Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients

Laura S. Mertens, Francesco Claps, Roman Mayr, Peter J. Bostrom, Shahrokh F. Shariat, 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, Dennis Peters, Michiel S. van der Heijden, Michael A. S. Jewett, Robert Stöhr, Alexandre R. ZlottaMarkus Eckstein, Yanish Soorojebally, Deric K. E. van der Schoot, Bernd Wullich, Maximilian Burger, Wolfgang Otto, François Radvanyi, Nanour Sirab, Damien Pouessel, Theo H. van der Kwast, Arndt Hartmann, Yair Lotan, Yves Allory, Tahlita C. M. Zuiverloon, Bas W. G. van Rhijn

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Abstract

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. Patients and methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). Results: pT-stage was <pT2 in 80, pT2 in 266, pT3 in 513 and pT4 in 199 patients, respectively. Cancer-positive nodes were found in 410 (39%) patients. An FGFR3 mutation was detected in 107 (10%) and aberrant p53 and Ki-67 expression in 718 (68%) and 581(55%) tumors, respectively. The FGFR3 mutation was associated with lower pT-stage (P<0.001), lower grade (P<0.001), pN0 (P=0.001) and prolonged DSS (P<0.001). Aberrant Ki-67 and p53 expression were associated with higher pT-stage and G3-tumors, but not with pN-stage or worse DSS, even if these IHC-biomarkers were combined (P=0.81). Significant predictors for DSS in multivariable analysis were pT-stage (HR1.5, 95%CI:1.3-1.6; P<0.001), lympho-vascular invasion (LVI) (HR1.4, 95%CI:1.2-1.7; P=0.001), pN-stage (HR1.9, 95%CI:1.6-2.4; P<0.001) and FGFR3 mutation status (HR1.6, 95%CI:1.1-2.2; P=0.011). Conclusion: The FGFR3 mutation selectively identified patients with favorable BC at RC while p53 and Ki-67 were only associated with adverse tumor characteristics. Our results suggest that, besides tumor-stage, nodal-status and LVI, the oncogenic FGFR3 mutation may represent a valuable tool to guide adjuvant treatment and follow-up strategies after RC.

Original languageEnglish
JournalUrologic oncology
Early online date2021
DOIs
Publication statusE-pub ahead of print - 2021

Keywords

  • Bladder
  • Cancer
  • Cystectomy
  • FGFR3
  • Immunohistochemistry
  • Ki-67
  • Mutation
  • Urothelial carcinoma
  • p53

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