Prognostic Impact and Clinicopathological Correlates of HER2 Status in Gastric Cancer: A Multicenter Retrospective Turkish Oncology Group Study

Background: Gastric cancer remains one of the most common malignancies and a leading cause of cancer-related mortality worldwide. Human epidermal growth factor receptor 2 (HER2) status is a key biomarker influencing both prognosis and treatment selection. While HER2-positive patients benefit from trastuzumab, outcomes for HER2-low and HER2-zero groups remain less clearly defined. Methods: In this retrospective cohort study, we reviewed 507 patients diagnosed with metastatic gastric adenocarcinoma between 2015 and 2023. Patients were classified as HER2-zero (n = 134), HER2-low (n = 303), or HER2-positive (n = 70) based on immunohistochemistry and in situ hybridization results. Clinicopathologic features, treatment strategies, and survival outcomes were analyzed. Kaplan-Meier methods estimated progression-free survival (PFS) and overall survival (OS), whereas Cox regression identified independent prognostic factors. Results: The HER2-positive group achieved a median PFS of 9.0 months and OS of 20.0 months, superior to HER2-zero patients (PFS: 6.1; OS: 14.5; P < .001). HER2-low patients demonstrated intermediate outcomes (PFS: 6.7; OS: 16.6 months). Group distribution was HER2-zero 26.4%, HER2-low 59.8%, and HER2-positive 13.8%. All HER2-positive patients received trastuzumab-based therapy. Multivariate analysis confirmed HER2-positive status as an independent predictive factor for both progression (hazard ratio [HR] = 0.65) and mortality (HR = 0.62). Conclusions: HER2 status is a strong predictive determinant in metastatic gastric cancer. Trastuzumab provided significant real-world benefit for HER2-positive patients, validating the impact of targeted therapy. Notably, HER2-low patients had better outcomes than HER2-zero, supporting the recognition of HER2-low as a distinct subgroup with potential eligibility for future HER2-directed treatments.