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

Urol Oncol. 2022 Mar;40(3):110.e1-110.e9. doi: 10.1016/j.urolonc.2021.10.010. Epub 2021 Dec 11.

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.

Keywords: Bladder; Cancer; Cystectomy; FGFR3; Immunohistochemistry; Ki-67; Mutation; Urothelial carcinoma; p53.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cystectomy / methods
  • Female
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Mutation
  • Prognosis
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Retrospective Studies
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism
  • Urinary Bladder Neoplasms* / genetics
  • Urinary Bladder Neoplasms* / pathology
  • Urinary Bladder Neoplasms* / surgery

Substances

  • Ki-67 Antigen
  • MKI67 protein, human
  • Tumor Suppressor Protein p53
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3