title: Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy.
abstract: BACKGROUND
  Tested was whether the assessment of 5 established bladder cancer biomarkers (p53, pRB, p21, p27, and cyclin E1) could improve the ability to predict disease recurrence and cancer-specific survival after radical cystectomy in patients with pTa-3N0M0 urothelial carcinoma of the bladder (UCB).
  
  
  METHODS
  The study comprised 191 patients with pTa-3N0M0 UCB treated with radical cystectomy and bilateral lymphadenectomy (median follow-up, 3.1 years). Biomarker expression was assayed on serial tissue microarray slides using quantitative immunohistochemistry using advanced cell imaging and color detection software. Predictive accuracy was quantified using the concordance index and 200-bootstrap resamples were used to reduce overfit bias. Bootstrap-adjusted predictive accuracy estimates were compared using the Mantel-Haenszel test.
  
  
  RESULTS
  UCB recurred in 36 (18.8%) patients and 30 (15.7%) died of bladder cancer; 157 (82.2%) patients had altered expression of at least 1 biomarker. In univariate analyses the number of altered biomarkers had the highest predictive accuracy for both disease recurrence (76.8%, P< .001) and cancer-specific mortality (78.3%, P< .001). Addition of the number of altered biomarkers increased the predictive accuracy of nomograms based on the TNM staging system for disease recurrence and cancer-specific mortality by 10.9% (83.4% vs 72.5%, P< .001) and 8.6% (86.9% vs 78.3, P< .001), respectively.
  
  
  CONCLUSIONS
  Assessment of the number of altered biomarkers in the cystectomy specimen improves the prediction of bladder cancer recurrence and survival in patients with pTa-3N0M0 disease. Prospective evaluation of alteration in these biomarkers can help identify patients who would benefit from adjuvant treatment after radical cystectomy.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA. Shahrokh.Shariat@UTSouthwestern.edu
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Pierre I
authors.initials: PI
authors.lastname: Karakiewicz
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.forename: Ganesh S
authors.initials: GS
authors.lastname: Palapattu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cote
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D019927:Cyclin E / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D015653:Cystectomy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis*; D015513:Oncogene Proteins / Q000032:analysis; D012044:Regression Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27