Prognostic Impact of Telomere Maintenance Mechanisms in Neuroblastoma

Purpose Neuroblastoma, a common cancer in children, is characterized by striking clinical heterogeneity, ranging from spontaneous regression to fatal disease. Precise risk classification is therefore essential for appropriate treatment stratification. Given that genotoxic chemotherapy constitutes the mainstay of neuroblastoma treatment, it is particularly important to avoid overtreatment in patients with biologically favorable disease, notably in the heterogeneous group of current non–high-risk patients. Here, we tested the hypothesis that telomere maintenance mechanisms (TMM), which have been proposed as key hallmark of high-risk neuroblastoma, may improve neuroblastoma risk classification over current standard of care. Methods We examined the prognostic accuracy of TMM in comparison with current standard-of-care prognostic variables in 366 patients with neuroblastoma, including 259 non–high-risk patients (test set, n = 116; validation set, n = 143). Patient event-free survival (EFS) and overall survival (OS) were determined according to TMM and currently used molecular classification by chromosomal copy-number alterations or gene expression profiles. The prognostic impact of the three molecular classifications was compared pairwise and with standard-of-care prognostic variables in multivariable analyses. Results TMM-based and gene expression-based classification accurately distinguished non–high-risk patients with excellent and adverse EFS and OS in both the test and validation sets. On multivariable analyses of standard-of-care prognostic factors, TMM-based classification remained the only risk factor in the final models (EFS, hazard ratio [HR], 6.4 [95% CI, 3.9 to 10.6], P < .001; OS, HR, 29.4 [95% CI, 9.6 to 90.0], P < .001), in contrast to the two other molecular classifiers. In pairwise comparisons, TMM-based classification outperformed the two other molecular classifications in models built on both EFS and OS ( P < .001 each). Conclusion TMM-based classification improves risk assessment in neuroblastoma, providing a rationale for clinical implementation as a new standard for risk stratification of patients with neuroblastoma.