title: Prognostic impact of gene expression-based classification for neuroblastoma.
abstract: OBJECTIVE
  To evaluate the impact of a predefined gene expression-based classifier for clinical risk estimation and cytotoxic treatment decision making in neuroblastoma patients.
  
  
  METHODS
  Gene expression profiles of 440 internationally collected neuroblastoma specimens were investigated by microarray analysis, 125 of which were examined prospectively. Patients were classified as either favorable or unfavorable by a 144-gene prediction analysis for microarrays (PAM) classifier established previously on a separate set of 77 patients. PAM classification results were compared with those of current prognostic markers and risk estimation strategies.
  
  
  RESULTS
  The PAM classifier reliably distinguished patients with contrasting clinical courses (favorable [n = 249] and unfavorable [n = 191]; 5-year event free survival [EFS] 0.84 +/- 0.03 v 0.38 +/- 0.04; 5-year overall survival [OS] 0.98 +/- 0.01 v 0.56 +/- 0.05, respectively; both P < .001). Moreover, patients with divergent outcome were robustly discriminated in both German and international cohorts and in prospectively analyzed samples (P <or= .001 for both EFS and OS for each). In subgroups with clinical low-, intermediate-, and high-risk of death from disease, the PAM predictor significantly separated patients with divergent outcome (low-risk 5-year OS: 1.0 v 0.75 +/- 0.10, P < .001; intermediate-risk: 1.0 v 0.82 +/- 0.08, P = .042; and high-risk: 0.81 +/- 0.08 v 0.43 +/- 0.05, P = .001). In multivariate Cox regression models based on both EFS and OS, PAM was a significant independent prognostic marker (EFS: hazard ratio [HR], 3.375; 95% CI, 2.075 to 5.492; P < .001; OS: HR, 11.119, 95% CI, 2.487 to 49.701; P < .001). The highest potential clinical impact of the classifier was observed in patients currently considered as non-high-risk (n = 289; 5-year EFS: 0.87 +/- 0.02 v 0.44 +/- 0.07; 5-year OS: 1.0 v 0.80 +/- 0.06; both P < .001).
  
  
  CONCLUSIONS
  Gene expression-based classification using the 144-gene PAM predictor can contribute to improved treatment stratification of neuroblastoma patients.
authors.affiliation: University of Cologne, Cologne, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
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authors.initials: F
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authors.forename: Dilafruz
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authors.lastname: Faldum
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.forename: Shahab
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authors.lastname: Asgharzadeh
authors.forename: Robert
authors.initials: R
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authors.forename: Paola
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authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Olivier
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authors.lastname: Delattre
authors.forename: Gudrun
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authors.lastname: Schleiermacher
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: Marta
authors.initials: M
authors.lastname: Piqueras
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.forename: Smadar
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authors.lastname: Avigad
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Axel
authors.initials: A
authors.lastname: Weber
authors.forename: Holger
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authors.lastname: Christiansen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.forename: Katharina
authors.initials: K
authors.lastname: Schardt
authors.forename: Manfred
authors.initials: M
authors.lastname: Schwab
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Patrick
authors.initials: P
authors.lastname: Warnat
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.forename: Thorsten
authors.initials: T
authors.lastname: Simon
authors.forename: Boris
authors.initials: B
authors.lastname: Decarolis
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009447:Neuroblastoma / Q000145:classification* / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models