Frequency and Prognostic Impact of Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.

Materials And Methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine amplification status (n = 330), mutational profile (n = 191), or both (n = 571).

Results: Genomic amplification (a) was detected in 4.5% of cases (41 out of 901), all except one with amplification (MNA). a was associated with a significantly poorer overall survival (OS) (5-year OS: a [n = 41] 28% [95% CI, 15 to 42]; no-a [n = 860] 51% [95% CI, 47 to 54], [ < .001]), particularly in cases with metastatic disease. mutations (m) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of m and MNA ( < .001). Among 571 cases with known a and m status, a statistically significant difference in OS was observed between cases with a or clonal m versus subclonal m or no alterations (5-year OS: a [n = 19], 26% [95% CI, 10 to 47], clonal m [n = 65] 33% [95% CI, 21 to 44], subclonal m (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; < .001), a (HR, 2.38; = .004), and clonal (HR, 1.77; = .001) were independent predictors of poor outcome.

Conclusion: Genetic alterations of (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with alterations.