Pure high-grade papillary urothelial bladder cancer: a luminal-like subgroup with potential for targeted therapy
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ORIGINAL PAPER
Pure high-grade papillary urothelial bladder cancer: a luminal-like subgroup with potential for targeted therapy Tician Schnitzler 1 & Nadina Ortiz-Brüchle 1 & Ursula Schneider 1 & Isabella Lurje 1 & Karolina Guricova 1 & Alexander Buchner 2 & Gerald Bastian Schulz 2 & Axel Heidenreich 3,4 & Nadine Therese Gaisa 1 & Ruth Knüchel 1 & Stefan Garczyk 1 Received: 17 December 2019 / Revised: 6 April 2020 / Accepted: 15 April 2020 # The Author(s) 2020
Abstract Purpose Non-invasive high-grade (HG) bladder cancer is a heterogeneous disease that is characterized insufficiently. First-line Bacillus Calmette-Guérin instillation fails in a substantial amount of cases and alternative bladder-preserving treatments are limited, underlining the need to promote a further molecular understanding of non-invasive HG lesions. Here, we characterized pure HG papillary urothelial bladder cancer (pure pTa HG), a potential subgroup of non-invasive HG bladder carcinomas, with regard to molecular subtype affiliation and potential for targeted therapy. Methods An immunohistochemistry panel comprising luminal (KRT20, ERBB2, ESR2, GATA3) and basal (KRT5/6, KRT14) markers as well as p53 and FGFR3 was used to analyze molecular subtype affiliations of 78 pure pTa HG/papillary pT1(a) HG samples. In 66 of these, ERBB2 fluorescence in situ hybridization was performed. Additionally, targeted sequencing (31 genes) of 19 pTa HG cases was conducted, focusing on known therapeutic targets or those described to predict response to targeted therapies noted in registered clinical trials or that are already approved. Results We found that pure pTa HG/papillary pT1(a) HG lesions were characterized by a luminal-like phenotype associated with frequent (58% of samples) moderate to high ERBB2 protein expression, rare FGFR3 alterations on genomic and protein levels, and a high frequency (89% of samples) of chromatin-modifying gene alterations. Of note, 95% of pTa HG/papillary pT1 HG cases harbored at least one potential druggable genomic alteration. Conclusions Our data should help guiding the selection of targeted therapies for investigation in future clinical trials and, additionally, may provide a basis for prospective mechanistic studies of pTa HG pathogenesis. Keywords Papillary bladder cancer . Non-muscle-invasive, high-grade bladder cancer . pTa HG . Targeted therapy . Molecular subtype . Luminal and basal markers
1 Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00524-6) contains supplementary material, which is available to authorized users. * Stefan Garczyk [email protected] 1
Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
2
Department of Urology, Ludwig-Maximilians-University Munich, Munich, Germany
3
Department of Urology, University Hospital Cologne, Cologne, Germany
4
Department of Urology, University Hospital RWTH Aachen, Aachen, Germany
Bladder cancer (BC) is the most common malignancy of the urinary tract
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