Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status.

To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format.

The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis.

Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

Frontiers in oncology. 2024 Jan 12*** epublish ***

Jan H Müller, Henning Plage, Sefer Elezkurtaj, Tim Mandelkow, Zhihao Huang, Magalie C J Lurati, Jonas B Raedler, Nicolaus F Debatin, Eik Vettorazzi, Henrik Samtleben, Sebastian Hofbauer, Kira Furlano, Jörg Neymeyer, Irena Goranova, Bernhard Ralla, Sarah Weinberger, David Horst, Florian Roßner, Simon Schallenberg, Andreas H Marx, Margit Fisch, Michael Rink, Marcin Slojewski, Krystian Kaczmarek, Thorsten Ecke, Steffen Hallmann, Stefan Koch, Nico Adamini, Maximilian Lennartz, Sarah Minner, Ronald Simon, Guido Sauter, Henrik Zecha, Thorsten Schlomm, Elena Bady

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of Urology, Charité Berlin, Berlin, Germany., Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Insitute of Pathology, Charité Berlin, Berlin, Germany., Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany., Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of Urology, University Hospital Stettin, Stettin, Poland., Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany., Department of Pathology, Helios Hospital Bad Saarow, Bad Saarow, Germany., Department of Urology, Albertinen Hospital, Hamburg, Germany.