Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Langenbeck s Archives of Surgery

DOI: 10.1007/s00423-026-04340-8