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FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment?

  • Mertens L.S. 1,
  • Van Rhijn B.W.G. 1,
  • Mayr R. 2,
  • Bostrom P.J. 3,
  • Marquez M. 4,
  • Zwarthoff E.C. 5,
  • Boormans J.L. 6,
  • Abas C. 5,
  • Van Leenders G. 5,
  • Neuzillet Y. 1,
  • Van Der Heijden M.S. 7,
  • Real F.X. 4,
  • Stohr R. 8,
  • Zlotta A.R. 9,
  • Eckstein M. 8,
  • Soorojebally Y. 10,
  • Burger M. 2,
  • Radvanyi F. 10,
  • Sirab N. 10,
  • Pouessel D. 10,
  • Van Der Kwast T.H. 11,
  • Malats N. 4,
  • Hartmann A. 8,
  • Allory Y. 10,
  • Zuiverloon T. 6
1 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Dept of Surgical Oncology, Urology, Amsterdam, The Netherlands 2 Caritas St Joseph Medical Center, University of Regensburg , Dept. of Urology, Regensburg, Germany 3 University of Turku, Dept. of Urology, Turku, Finland 4 CNIO, Dept. of Genetic Molecular Epidemiology and Cancer Biology, Madrid, Spain 5 Erasmus MC, Dept. of Pathology, Rotterdam, The Netherlands 6 Erasmus MC, Dept. of Urology, Rotterdam, The Netherlands 7 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Dept. of Medical Oncology, Amsterdam, The Netherlands 8 University of Erlangen, Dept. of Pathology, Erlangen, Germany 9 University Health Network, Dept. of Urology, Toronto, Canada 10 Institut Curie, Dept. of Pathology, Paris, France 11 University Health Network, Dept. of Pathology, Toronto, Canada

Publication: March 2019

Introduction & Objectives

Fibroblast Growth Factor Receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Over-expression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations, protein-expression of FGFR3 and p53 and assessed their prognostic value in a multi-center, multi-laboratory setting.

Materials & Methods

We included 1000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uro-pathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expressions were correlated to each-other, clinico-pathological parameters and disease-specific survival (DSS).


FGFR3 mutations were found in 107/1000 RCs (11%), of which 67 were S249C. Over-expression of FGFR3 was found in 279/1000 (28%) of tumors. p53 overexpression (cut-off>10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 over-expression. Among FGFR3 wild-type tumors, 22% had FGFR3 over-expression. FGFR3 mutations were associated with lower pT-stage (P<0.001), lower grade (G2-WHO 1973) (P<0.001), absence of CIS (P=0.009), pN0 (P<0.001), normal p53 (P<0.001) and prolonged DSS (Plog-rank=0.001). FGFR3 over-expression was associated with lower pT-stage (P<0.001) and G2 (P<0.001) but not with absence of CIS (P=0.860), pN0 (P=0.230), normal p53 (P=0.330) nor prolonged DSS (Plog-rank=0.204). We found no significant difference in DSS for patients with FGFR3 mutant tumors comparing normal vs over-expression of FGFR3 (Plog-rank=0.444). Furthermore, we also found no significant difference in DSS for patients with FGFR3 wild-type tumors comparing normal vs over-expression of FGFR3 (Plog-rank=0.754).


FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 over-expression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 over-expression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only over-expression of FGFR3.