Heterogeneity of predictive biomarker expression in gastric and esophago-gastric junction carcinoma with peritoneal dissemination

Abstract

Background: Temporal and spatial molecular heterogeneity contributes to resistance to targeted and immune therapies in gastric and esophagogastric junction carcinoma (G/EGJ). This study evaluates differences in biomarker expression between primary G/EGJ and paired peritoneal metastases (PM).

Methods: We analyzed 74 cases of primary G/EGJ and paired PM using immunohistochemistry for HER2, PD-L1, Claudin18 (CLDN18), DNA mismatch repair (MMR) proteins, p53, E-cadherin, and in situ hybridization for EBER. Biomarker concordance between primary and metastatic tumors was assessed.

Results: Primary G/EGJ were predominantly poorly cohesive (45.9%) or mixed-type (37.8%). Regarding predictive biomarkers, low rates of HER2 overexpression (5.4%), MMR deficiency (4.1%), and EBER positivity (1.4%) were observed, while PD-L1 CPS ≥ 1 occurred in 79.7% of cases and CLDN18 positivity was observed in 31.1% of cases. Concordance was perfect for MMR and EBER, while PD-L1 showed the highest discordance (32.4%). HER2 had a low discordance rate (2.7%). CLDN18 exhibited good concordance (86.5%) and showed consistent positivity in PD-L1- and HER2-negative primary tumors (28.6%).

Conclusion: G/EGJ with PM show distinct molecular features and spatial heterogeneity, with MMR, EBER, and HER2 demonstrating strong concordance, while PD-L1 showed greater variability. As for novel biomarkers, CLDN18.2 shows substantial concordance between primary G/EGJ and PM and could be a promising target in HER2/PD-L1-negative G/EGJ with PM.

Keywords: Biomarkers; Gastroesophageal cancer; Heterogeneity; Targeted therapy.

Fig. 1

A Histotype and status of predictive biomarkers in gastric and esophago-gastric junction carcinomas with paired peritoneal metastases and B combinations of concordant and discordant biomarkers in each patient (n = 74). Cases with both synchronous and metachronous peritoneal metastases (PM) were considered only once; when the expression differed between synchronous and metachronous (PM), the discordant case was considered. CPS Combined Positive Score, CLDN18 Claudin18, EBER Epstein–Barr virus–encoded small RNA, PD-L1 programmed cell death ligand 1, MMRd mismatch repair deficient, MMRp mismatch repair proficient

Fig. 2

A PD-L1 and B CLDN18 expression in primary tumors (n = 74) and paired peritoneal metastases (PM). Cases with both synchronous and metachronous PM were considered only once; when the expression differed between synchronous and metachronous PM, the discordant case was considered. PD-L1 programmed cell death ligand 1, CPS Combined Positive Score, CLDN18 Claudin18

Fig. 3

Representative images of discordant biomarkers’ status between primary tumor and matched peritoneal metastasis: A Claudin 18 (CLDN18)-negative primary tumor and B CLDN18-positive peritoneal metastasis, C HER2-overexpressed (3 +) primary tumor and D HER2-not overexpressed (0) peritoneal metastasis, E PD-L1 Combined Positive Score (CPS) 90 in primary tumor and F PD-L1 CPS 0 in peritoneal metastasis