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

Mertens, Laura S.

; Claps, Francesco

; Mayr, Roman ; Bostrom, Peter J. ; Shariat, Shahrokh F.

; Zwarthoff, Ellen C.

; Boormans, Joost L. ; Abas, Cheno ; van Leenders, Geert J.L.H.

; Götz, Stefanie ; Hippe, Katrin ; Bertz, Simone ; Neuzillet, Yann ; Sanders, Joyce ; Broeks, Annegien ; Peters, Dennis ; van der Heijden, Michiel S. ; Jewett, Michael A.S. ; Stöhr, Robert ; Zlotta, Alexandre R. ; Eckstein, Markus ; Soorojebally, Yanish ; van der Schoot, Deric K.E. ; Wullich, Bernd ; Burger, Maximilian ; Otto, Wolfgang ; Radvanyi, François ; Sirab, Nanour ; Pouessel, Damien ; van der Kwast, Theo H. ; Hartmann, Arndt ; Lotan, Yair ; Allory, Yves ; Zuiverloon, Tahlita C.M. ; van Rhijn, Bas W.G.

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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 (cutoff> 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. (C) 2021 Elsevier Inc. All rights reserved.

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