Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups

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    Kim E M van Kessel, Department of Urology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands., Kirstin A van der Keur, Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands.,
  • Lars Dyrskjøt
  • Ferran Algaba, Section of Pathology, Fundacio Puigvert, Universitat Autónoma de Barcelona, Barcelona, Spain., Naeromy Y C Welvaart, Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands., Willemien Beukers, Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands., Ulrika Segersten, Department of Surgical Sciences, Thoracic Surgery, Uppsala University, Uppsala, Sweden., Bastian Keck, Department of Urology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Tobias Maurer, Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany., Tatjana Simic, Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia., Marcus Horstmann, Department of Urology, Friedrich-Schiller-University Jena, Jena, Germany., Marc-Oliver Grimm, Department of Urology, Friedrich-Schiller-University Jena, Jena, Germany., Gregers G Hermann, Department of Urology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark., Karin Mogensen, Department of Urology, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark., Arndt Hartmann, Institute of Pathology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Niels Harving, Department of Urology, Aalborg University Hospital, Aalborg, Denmark., Astrid C Petersen, Department of Pathology, Aalborg University Hospital, 9100 Aalborg, Denmark.,
  • Jørgen B Jensen
  • Kerstin Junker, Department of Urology and Pediatric Urology, Saarland University Medical Center, 66424 Homburg, Germany., Joost L Boormans, Department of Urology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands., Francisco X Real, Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid; Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain., Núria Malats, Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, CIBERONC, Spain., Per-Uno Malmström, Department of Surgical Sciences, Thoracic Surgery, Uppsala University, Uppsala, Sweden.,
  • Torben F Ørntoft
  • Ellen C Zwarthoff, Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, the Netherlands. e.zwarthoff@erasmusmc.nl.

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.

Original languageEnglish
JournalClinical Cancer Research
Volume24
Issue number7
Pages (from-to)1586-1593
Number of pages8
ISSN1078-0432
DOIs
StatePublished - 1 Apr 2018

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