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. 2024 Feb;116(1):55-61.
doi: 10.32074/1591-951X-937.

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

Matteo Brunelli  1 , Stefano Gobbo  2 , Giorgio Malpeli  3 , Grazia Sirgiovanni  4 , Claudia Caserta  4 , Enrico Munari  5 , Simona Francesconi  6 , Anna Caliò  1 , Guido Martignoni  7 , Alessia Cimadamore  8 , Alessandro Veccia  9 , Alessandro Antonelli  9 , Marcello Tucci  10 , Francesco Pierconti  11 , Isabelle Malak Hattab  12 , Albino Eccher  13 , Stefano Ascani  14 , Michele Milella  15 , Lucio Buffoni  16 , Liang Cheng  12 , Sergio Bracarda  4
Affiliations

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

Matteo Brunelli et al. Pathologica. 2024 Feb.

Abstract

Introduction: The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC.

Aims: In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways.

Results: Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC.

Conclusion: Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

Keywords: NECTIN-4; TROP-2; biomarker; bladder; urothelial carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Heat map for TROP-2, NECTIN-4 and other biomarkers in 35 undifferentiated urothelial bladder carcinoma (Red: positive; Green; negative).
Figure 2.
Figure 2.
(A) Sarcomatoid urothelial bladder carcinoma (H&E; 200x). (B) Rhabdoid urothelial bladder carcinoma (H&E; 200x). (C) Sarcomatoid urothelial bladder carcinoma, TROP-2 diffuse immunoexpression. (D) Rhabdoid urothelial bladder carcinoma, NECTIN-4 diffuse immunoexpression. (E, F) Absence of TROP-2 and NECTIN-4 immunoexpression in sarcomatoid urothelial bladder carcinoma and rhabdoid urothelial bladder carcinoma respectively.
Figure 3.
Figure 3.
(A) Heat map of 100 microtubule genes in addition to NECTIN4 and TACSTD2 of 411 bladder urothelial carcinoma cases extracted from the TCGA, PanCancer Atlas study by cBioPortal; clustering function included in cBioPortal applied to mRNA levels. (B) Enriched pathway of gene cluster 1 and gene cluster 2.
See this image and copyright information in PMC

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