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. 2024 Jan 12:13:1342367.
doi: 10.3389/fonc.2023.1342367. eCollection 2023.

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

Jan H Müller  1 , Henning Plage  2 , Sefer Elezkurtaj  2 , Tim Mandelkow  1 , Zhihao Huang  1 , Magalie C J Lurati  1 , Jonas B Raedler  1   3 , Nicolaus F Debatin  1 , Eik Vettorazzi  4 , Henrik Samtleben  2 , Sebastian Hofbauer  2 , Kira Furlano  2 , Jörg Neymeyer  2 , Irena Goranova  2 , Bernhard Ralla  2 , Sarah Weinberger  2 , David Horst  5 , Florian Roßner  5 , Simon Schallenberg  5 , Andreas H Marx  6 , Margit Fisch  7 , Michael Rink  7 , Marcin Slojewski  8 , Krystian Kaczmarek  8 , Thorsten Ecke  9 , Steffen Hallmann  9 , Stefan Koch  10 , Nico Adamini  11 , Maximilian Lennartz  1 , Sarah Minner  1 , Ronald Simon  1 , Guido Sauter  1 , Henrik Zecha  11 , Thorsten Schlomm  2 , Elena Bady  1
Affiliations

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

Jan H Müller et al. Front Oncol. .

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: EpCAM; TROP2; bladder cancer; multiplex fluorescence immunohistochemistry; muscle invasive urothelial cancer.

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Conflict of interest statement

The recombinant EpCAM antibody clone MSVA-326R, the recombinant TROP2 antibody clone MSVA-733R, the recombinant panCK antibody clone MSVA-000R were provided by MS Validated Antibodies GmbH owned by a family member of GS.

Figures

Figure 1
Figure 1
(A) TROP2 (red), EpCAM (yellow) and combined staining intensity (co-expression) on normal urothelial tissue. Epithelial cells are displayed with panCK (green). (B) TROP2 (red), EpCAM (yellow) and combined staining intensity (co-expression) in pTa and muscle invasive urothelial carcinomas. Epithelial cells are displayed with panCK (green).
Figure 2
Figure 2
TROP2 and EpCAM intensity in pTa G2 low, pTa G3 and muscle invasive (pT2-4) bladder cancer.
Figure 3
Figure 3
Survival assessment of TROP2 expression in muscle invasive urothelial bladder cancer. (A) Survival assessment of Trop2 expression according to overall survival. (B) Survival assessment of Trop2 expression according to cancer specific survival.
Figure 4
Figure 4
Survival assessment of EpCAM expression in muscle invasive urothelial bladder cancer. (A) Survival assessment of EpCAM expression according to overall survival. (B) Survival assessment of EpCAM expression according to cancer specific survival.
Figure 5
Figure 5
Survival assessment of TROP2/EpCAM ratio in muscle invasive urothelial bladder cancer. (A) Survival assessment of Trop2/EpCAM ratio according to overall survival. (B) Survival assessment of Trop2/EpCAM ratio according to cancer specific survival.
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