PMID- 38482675 OWN - NLM STAT- MEDLINE DCOM- 20240315 LR - 20240316 IS - 1591-951X (Electronic) IS - 0031-2983 (Print) IS - 0031-2983 (Linking) VI - 116 IP - 1 DP - 2024 Feb TI - TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma. PG - 55-61 LID - 10.32074/1591-951X-937 [doi] AB - 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. CI - Copyright (c) 2024 Societa Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology. FAU - Brunelli, Matteo AU - Brunelli M AD - Department of Diagnostics and Public Health, University of Verona, Italy. FAU - Gobbo, Stefano AU - Gobbo S AD - Department of Translational Medicine, University of Ferrara, Italy. FAU - Malpeli, Giorgio AU - Malpeli G AD - Department of Human Sciences for the Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy. FAU - Sirgiovanni, Grazia AU - Sirgiovanni G AD - Medical and Translational Oncology, Department of Oncology, Azienda Ospedaliera S. Maria, Terni, Italy. FAU - Caserta, Claudia AU - Caserta C AD - Medical and Translational Oncology, Department of Oncology, Azienda Ospedaliera S. Maria, Terni, Italy. FAU - Munari, Enrico AU - Munari E AD - Department of Molecular and Translational Medicine, University of Brescia, Italy. FAU - Francesconi, Simona AU - Francesconi S AD - Pathology Unit, Azienda Ospedaliera S. Maria, Terni, Italy. FAU - Calio, Anna AU - Calio A AD - Department of Diagnostics and Public Health, University of Verona, Italy. FAU - Martignoni, Guido AU - Martignoni G AD - Pathology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy. FAU - Cimadamore, Alessia AU - Cimadamore A AD - Institute of Pathological Anatomy, Department of Medicine, University of Udine, Udine, Italy. FAU - Veccia, Alessandro AU - Veccia A AD - Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. FAU - Antonelli, Alessandro AU - Antonelli A AD - Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. FAU - Tucci, Marcello AU - Tucci M AD - Oncology Unit, Cardinal Massaia Hospital, Asti, Italy. FAU - Pierconti, Francesco AU - Pierconti F AD - Gemelli Hospital, Universita Cattolica del S. Cuore di Roma, Italy. FAU - Hattab, Isabelle Malak AU - Hattab IM AD - Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center and the Legorreta Cancer Center at Brown University, Providence, RI, USA. FAU - Eccher, Albino AU - Eccher A AD - Section of Pathology, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, University Hospital of Modena, Italy. FAU - Ascani, Stefano AU - Ascani S AD - Unit of Pathology, S. Maria di Terni Hospital, University of Perugia, Terni, Italy. FAU - Milella, Michele AU - Milella M AD - Section of Oncology, University of Verona - School of Medicine, Verona University Hospital Trust, Italy. FAU - Buffoni, Lucio AU - Buffoni L AD - Medical Oncology, Humanitas Gradenigo, Torino, Italy. FAU - Cheng, Liang AU - Cheng L AD - Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center and the Legorreta Cancer Center at Brown University, Providence, RI, USA. FAU - Bracarda, Sergio AU - Bracarda S AD - Medical and Translational Oncology, Department of Oncology, Azienda Ospedaliera S. Maria, Terni, Italy. LA - eng PT - Journal Article PL - Italy TA - Pathologica JT - Pathologica JID - 0401123 RN - 0 (B7-H1 Antigen) RN - 0 (Nectins) RN - 0 (Biomarkers, Tumor) SB - IM MH - Humans MH - *Carcinoma, Transitional Cell/pathology MH - *Urinary Bladder Neoplasms/diagnosis/genetics MH - B7-H1 Antigen MH - Nectins/genetics MH - Urinary Bladder/pathology MH - In Situ Hybridization, Fluorescence MH - Biomarkers, Tumor/analysis PMC - PMC10938277 OTO - NOTNLM OT - NECTIN-4 OT - TROP-2 OT - biomarker OT - bladder OT - urothelial carcinoma COIS- The authors declare no conflict of interest. EDAT- 2024/03/14 06:47 MHDA- 2024/03/15 06:43 PMCR- 2024/03/01 CRDT- 2024/03/14 05:35 PHST- 2023/10/17 00:00 [received] PHST- 2024/01/22 00:00 [accepted] PHST- 2024/03/15 06:43 [medline] PHST- 2024/03/14 06:47 [pubmed] PHST- 2024/03/14 05:35 [entrez] PHST- 2024/03/01 00:00 [pmc-release] AID - 10.32074/1591-951X-937 [doi] PST - ppublish SO - Pathologica. 2024 Feb;116(1):55-61. doi: 10.32074/1591-951X-937.