title: Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer.
abstract: BACKGROUND
  Nearly half of muscle-invasive bladder cancer patients succumb to their disease following cystectomy. Selecting candidates for adjuvant therapy is currently based on clinical parameters with limited predictive power. This study aimed to develop and validate genomic-based signatures that can better identify patients at risk for recurrence than clinical models alone.
  
  
  METHODS
  Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. Genomic (GC) and clinical (CC) classifiers for predicting recurrence were developed on a discovery set (n = 133). Performances of GC, CC, an independent clinical nomogram (IBCNC), and genomic-clinicopathologic classifiers (G-CC, G-IBCNC) were assessed in the discovery and independent validation (n = 66) sets. GC was further validated on four external datasets (n = 341). Discrimination and prognostic abilities of classifiers were compared using area under receiver-operating characteristic curves (AUCs). All statistical tests were two-sided.
  
  
  RESULTS
  A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. This was higher than individual clinical variables, IBCNC (AUC = 0.73), and comparable to CC (AUC = 0.78). Performance was improved upon combining GC with clinical nomograms (G-IBCNC, AUC = 0.82; G-CC, AUC = 0.86). G-CC high-risk patients had elevated recurrence probabilities (P < .001), with GC being the best predictor by multivariable analysis (P = .005). Genomic-clinicopathologic classifiers outperformed clinical nomograms by decision curve and reclassification analyses. GC performed the best in validation compared with seven prior signatures. GC markers remained prognostic across four independent datasets.
  
  
  CONCLUSIONS
  The validated genomic-based classifiers outperform clinical models for predicting postcystectomy bladder cancer recurrence. This may be used to better identify patients who need more aggressive management.
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB). apmitra@gmail.com.
authors.forename: Anirban P
authors.initials: AP
authors.lastname: Mitra
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Lucia L
authors.initials: LL
authors.lastname: Lam
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Mercedeh
authors.initials: M
authors.lastname: Ghadessi
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Ismael A
authors.initials: IA
authors.lastname: Vergara
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Christine
authors.initials: C
authors.lastname: Buerki
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Zaid
authors.initials: Z
authors.lastname: Haddad
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Thomas
authors.initials: T
authors.lastname: Sierocinski
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Eila C
authors.initials: EC
authors.lastname: Skinner
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Siamak
authors.initials: S
authors.lastname: Daneshmand
authors.affiliation: Department of Pathology and Center for Personalized Medicine (APM, TJT) and Institute of Urology and Norris Comprehensive Cancer Center (SD), University of Southern California, Los Angeles, CA; GenomeDx Biosciences, Inc., Vancouver, BC (LLL, MG, NE, IAV, MA, CB, ZH, TS, TJT, ED); Department of Urology and the Stanford Cancer Institute, Stanford University, Stanford, CA (ECS); Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada (PCB).
authors.forename: Peter C
authors.initials: PC
authors.lastname: Black
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015653:Cystectomy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000235:genetics*; D049451:Nomograms; D011237:Predictive Value of Tests; D012334:RNA, Neoplasm / Q000032:analysis; D012372:ROC Curve; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000601:surgery
chemical_list: D012334:RNA, Neoplasm