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Publications

Journal Article Epublish

PubMed: 42925415 DOI: 10.1007/s00423-026-04340-8

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

Langenbecks Arch Surg 411(1)

Authors: Tristan Wagner, Richard Weiten, Su Ir Lyu, Aylin Pamuk, Axel Heidenreich, Christiane J Bruns, Alexander Quaas, Hakan Alakus, Nikolai Schleussner

Affiliations

  • Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Cologne, Kerpenertsr. 62, 50937, Cologne, Germany. Department of Surgery, Center for Life Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
  • Department of Urology, Uro-Oncology, Robot-Assisted, and Specialized Urologic Surgery, University Hospital Cologne, Cologne, Germany.
  • Institute of Pathology, University Hospital Cologne, Cologne, Germany.
  • Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Cologne, Kerpenertsr. 62, 50937, Cologne, Germany.

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.

MeSH

Cells, Antigens, Surface, Pharmaceutical Preparations, Neoplasms, Herpesvirus 4, Human, Prevalence, Therapeutics, Stomach Neoplasms