Revised Risk Estimation and Treatment Stratification of Low- and Intermediate-Risk Neuroblastoma Patients by Integrating Clinical and Molecular Prognostic Markers

Abstract

Purpose: To optimize neuroblastoma treatment stratification, we aimed at developing a novel risk estimation system by integrating gene expression-based classification and established prognostic markers.Experimental Design: Gene expression profiles were generated from 709 neuroblastoma specimens using customized 4 Â 44 K microarrays. Classification models were built using 75 tumors with contrasting courses of disease. Validation was performed in an independent test set (n ¼ 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 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 AE 0.08; 5-year OS, 0.59 AE 0.1), for whom we propose intensified treatment, and with beneficial outcome (5-year EFS, 0.87 AE 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.

A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature)

“…Additionally, we successfully validated the prognostic power of these seven indexes using the expression profiles of 243 patients with newly diagnosed HR-NB 48, 49 (P < 0.05, hazard ratio >1.5, Table 2). In contrast, MYCN-amplification only moderately stratified the event-free survival in these two cohorts (P = 0.008 and 0.025, Supplementary Fig.…”

“…Roniciclib (BAY 1000394) is a novel oral cytotoxic agent against cell-cycle and transcriptional cyclin-dependent kinases ( CDKs ) 42,43,48 . Roniciclib is currently in Phase II clinical development as a first-line therapy in combination with chemotherapy for extensive small cell lung cancer.…”

Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients

“…Our analyses showed that the associations between candidate genes and survival could not be observed by chance alone ( P = 0.039 and P = 0.0087 for Cohorts I and 2, respectively). Second, we analyzed transcriptome data from a third independent cohort (Cohort 3), consisting of 233 neuroblastoma patients extracted from the larger group in E-MTAB-1781 who were not included in Patient Cohort 1 [19]. This cohort included patients with stage 1 ( n = 41), stage 2 ( n = 40), stage 3 ( n = 22), stage 4 ( n = 111), and stage 4S ( n = 19) tumors.…”

Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients

“…Patient-specific simulations of JNK signaling were performed using three existing independent patient cohorts (55 JNK inhibitor II (SP600125) was from Merck and JNK Inhibitor VIII was from Cayman Chemical.…”