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Angiogenesis and VEGF in Cancer · Review
ESMO Gastrointestinal Oncology · September 10, 2026
Well-designed and adequately powered for the question it asks.
This meta-analysis of 25 studies quantifies substantial spatial heterogeneity of Claudin-18.2 expression in gastric and gastroesophageal junction cancers, finding intratumoral discordance in 35.8% and intertumoral discordance in 20.3% of cases. Single-specimen immunohistochemistry testing may misclassify patient eligibility for Claudin-18.2-targeted therapy, and multisite sampling warrants consideration in clinical practice.
Systematic review and meta-analysis. Patients with gastric/gastroesophageal junction cancer with available Claudin-18.2 immunohistochemistry data from primary tumors and/or matched metastatic sites. Intervention: Claudin-18.2 immunohistochemistry assessment of intratumoral expression or primary–metastasis paired samples. Compared with: Positivity classification concordance; spatial homogeneity of expression. Not specified.
Pooled intratumoral discordance rate was 35.8% (95% CI 20.5–54.7) across 13 studies with 3097 patients Pooled intertumoral discordance rate was 20.3% (95% CI 17.3–23.7) across 12 studies with 987 patients High heterogeneity in intratumoral discordance (I² = 94.3%) but moderate heterogeneity in intertumoral discordance (I² = 17.9%)
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Clinicians should recognize that a single tumor specimen may misclassify Claudin-18.2 positivity status in up to one third of gastric/GEJ cancers. Multisite sampling should be considered to improve accuracy of patient selection for Claudin-18.2-targeted therapies such as zolbetuximab.
Rigorous meta-analysis of 25 studies with adequate pooled sample sizes quantifies clinically meaningful spatial heterogeneity in Claudin-18.2 expression, with clear implications for specimen selection in targeted therapy decisions.
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Clinicians should recognize that a single tumor specimen may misclassify Claudin-18.2 positivity status in up to one third of gastric/GEJ cancers. Multisite sampling should be considered to improve accuracy of patient selection for Claudin-18.2-targeted therapies such as zolbetuximab.
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Background Claudin-18.2 status is increasingly used to guide targeted therapy based on immunohistochemistry of limited tumor tissue. Spatial heterogeneity may produce discordant expression patterns within a primary tumor or discordant positivity classification between primary and metastatic sites, limiting the representativeness of a single specimen. No prior meta-analysis has quantified the magnitude of this discordance, either in gastric/gastroesophageal junction (GEJ) cancer or in other tumor types. Materials and methods We carried out a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis. MEDLINE, Embase, and Scopus were searched for studies reporting Claudin-18.2 intratumoral discordance within primary tumors and/or intertumoral discordance between primary tumors and matched metastases. Intratumoral discordance was operationalized according to each study's reported evidence of spatial variation in expression, whereas intertumoral discordance was defined as disagreement in positivity classification between matched primary and metastatic samples using study-specific cut-offs. Random-effects models pooled logit-transformed discordance proportions. Robustness was evaluated using leave-one-out sensitivity analyses and subgroup analyses explored potential sources of heterogeneity. Between-study heterogeneity and small-study effects were assessed using Cochran's Q, I 2, Tau 2, funnel plots, and Egger's regression. Results Thirteen studies ( n = 3097 patients) contributed to intratumoral discordance and 12 studies ( n = 987 patients) contributed to intertumoral discordance in gastric/GEJ-specific cohorts. The pooled intratumoral discordance rate was 35.8% [95% confidence interval (CI) 20.5-54.7, I 2 = 94.3%]. The pooled intertumoral discordance rate was 20.3% (95% CI 17.3-23.7, I 2 = 17.9%). Conclusion Claudin-18.2 expression shows substantial intratumoral and clinically meaningful discordance between primary and metastatic tumors in gastric/GEJ cancer. Single-specimen testing may misclassify eligibility and multisite testing should be considered.
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