title: Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers.
abstract: OBJECTIVE
  To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression-based classification and established prognostic markers.
  
  
  METHODS
  Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4 × 44 K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n = 634) by Kaplan-Meier estimates and Cox regression analyses.
  
  
  RESULTS
  The best-performing classifier predicted patient outcome with an accuracy of 0.95 (sensitivity, 0.93; specificity, 0.97) in the validation cohort. The highest potential clinical value of this predictor was observed for current low-risk patients [5-year event-free survival (EFS), 0.84 ± 0.02 vs. 0.29 ± 0.10; 5-year overall survival (OS), 0.99 ± 0.01 vs. 0.76 ± 0.11; both P < 0.001] and intermediate-risk patients (5-year EFS, 0.88 ± 0.06 vs. 0.41 ± 0.10; 5-year OS, 1.0 vs. 0.70 ± 0.09; both P < 0.001). In multivariate Cox regression models for low-risk/intermediate-risk patients, the classifier outperformed risk assessment of the current German trial NB2004 [EFS: hazard ratio (HR), 5.07; 95% confidence interval (CI), 3.20-8.02; OS: HR, 25.54; 95% CI, 8.40-77.66; both P < 0.001]. On the basis of these findings, we propose to integrate the classifier into a revised risk stratification system for low-risk/intermediate-risk patients. According to this system, we identified novel subgroups with poor outcome (5-year EFS, 0.19 ± 0.08; 5-year OS, 0.59 ± 0.1), for whom we propose intensified treatment, and with beneficial outcome (5-year EFS, 0.87 ± 0.05; 5-year OS, 1.0), who may benefit from treatment de-escalation.
  
  
  CONCLUSIONS
  Combination of gene expression-based classification and established prognostic markers improves risk estimation of patients with low-risk/intermediate-risk neuroblastoma. We propose to implement our revised treatment stratification system in a prospective clinical trial.
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.affiliation: Department of Theoretical Bioinformatics (B080), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Dilafruz
authors.initials: D
authors.lastname: Juraeva
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Volland
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sterz
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Faldum
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Engesser
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Seeger
authors.affiliation: Laboratory of Cancer Genomics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba, Japan.
authors.forename: Akira
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authors.lastname: Nakagawara
authors.affiliation: Center of Physiopathology of Human Reproduction, Department of Obstetrics and Gynecology, IRCCS San Martino Hospital, National Cancer Research Institute (IST), Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
authors.affiliation: Laboratory of Neuroblastoma, Onco/Hematology Laboratory Department SDB University of Padua, Pediatric Research Institute, Padua, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: Institut Curie, INSERM Unit 830, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.affiliation: Institut Curie, INSERM Unit 830, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Institut Curie, INSERM Unit 830, Paris, France.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Department of Pathology, University of Valencia, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.affiliation: Department of Pathology, University of Valencia, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Piqueras
authors.affiliation: Department of Tumor Genetics, Institut Gustave Roussy, Villejuif, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.affiliation: Department of Tumor Genetics, Institut Gustave Roussy, Villejuif, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.affiliation: Schneider Children's Medical Center of Israel, Pediatric Hematology Oncology, Petah Tikva, Israel. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.affiliation: Schneider Children's Medical Center of Israel, Pediatric Hematology Oncology, Petah Tikva, Israel. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.affiliation: Children's Cancer Leukaemia Group, University of Leicester, Leicester, United Kingdom.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.affiliation: Department of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ortmann
authors.affiliation: Department of Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Chunxuan
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Theoretical Bioinformatics (B080), German Cancer Research Center, Heidelberg, Germany. Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Simon
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.affiliation: Department of Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Department of Theoretical Bioinformatics (B080), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. matthias.fischer@uk-koeln.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016000:Cluster Analysis; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D011379:Prognosis; D012044:Regression Analysis; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor