Distinct clinicopathological and survival profiles of CLDN18.2 and PD-L1 expression in advanced gastric cancer and gastroesophageal junction adenocarcinoma

Claudin 18.2 (CLDN18.2)-targeted therapy and immune checkpoint blockade have transformed the frontline treatment landscape of gastric and gastroesophageal junction (GC/GEJ) cancers, marking a major advance in precision oncology. However, the optimal sequencing and integration of these biomarker-driven therapies remain undefined. A comprehensive evaluation of the relationship between CLDN18.2 and programmed death-ligand 1 (PD-L1) expression, along with co-occurring genomic alterations and metastatic patterns, is critical to refine patient selection and improve survival outcomes. We retrospectively analyzed 70 patients with microsatellite-stable, human epidermal growth factor receptor 2 (HER2)-negative metastatic GC/GEJ adenocarcinoma treated with first-line chemoimmunotherapy. CLDN18.2 positivity was defined as ≥75% of tumor cells with moderate to strong membranous staining, and PD-L1 positivity as a combined positive score (CPS) ≥1. Molecular profiling of pretreatment tumor biopsies was carried out using a hybrid DNA/RNA sequencing panel covering 720 cancer-related genes. The incidence of key genomic alterations ( TP53, KRAS, CDH1, PIK3CA, RHOA, POLE, and CLDN18–ARHGAP6 fusion) was compared between CLDN18.2-positive and -negative tumors. Clinicopathological variables, including age, sex, race, Lauren classification, metastatic site, PD-L1 CPS, CLDN18.2 status, and receipt of hyperthermic intraperitoneal chemotherapy (HIPEC), were evaluated. Survival outcomes were estimated using the Kaplan–Meier method, and univariate and multivariate Cox regression analyses were carried out to identify prognostic factors. Thirty-eight tumors (54%) were CLDN18.2-positive. CLDN18.2-negative tumors were more likely to harbor KRAS mutations and higher PD-L1 CPS. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed between CLDN18.2-positive and -negative groups. Among all covariates, metastatic burden (oligometastatic versus polymetastatic) and race were independently associated with OS. In contrast, age, sex, histology, PD-L1 CPS, and CLDN18.2 expression were not prognostic. HIPEC did not significantly improve PFS or OS compared with non-HIPEC treatment; however, a trend toward improved outcomes suggests potential benefit in selected patients, supporting further prospective evaluation. CLDN18.2 and PD-L1 expression delineate distinct molecular and metastatic subgroups of GC/GEJ cancer. Personalized strategies integrating biomarker-driven systemic and regional therapies may enhance outcomes in this heterogeneous disease. Although HIPEC did not significantly improve survival, the observed trend warrants further validation in prospective studies. • Retrospective study of 70 MSS, HER2− GC/GEJ tumors treated with first-line chemoimmunotherapy. • No OS or PFS difference between CLDN18.2+ and CLDN18.2− subgroups. • CLDN18.2-negative tumors were more likely to harbor KRAS mutations and show higher PD-L1 CPS. • Oligometastatic burden and race independently predicted OS.HIPEC did not improve OS or PFS versus non-HIPEC treatment. Trend toward benefit with HIPEC in selected patients warrants validation. • Findings highlight complex interplay of CLDN18.2, PD-L1, and molecular subsets.