Abstract
PURPOSEIn 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 METHODSDiagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571).RESULTSGenomic 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 = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 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 = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .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 = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome.CONCLUSIONGenetic 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.
Highlights
Neuroblastoma (NB), the most frequent solid, extracranial malignancy in children, exhibits wide clinical and genetic heterogeneity
Of 3,334 patients enrolled on the HR-NBL1/SIOPEN trial between November 24, 2002, and December 31, 2019, 1,092 patients were included in the anaplastic lymphoma kinase (ALK) analysis cohort (Fig 1; Appendix Table A1, online only)
Within the ALK cohort, the ALK mutational (ALKm) status was analyzed in patients, the ALK amplification (ALKa) status in 901 cases, with both ALKm and ALKa studied in 571 patients (Fig 1, Table 1)
Summary
Neuroblastoma (NB), the most frequent solid, extracranial malignancy in children, exhibits wide clinical and genetic heterogeneity. High-risk neuroblastoma (HR-NB), defined as metastatic disease over the age of months or MYCN-amplified (MNA) disease at any age, remains associated with long-term survival rates of only 50%.1. Current treatment approaches consist of intensive induction chemotherapy, surgical resection of the primary tumor, consolidation with high-dose chemotherapy (HDC), and autologous stem-cell rescue, and for minimal residual disease, isotretinoin in combination with human or mouse chimeric anti-GD2 antibody, ch14.18.2-8. In NB, several recurrent genetic alterations have been described. MNA is a strong biomarker associated with. High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1)
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