FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment?†

Bas W G van Rhijn; Laura S Mertens; Roman Mayr; Peter J Bostrom; Francisco X Real; Ellen C Zwarthoff; Joost L Boormans; Cheno Abas; Geert J L H van Leenders; Stefanie Götz; Katrin Hippe; Simone Bertz; Yann Neuzillet; Joyce Sanders; Annegien Broeks; Michiel S van der Heijden; Michael A S Jewett; Mirari Marquez; Robert Stoehr; Alexandre R Zlotta; Markus Eckstein; Yanish Soorojebally; Hossain Roshani; Maximilian Burger; Wolfgang Otto; François Radvanyi; Nanor Sirab; Damien Pouessel; Bernd Wullich; Theo H van der Kwast; Núria Malats; Arndt Hartmann; Yves Allory; Tahlita C M Zuiverloon

doi:10.1016/j.eururo.2020.07.002

FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment?^†

Eur Urol. 2020 Nov;78(5):682-687. doi: 10.1016/j.eururo.2020.07.002. Epub 2020 Jul 15.

Authors

Bas W G van Rhijn¹, Laura S Mertens², Roman Mayr³, Peter J Bostrom⁴, Francisco X Real⁵, Ellen C Zwarthoff⁶, Joost L Boormans⁷, Cheno Abas⁶, Geert J L H van Leenders⁸, Stefanie Götz³, Katrin Hippe⁹, Simone Bertz¹⁰, Yann Neuzillet², Joyce Sanders¹¹, Annegien Broeks¹¹, Michiel S van der Heijden¹², Michael A S Jewett¹³, Mirari Marquez¹⁴, Robert Stoehr¹⁰, Alexandre R Zlotta¹³, Markus Eckstein¹⁰, Yanish Soorojebally¹⁵, Hossain Roshani¹⁶, Maximilian Burger³, Wolfgang Otto³, François Radvanyi¹⁵, Nanor Sirab¹⁵, Damien Pouessel¹⁷, Bernd Wullich¹⁸, Theo H van der Kwast¹⁹, Núria Malats¹⁴, Arndt Hartmann¹⁰, Yves Allory²⁰, Tahlita C M Zuiverloon²¹

Affiliations

¹ Departments of Surgery (Urology) and Surgical Oncology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada; Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Urology, Caritas St Josef Medical Center, University of Regensburg, Regensburg, Germany. Electronic address: [email protected].
² Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
³ Department of Urology, Caritas St Josef Medical Center, University of Regensburg, Regensburg, Germany.
⁴ Departments of Surgery (Urology) and Surgical Oncology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada; Department of Urology, Turku University Hospital and University of Turku, Turku, Finland.
⁵ Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO) & CIBERONC, Madrid, Spain; Department of de Ciències Experimentals i de la Salut, University Pompeu Fabra, Barcelona, Spain.
⁶ Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
⁷ Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
⁸ Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands; Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
⁹ Department of Pathology, University Medical Center-Regensburg, Regensburg, Germany.
¹⁰ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen/Nürnberg, Erlangen, Germany.
¹¹ Core Facility Molecular Pathology & Biobank, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹² Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹³ Departments of Surgery (Urology) and Surgical Oncology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
¹⁴ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁵ Institut Curie, CNRS, UMR144, Molecular Oncology Team, PSL Research University, Paris, France.
¹⁶ Department of Urology, Haga Ziekenhuis, The Hague, The Netherlands.
¹⁷ Institut Curie, CNRS, UMR144, Molecular Oncology Team, PSL Research University, Paris, France; Department of Medical Oncology, Claudius Regaud Institute, Toulouse University Cancer Center (IUCT) Oncopole, Toulouse, France.
¹⁸ Department of Urology & Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen/Nürnberg, Erlangen, Germany.
¹⁹ Department of Pathology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
²⁰ Institut Curie, CNRS, UMR144, Molecular Oncology Team, PSL Research University, Paris, France; Department of Pathology, Institut Curie, Paris, France.
²¹ Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands; Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands. Electronic address: [email protected].

PMID: 32682615
DOI: 10.1016/j.eururo.2020.07.002

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer (BC). FGFR3 mutations are common in noninvasive BC and associated with favorable BC prognosis. Overexpression was reported in up to 40% of FGFR3 wild-type muscle-invasive BC. We analyzed FGFR3 mutations, FGFR3, and p53 protein expression and assessed their prognostic value in a cohort of 1000 chemotherapy-naive radical cystectomy specimens. FGFR3 mutations were found in 11%, FGFR3 overexpression was found in 28%, and p53 overexpression was found in 69% of tumors. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression versus 22% among FGFR3 wild-type tumors. FGFR3 mutations were significantly associated with lower pT stage, tumor grade, absence of carcinoma in situ, pN0, low-level p53, and longer disease-specific survival (DSS). FGFR3 overexpression was associated only with lower pT stage and tumor grade. Moreover, FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. In conclusion, FGFR3 mutations identified patients with favorable BC at cystectomy. Our results suggest that FGFR3 mutations have a driver role and are functionally distinct from FGFR3 overexpression. Hence, patients with FGFR3 mutations would be more likely to benefit from anti-FGFR3 therapy. Ideally, further research is needed to test this hypothesis. PATIENT SUMMARY: Oncogenic fibroblast growth factor receptor 3 (FGFR3) mutations are very common in bladder cancer. In this report, we found that these FGFR3 mutations were associated with favorable features and prognosis of bladder cancer compared with patients with FGFR3 overexpressed tumors only. As a consequence, patients with FGFR3 mutant tumors would be more likely to benefit from anti-FGFR3 therapy than patients with FGFR3 protein overexpression only.

Keywords: Bladder; Cancer; Cystectomy; Expression; FGFR3; Mutation; Urothelial carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Cohort Studies
Cystectomy* / methods
Female
Gene Expression Regulation, Neoplastic*
Humans
Male
Middle Aged
Mutation*
Prognosis
Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 / genetics*
Survival Rate
Urinary Bladder Neoplasms / drug therapy
Urinary Bladder Neoplasms / genetics*
Urinary Bladder Neoplasms / mortality
Urinary Bladder Neoplasms / surgery*

Substances

FGFR3 protein, human
Receptor, Fibroblast Growth Factor, Type 3