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.
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.
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.
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.
Pathologica. 2024 Feb [Epub]
Matteo Brunelli, Stefano Gobbo, Giorgio Malpeli, Grazia Sirgiovanni, Claudia Caserta, Enrico Munari, Simona Francesconi, Anna Caliò, Guido Martignoni, Alessia Cimadamore, Alessandro Veccia, Alessandro Antonelli, Marcello Tucci, Francesco Pierconti, Isabelle Malak Hattab, Albino Eccher, Stefano Ascani, Michele Milella, Lucio Buffoni, Liang Cheng, Sergio Bracarda
Department of Diagnostics and Public Health, University of Verona, Italy., Department of Translational Medicine, University of Ferrara, Italy., Department of Human Sciences for the Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy., Medical and Translational Oncology, Department of Oncology, Azienda Ospedaliera S. Maria, Terni, Italy., Department of Molecular and Translational Medicine, University of Brescia, Italy., Pathology Unit, Azienda Ospedaliera S. Maria, Terni, Italy., Pathology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy., Institute of Pathological Anatomy, Department of Medicine, University of Udine, Udine, Italy., Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy., Oncology Unit, Cardinal Massaia Hospital, Asti, Italy., Gemelli Hospital, Università Cattolica del S. Cuore di Roma, Italy., 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., Section of Pathology, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, University Hospital of Modena, Italy., Unit of Pathology, S. Maria di Terni Hospital, University of Perugia, Terni, Italy., Section of Oncology, University of Verona - School of Medicine, Verona University Hospital Trust, Italy., Medical Oncology, Humanitas Gradenigo, Torino, Italy.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/38482675