title: Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer.
abstract: OBJECTIVE
  We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker.
  
  
  METHODS
  The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy.
  
  
  RESULTS
  Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly higher predictive accuracy than any single biomarker (p <0.001). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p <0.001) and cancer specific mortality (4.3%, p <0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p <0.001).
  
  
  CONCLUSIONS
  While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 10065, USA.
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
authors.forename: Daher C
authors.initials: DC
authors.lastname: Chade
authors.forename: Pierre I
authors.initials: PI
authors.lastname: Karakiewicz
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Hendrik
authors.initials: H
authors.lastname: Isbarn
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bastian
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Nielsen
authors.forename: Umberto
authors.initials: U
authors.lastname: Capitanio
authors.forename: Claudio
authors.initials: C
authors.lastname: Jeldres
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.forename: Seth P
authors.initials: SP
authors.lastname: Lerner
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Sagalowsky
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cote
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*; D002295:Carcinoma, Transitional Cell / Q000737:chemistry* / Q000453:epidemiology / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016160:Retinoblastoma Protein / Q000032:analysis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000453:epidemiology / Q000401:mortality* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C413374:p27 antigen