Prognostic impact of gene expression-based classification for neuroblastoma.
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.
Oberthuer
André
A
University of Cologne, Cologne, Germany.
Hero
Barbara
B
Berthold
Frank
F
Juraeva
Dilafruz
D
Faldum
Andreas
A
Kahlert
Yvonne
Y
Asgharzadeh
Shahab
S
Seeger
Robert
R
Scaruffi
Paola
P
Tonini
Gian Paolo
GP
Janoueix-Lerosey
Isabelle
I
Delattre
Olivier
O
Schleiermacher
Gudrun
G
Vandesompele
Jo
J
Vermeulen
Joëlle
J
Speleman
Frank
F
Noguera
Rosa
R
Piqueras
Marta
M
Bénard
Jean
J
Valent
Alexander
A
Avigad
Smadar
S
Yaniv
Isaac
I
Weber
Axel
A
Christiansen
Holger
H
Grundy
Richard G
RG
Schardt
Katharina
K
Schwab
Manfred
M
Eils
Roland
R
Warnat
Patrick
P
Kaderali
Lars
L
Simon
Thorsten
T
Decarolis
Boris
B
Theissen
Jessica
J
Westermann
Frank
F
Brors
Benedikt
B
Fischer
Matthias
M
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