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. 2025 Jul;28(4):569-578.
doi: 10.1007/s10120-025-01609-7. Epub 2025 Apr 9.

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

Valentina Angerilli  1   2   3 , Matilde Callegarin  1 , Ilaria Govoni  4 , Giuseppe De Lisi  5   6 , Michele Paudice  7   8 , Paola Fugazzola  9 , Alessandro Vanoli  5   6 , Paola Parente  10 , Francesca Bergamo  11 , Claudio Luchini  12 , Angelo Paolo Dei Tos  1 , Federica Grillo  7   8 , Sara Lonardi  11 , Luca Mastracci  7   8 , Gaya Spolverato  4 , Matteo Fassan  13   14
Affiliations

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

Valentina Angerilli et al. Gastric Cancer. 2025 Jul.

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.

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Conflict of interest statement

Declarations. Conflict of interest: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Ethical approval and consent to participate: All clinical specimens used in this study were approved by our Institutional Review Board, and was included in the observational retrospective study “GAS-ALL-IN—GAStric cancers a retrospective analysis of ALL major prognostic and predictive determINants”. The study was performed according to the clinical standards of the 1975 and 1983 Declaration of Helsinki. Consent for publication: Not applicable.

Figures

Fig. 1
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
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
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
See this image and copyright information in PMC

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