Prospective evaluation of a molecular marker panel for prediction of recurrence and cancer-specific survival after radical cystectomy

Eur Urol. 2013 Sep;64(3):465-71. doi: 10.1016/j.eururo.2013.03.043. Epub 2013 Apr 3.


Background: Retrospective studies demonstrated that cell cycle-related and proliferation biomarkers add information to standard pathologic tumor features after radical cystectomy (RC). There are no prospective studies validating the clinical utility of markers in bladder cancer.

Objective: To prospectively determine whether a panel of biomarkers could identify patients with urothelial carcinoma of the bladder (UCB) who were likely to experience disease recurrence or mortality.

Design, setting, and participants: Between January 2007 and January 2012, every patient with high-grade bladder cancer, including 216 patients treated with RC and lymphadenectomy, underwent immunohistochemical staining for tumor protein p53 (Tp53); cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A); cyclin-dependent kinase inhibitor 1B (p27, Kip1); antigen identified by monoclonal antibody Ki-67 (MKI67); and cyclin E1.

Intervention: Every patient underwent RC and lymphadenectomy, and marker staining.

Outcome measurements and statistical analysis: Cox regression analyses tested the ability of the number of altered biomarkers to predict recurrence or cancer-specific mortality (CSM).

Results and limitations: Pathologic stage among the study population was pT0 (5%), pT1 (35%), pT2 (19%), pT3 (29%), and pT4 (13%); lymphovascular invasion (LVI) was seen in 34%. The median number of removed lymph nodes was 23, and 60 patients had lymph node involvement (LNI). Median follow-up was 20 mo. Expression of p53, p21, p27, cyclin E1, and Ki-67 were altered in 54%, 26%, 46%, 15%, and 75% patients, respectively. In univariable analyses, pT stage, LNI, LVI, perioperative chemotherapy (CTx), margin status, and number of altered biomarkers predicted disease recurrence. In a multivariable model adjusting for pathologic stage, margins, LNI, and adjuvant CTx, only LVI and number of altered biomarkers were independent predictors of recurrence and CSM. The concordance index of a baseline model predicting CSM (including pathologic stage, margins, LVI, LNI, and adjuvant CTx) was 80% and improved to 83% with addition of the number of altered markers.

Conclusions: Molecular markers improve the prediction of recurrence and CSM after RC. They may identify patients who might benefit from additional treatments and closer surveillance after cystectomy.

Keywords: Bladder cancer; Cystectomy; Molecular markers.

Publication types

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

MeSH terms

  • Aged
  • Biomarkers, Tumor / analysis*
  • Carcinoma / chemistry*
  • Carcinoma / mortality
  • Carcinoma / pathology
  • Carcinoma / surgery*
  • Cystectomy* / adverse effects
  • Cystectomy* / mortality
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lymph Node Excision
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / chemistry*
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Assessment
  • Risk Factors
  • Treatment Outcome
  • Urinary Bladder Neoplasms / chemistry*
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / surgery*


  • Biomarkers, Tumor