Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates

Table 6 A comprehensive framework for biomarker-driven precision medicine in human epidermal growth factor receptor 2-positive gastric cancer

Core domain	Key technologies/strategies	Clinical application and value	Current limitations and challenges	Ref.
Standardized HER2 testing	IHC; FISH/CISH; NGS	IHC is the primary screening method. FISH/CISH confirm gene amplification. NGS provides a comprehensive genomic profile (e.g., HER2 amp, mutations, co-alterations like PIK3CA)	Subjectivity in IHC interpretation. Tumor heterogeneity leading to false-negatives. Chromosome 17 polysomy confounding FISH. NGS is not yet a routine primary test	Jebbink et al[99]; McLemore et al[134]; Taylor et al[135]; Klc et al[136]; Ciesielski et al[137]; Vermij et al[138]
Liquid biopsy	ctDNA; CTCs; exosomes	Enables dynamic monitoring of resistance and evolution. ctDNA tracks HER2 status and resistance mutations. CTC enumeration and phenotyping reflect tumor burden	Variable sensitivity in early-stage disease. Lack of standardization across platforms. Integration strategy with tissue biopsy is not yet defined	Ho et al[139]; Koessler et al[140]; Rossi and Ignatiadis[141]; Li et al[142]; Massihnia et al[143]
Integrated multi-omics analysis	Genomics; transcriptomics; proteomics	Provides a holistic view of tumor biology. Identifies molecular subtypes for targeted therapies (e.g., ADCs). Guides rational combination strategies	Requires bioinformatics expertise. High cost challenges routine use. Needs prospective validation for clinical utility	Yuan et al[144]; Pfeifer and Schimek[145]; Kerr and Yang[146]; Bueno et al[147]
Future directions	AI; biomarker-driven individualized framework	AI enhances IHC objectivity and integrates multi-omics for predictive modeling. Establishes refined molecular characterization to guide personalized therapy intensity	AI models require large-scale data for validation. Translating novel biomarkers requires interdisciplinary collaboration and workflow redesign	Jebbink et al[99]; Yuan et al[144]; Bueno et al[147]

HER2: Human epidermal growth factor receptor 2; IHC: Immunohistochemistry; FISH: Fluorescence in situ hybridization; CISH: Chromogenic in situ hybridization; NGS: Next-generation sequencing; ctDNA: Circulating tumor DNA; CTC: Circulating tumor cell; AI: Artificial intelligence; ADC: Antibody-drug conjugate.