Frequency and prognostic impact of alk amplifications and mutations in the european neuroblastoma study group (siopen) high-risk neuroblastoma trial (hr-nbl1)

Abstract

PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK 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 ALK amplification status (n 5 330), ALK mutational profile (n 5 191), or both (n 5 571). RESULTS Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n 5 41] 28% [95% CI, 15 to 42]; no-ALKa [n 5 860] 51% [95% CI, 47 to 54], [P , .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) 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 ALKm and MNA (P , .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n 5 19], 26% [95% CI, 10 to 47], clonal ALKm[n565] 33% [95% CI, 21 to 44], subclonal ALKm(n522) 48% [95% CI, 26 to 67], and no alteration [n 5 465], 51% [95% CI, 46 to 55], respectively; P 5 .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P , .001), ALKa (HR, 2.38; P 5 .004), and clonal ALKm (HR, 1.77; P 5 .001) were independent predictors of poor outcome. CONCLUSION Genetic alterations of ALK (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 ALK alterations.