High prevalence of TROP2 expression identifies EBV-positive gastric cancer as a candidate for TROP2-directed antibody–drug conjugates

Purpose Trophoblast cell surface antigen 2 (TROP2) is a glycoprotein expressed on epithelial tumor cells and therefore an established target for antibody-drug conjugates (ADCs). Epstein-Barr virus (EBV)-positive gastric cancer is a molecularly distinct subtype characterized by unique immunological features, including frequent responsiveness to immune checkpoint inhibitors (ICIs). Nevertheless, a subset of these patients fails to benefit from ICI therapy, leaving an unmet need for non-immunotherapeutic treatment options. Tumors lacking TROP2, fail to respond to TROP2-directed ADCs. We therefore assessed the prevalence of TROP2 expression in gastric cancer including the EBV-positive subtype, which has not been characterized to date. Methods TROP2 expression was evaluated by immunohistochemistry in 525 patients with gastric cancer classified according to TCGA molecular subtypes, representing the largest Caucasian cohort assessed for TROP2 to date. Results TROP2 expression differed significantly across molecular subtypes (p < 0.01), with EBV-positive tumors showing the highest median expression (H-score 150). Complete absence of TROP2, the expression pattern associated with treatment failure, was observed in only 3.7% of EBV-positive tumors, compared with 18.8% of chromosomal instability, 25.4% of genomically stable, and 36.2% of microsatellite instability tumors. Conclusion Nearly all EBV-positive gastric cancers therefore express TROP2 at levels compatible with ADC targeting. These findings identify TROP2 as a target in EBV-positive gastric cancer and provide a rationale for clinical investigation of TROP2-directed ADCs in this molecularly defined population, particularly as a non-immunotherapeutic option for patients who fail ICI therapy.