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

Abstract

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).

Results

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).

Conclusions

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.