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. 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: b.v.rhijn@nki.nl. 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: t.zuiverloon@erasmusmc.nl.
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.
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.
Authors: Sophie Wucherpfennig; Michael Rose; Angela Maurer; Maria Angela Cassataro; Lancelot Seillier; Ronja Morsch; Ehab Hammad; Philipp Heinrich Baldia; Thorsten H Ecke; Thomas-Alexander Vögeli; Ruth Knüchel; Nadine T Gaisa Journal: Int J Mol Sci Date: 2021-10-26 Impact factor: 5.923