Prevalence of high Claudin 18 expression in gallbladder cancer and association with survival: Implications for CLDN18.2-targeted therapy.

e16299 Prevalence of high Claudin 18 expression in gallbladder cancer and association with survival: implications for CLDN18.2-targeted therapy Background: Claudin 18.2, an isoform of Claudin 18 (CLDN18) is a therapeutically actionable tight-junction target in upper gastrointestinal malignancies, with biomarker thresholds driving patient selection. Data in gallbladder cancer (GBC) are scarce. We evaluated the prevalence of high CLDN18 expression assessed by immunohistochemistry (IHC) on tissue microarrays (TMA) and explored its association with survival outcomes in GBC. Methods: We conducted a retrospective cohort analysis of patients with GBC with available clinicopathologic and survival data. CLDN18 expression was assessed by IHC on TMA from GBC specimens. High CLDN18 expression (CLDN18-high) was defined as membranous staining ≥2+ in ≥75% of tumor cells. Overall survival (OS) was estimated using Kaplan–Meier methods and compared by log-rank testing for (i) all-cause mortality and (ii) GBC-specific cause of death. Cox proportional hazards models evaluated the independent association of stage group and CLDN18-high status with OS. Results: Among patients with available CLDN18 assessment (N = 122), CLDN18-high was observed in 9.0% (11/122). Baseline clinicopathologic characteristics were broadly similar between CLDN18-high and non-high tumors (all p > 0.05). In the survival cohort (N = 159), median OS was 11.0 months for both all-cause and GBC-specific mortality analyses. In CLDN18-evaluable cases, CLDN18-high tumors showed numerically longer median OS compared with non-high, without statistical significance: all-cause OS 16.0 vs 9.0 months (p = 0.24) and GBC-specific OS 21.0 vs 10.0 months (p = 0.21). In multivariable analysis, stage III/IV was independently associated with worse OS (HR 3.06, 95% CI 1.41–6.65; p = 0.005), whereas CLDN18-high was not (HR 0.48, 95% CI 0.07–3.56; p = 0.476). Conclusions: Using IHC on TMA, high CLDN18 expression was detected in 9% of GBC tumors, identifying a biomarker-defined subgroup that could be considered for CLDN18-targeted approaches. CLDN18-high status was not independently prognostic after adjustment for stage, but the prevalence of high expression supports provides a rationale for biomarker-selected clinical trials of CLDN18.2-directed therapies in GBC.