Claudin-18.2 expression in gastro-oesophageal adenocarcinoma in a Western population: Overlap with other biomarkers and prognostic value.

4021 Background: Claudin 18.2 (CLDN18.2) is a novel biomarker for response to anti-CLDN18.2 therapy in gastroesophageal adenocarcinoma (GEA). Based on prevalence data, originating mostly from an Asian population, 40% of GEA are CLDN18.2 positive. We currently lack information on the cross-prevalence of CLDN18.2, HER2-status, microsatellite instability (MSI) and PDL1 expression in a Western population of localized and metastatic GEA. Methods: We present a single-center, retrospective study including localized and metastatic GEA patients diagnosed between 2019-2023. Histopathology with MMR status, HER2 status (IHC/SISH) and PDL1 CPS was obtained. CLDN18.2-positivity defined as ≥75% of tumor cells showing moderate-to-strong membranous staining was determined by IHC using the VENTANA CLDN18 [43-14A] RxDx Assay and underwent blind review by independent expert pathologists. Baseline characteristics and clinical follow-up data were gathered until august 2024. Kaplan-Meier curves were constructed for overall survival (OS), progression/relapse free survival (PFS/RFS) and survival after recurrence (SAR). Unrestricted grants/support was provided from Astellas, AMGEN and Roche diagnostics. Results: Of 405 patients with GEA, 261 presented with localized and 144 with metastatic disease. The majority were male (71%) with a median age of 65 years. 59% of tumors were junction tumors and 41% were gastric cancers. dMMR was detected in 6%. HER2 positivity (cfr. TOGA criteria) was seen in 16% of cases. PDL1 CPS ≥1 prevalence was 58%. CLDN18.2 positivity was seen in 42% of patients. Double CLDN18.2-HER2 and CLDN18.2-dMMR positivity was rare (5% and 3%), but strikingly in absolute numbers, about one third of HER2 positive tumors and half of dMMR tumors were CLDN18.2 positive. Double CLDN18.2-PDL1 ≥1//≥5//≥10 positivity was seen in 23%,15% and 9%. In patients with localized disease CLDN18.2 positivity did not affect RFS (HR: 0.99; 95%CI(0.68-1.43); p = 0.95) and OS (HR: 0,78; 95%CI(0.52-1.16) p = 0,22) with a median follow-up (FU) of 42 months. In the remaining 113 patients with primary metastatic disease no difference in terms of PFS (HR: 1.17; 95%CI(0,79-1.73); p = 0,43) or OS ( HR: 1.43; 95%CI(0,94-2.16); p = 0,1) was seen according to CLDN18.2 status with a median FU of 39 months. Median SAR in the localized group was statistically longer in the PDL1 CPS≥1 subgroup(HR: 0.51; 95%CI(0,34-0,79); p = 0,002). SAR was not different in CLDN18.2+ and CLDN18.2- patients (HR: 1,07; 95%CI(0,69-1.65) p = 0,77). Conclusions: We confirmed a 42% positivity rate of CLDN18.2 in a combination of localized and metastatic GEA in a Western population. dMMR was present in 6% of cases, PDL1 CPS ≥1 and HER2+ was seen in 58% and 16% of patients. CLDN18.2 positivity was strikingly present in half dMMR and one third of HER2+ cases. CLDN18.2 positivity did not affect survival in localized and metastatic disease.