Strategic integration of immunotherapy with chemotherapy, radiotherapy, and targeted therapy in gastric cancer management: A systematic review

Table 2 Predictive biomarkers in gastric cancer[119-122]

Biomarker	Clinical relevance	Alterations	Diagnosis	Targeted agents
HER2	Overexpressed in 15%-20% of GCs; associated with poor prognosis and aggressive disease	Gene amplification, protein overexpression	IHC, FISH	Trastuzumab, lapatinib
VEGF	Overexpression associated with angiogenesis and tumor progression	Protein overexpression	IHC, ELISA for serum VEGF levels	Bevacizumab, ramucirumab
MET	Amplification and overexpression linked to poor prognosis and aggressive behavior	Gene amplification, protein overexpression	IHC, FISH, NGS	MET inhibitors (e.g., crizotinib, onartuzumab)
PIK3CA	Mutations found in a subset of GCs; associated with activation of the PI3K/AKT pathway	Gene mutations	NGS, PCR-based mutation testing	PI3K inhibitors (e.g., buparlisib, alpelisib)
PD-L1	Linked to immune evasion by tumor cells; higher expression correlates with better response to immunotherapy	Protein overexpression	IHC	Pembrolizumab, nivolumab
CLDN18-ARHGAP26/ARHGAP	Fusions associated with a distinct subtype of GC; potential sensitivity to targeted therapy	Gene fusion	RNA sequencing, NGS	Ongoing research for specific targeted therapies
MSI-H/dMMR	Present in 15%-20% of GCs; associated with better prognosis and response to immunotherapy	Loss of mismatch repair protein function	PCR-based MSI testing, IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2)	Pembrolizumab
FGFR2	Amplification seen in 5%-10% of GCs; linked to poor prognosis	Gene amplification	FISH, NGS	FGFR inhibitors (e.g., AZD4547, FPA144)
EBV	Found in approximately 10% of GCs; distinct molecular subtype with unique immune microenvironment	EBER positivity	ISH for EBER	Immunotherapy (ongoing research)
KRAS	Mutations present in a small percentage of GCs; linked to resistance to anti-EGFR therapies	Gene mutations	NGS, PCR-based mutation testing	Investigational KRAS inhibitors (e.g., AMG 510)

EBER: Epstein-Barr virus-encoded RNA; EBV: Epstein-Barr virus; EGFR: Epidermal growth factor receptor; FGFR2: Fibroblast growth factor receptor 2; FISH: Fluorescence in situ hybridization; GC: Gastric cancer; HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; ISH: In situ hybridization; MET: Mesenchymal epidermal transition factor; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; NGS: Next-generation sequencing; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor.