HER2 and PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer: Insights for Combinatorial Targeting Approaches

Simple Summary In advanced, unresectable and metastatic gastric and gastroesophageal junction adenocarcinoma (GA/GEJA), Human Epidermal Growth Factor Receptor 2 (HER2) and programmed death-ligand 1 (PD-L1) expression play an important role in treatment selection. However, their potential clinical application in earlier stages of disease remains unexplored. The aim of this study was to evaluate the expression patterns of HER2 and PD-L1 in a curative-intent GA/GEJA cohort. Furthermore, we analyzed the association between HER2 expression and clinicopathological features. Among 107 patients, 8.4% were HER2-positive and seven of these also had a PD-L1 combined positive score of >= 1. HER2 status was not statistically significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. These novel findings indicate that combinatorial strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. These different biomarker expression patterns may have important therapeutic and prognostic implications.Abstract Gastric and gastroesophageal junction adenocarcinomas (GA/GEJA) are associated with a poor prognosis, primarily due to late disease diagnosis. Human Epidermal Growth Factor Receptor 2 (HER2) overexpression and programmed death-ligand 1 (PD-L1) expression are important biomarkers for treatment selection in locally advanced unresectable and metastatic GA/GEJA, and there is increasing interest in their role in earlier stages of disease. In this study, we aimed to evaluate HER2 and PD-L1 expression in a curative-intent GA/GEJA cohort to describe their expression patterns and analyze the association between HER2 expression and clinicopathological features. HER2 expression was evaluated in surgical and endoscopic submucosal dissection tumor samples, and PD-L1 was evaluated in HER2-positive cases. The clinical cohort included 107 patients, with 8.4% testing positive for HER2 (seven of whom also exhibited a PD-L1 combined positive score of >= 1. HER2 status was not significantly associated with survival outcomes. A pathologist-guided, region-specific analysis revealed that PD-L1 expression rarely overlaps with HER2-positive tumor areas. While the therapeutic implications of these observations remain unknown, these findings suggest that combination strategies targeting HER2 and PD-L1 might be directed toward distinct tumor subclones. The herein disclosed region-specific biomarker expression patterns may have important therapeutic and prognostic impacts, warranting further evaluation.