Perioperative immunotherapy in gastric cancer in the spotlight

Table 5 Biomarkers relevant to the management of gastric and gastroesophageal junction cancer

Biomarker	Description	Predictive/clinical implication	Current or potential application
PD-L1 (CPS)	Programmed death-ligand 1 expression in tumor and immune cells (CPS ≥ 1, ≥ 5, ≥ 10)	Higher response rates to ICIs	Used in metastatic setting; under evaluation perioperatively
MSI-H/dMMR	Microsatellite instability-high or mismatch repair deficiency	Strong predictor of response to ICIs; pCR > 50% in some trials	Approved in advanced setting; perioperative trials ongoing
EBV+ tumors	Epstein–Barr virus-associated gastric cancers (about 10% of cases)	Inflammatory microenvironment; often high PD-L1 expression and immune cell infiltration	Investigational use; potential future biomarker
TMB	High number of mutations per megabase of tumor DNA	Associated with increased neoantigen load and ICI responsiveness	Emerging biomarker; no standard use yet
ctDNA	Circulating tumor DNA detectable in plasma	May identify minimal residual disease. Early predictor of recurrence risk	Investigated to guide adjuvant therapy or intensification
Tumor immune microenvironment	Immune infiltrates, T-cell exhaustion markers, inflammatory gene signatures	May stratify tumors as “immune hot” or “cold” and guide combination strategies	Ongoing studies using transcriptomics and spatial profiling
TCGA molecular subtypes	TCGA classification: EBV, MSI, GS, CIN	May correlate with immunogenicity and therapy response; especially relevant for EBV and MSI subtypes	May guide therapy selection in precision oncology approaches
CLDN 18.2	Tight junction protein from the claudin family; detected by IHC	Emerging therapeutic target; clinical trials with zolbetuximab show benefit in CLDN18.2-positive gastric tumors	Approved in metastatic setting in some regions; under investigation in perioperative and earlier-stage disease
FGFR2b	Epithelial isoform of the FGFR2	Associated with poor prognosis and more aggressive tumor phenotype, predicts response to FGFR2b-targeted therapies	FGFR2b has been identified as a therapeutic target in G/GEJ cancers, particularly in subgroups with FGFR2 overexpression or amplification

PD-L1: Programmed death-ligand 1; CPS: Combined positive score; ICI: Immune checkpoint inhibitors; dMMR: Deficient mismatch repair; MSI: Microsatellite instability; MSI-H: Microsatellite instability-high; pCR: Complete pathological response; EBV: Epstein-Barr virus; TMB: Tumor mutational burden; ctDNA: Circulating tumor DNA; TCGA: The cancer genome atlas program; CLDN 18.2: Claudin 18.2; FRFR2b: Epithelial isoform of the fibroblast growth factor receptor; GS: Genomically stable; CIN: Chromosomal instability; IHC: Immunohistochemistry.