Abstract A044: CLDN18.2 Expression and Associations with KRAS Mutation Status and Survival in PDAC

Abstract Background: In pancreatic adenocarcinoma (PDAC) management, KRAS inhibitors are entering into clinical use and claudin 18.2 (CLDN18.2) is an emerging therapeutic target with a recent CAR-T approval in China. The expression levels of CLDN18.2 and KRAS mutation status and clinical outcome in PDAC is less studied. We would like to test the hypothesis of the relationship between CLDN18.2 expression levels with KRAS mutation status and survival. A cohort of pateints who had RNA sequencing and analysis is underway. Methods: Retrospective analysis of 135 tumors from PDAC patients with CLDN18.2 tested by immunohistochemistry (IHC, clone 43-14A, Ventana) and KRAS mutation status at MD Anderson were analyzed. CLDN18.2 expression levels by IHC were calculated as % of cells with 2+/3+ membranous staining intensity. The Palantir Foundry system was used to query clinical and molecular information including overall survival (OS) data. Correlations of CLDN18.2 expression, KRAS mutation and OS were tested. Non-parametric tests were used given non-normal distributions of CLDN18.2 levels (Shapiro-Wilk p<0.001). Results: CLDN18.2 staining intensity was mostly 2+/3+ (n=90, 66.7.2%) and 3+ (n=9, 6.7%). CLDN18.2 prevalence was strongly cutoff-dependent: 40.5% at ≥75%, 59.1% at ≥40%, 71.0% at ≥10%, 73.3% at ≥1%. 122 (90.4%) patients were KRAS mutated and 13 were KRAS wildtype (9.6%). Median CLDN18.2 expression levels were 60% in KRAS-mutated tumors (n=119) versus 10% in KRAS-wildtype tumors (n=13, Mann-Whitney p=0.20). 44 patients were initially diagnosed with stage IV disease and among them, higher CLDN18.2 expression ( ≥75%) was associated with a trend of better OS (HR=0.41, 95%CI 0.10–1.65, p=0.17), with consistent HR<1 at all cutoffs (≥10%–≥90%) with median follow-up of 21.6 months. Conclusions: In a real-world PDAC cohort: (1) CLDN18.2 prevalence is highly threshold-dependent, supporting trial design that accounts for varied expression cutoffs. (2) No statistically significant difference of expression levels of CLDN18.2 between KRAS wild type patients and mutated patients which could be due to limited sample size. (3) Stage IV-specific OS signal favoring positive patients (HR=0.41) warrants validation in larger cohorts Citation Format: Sacha El Khoury, Dan Zhao. CLDN18.2 Expression and Associations with KRAS Mutation Status and Survival in PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A044.