Spatial discordance of claudin18.2 in gastric cancer: clinical implications for patient selection in Zolbetuximab therapy.

purposeZolbetuximab, a monoclonal antibody against claudin18.2 (CLDN18.2), shows promise in the treatment of advanced gastric cancer. However, as treatment relies on CLDN18.2 expression in primary tumors, concordance with metastatic lesions remains unclear.

methodsWe retrospectively analyzed 50 patients with advanced gastric cancer. CLDN18.2 expression was assessed immunohistochemically in paired primary and metastatic lesions, being defined as positive when ≥ 75% of tumor cells showed moderate to strong membranous staining. Clinicopathological factors associated with the discordance were also evaluated.

resultsCLDN18.2 positivity was found in 36% of primary tumors and 18% of metastatic lesions. Concordance between sites was 78%, varying by route: 100% in hematogenous lesions, 80% in lymphatic lesions, and 72% in peritoneal lesions. In discordant cases, 89% showed loss of expression in metastases despite primary positivity, particularly in peritoneal lesions. A larger tumor size and nodal involvement (≥ N2) were significantly associated with discordance (p = 0.020 and p = 0.004, respectively). A receiver operating characteristic analysis identified 90 mm as the optimal cutoff (AUC = 0.73). A flowchart of tumor size and nodal status showed an 81.8% discordance when both were present.

conclusionsCLDN18.2 expression often differs between primary and metastatic sites, particularly with peritoneal spread. Tumor size and nodal status may help identify patients who are unlikely to benefit from primary tumor-based profiling.