Biomarker-Driven Precision Oncology in Advanced Gastroesophageal Adenocarcinoma: Current Standards and Future Directions

Abstract

: Advanced gastroesophageal adenocarcinomas (GEA) have undergone a major therapeutic shift from empiric chemotherapy toward biomarker-driven precision oncology. Routine incorporation of immunohistochemistry (IHC), in situ hybridization, next-generation sequencing (NGS), and liquid biopsy have enabled identification of actionable subgroups that now guide first-line and subsequent treatment selection. Four biomarkers have established clinical utility in current practice: mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status, human epidermal growth factor receptor 2 (HER2) amplification or overexpression, programmed death ligand 1 (PD-L1) expression, and claudin 18.2 (CLDN18.2). MSI-H/dMMR represents the strongest predictor of durable benefit from immune checkpoint inhibition across treatment lines. HER2-positive disease has evolved beyond trastuzumab-based therapy with the emergence of antibody–drug conjugates and bispecific antibodies that are redefining outcomes. PD-L1 combined positive score (CPS) remains most impactful in selecting patients for first-line chemo-immunotherapy, while its predictive role beyond first line is less consistent. Most recently, CLDN18.2 targeting has expanded therapeutic options in HER2-negative disease, with zolbetuximab establishing a new first-line standard and multiple antibody drug conjugate strategies emerging. This review aims to summarize the current evidence supporting biomarker-driven treatment strategies in advanced GEA, highlight practical biomarker testing considerations, and discuss ongoing challenges and future directions in precision oncology.