 expression levels were maintained in most recurrent lesions, decreased expression was frequently observed in cases of local recurrence and liver metastasis. Despite intrinsic heterogeneity and limited biopsy yield in pancreatic cancer, claudin-18 expression in small biopsy samples, assessed using the clinical trial-validated clone 43-14A, strongly correlated with that in resection specimens. These results suggest that claudin-18.2 is a clinically stable biomarker for zolbetuximab therapy in patients with pancreatic ductal adenocarcinoma.