Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). Issue 30 (20th October 2021)

• Record Type: Journal Article
• Authors: Bellini, Angela; Pötschger, Ulrike; Bernard, Virginie; Lapouble, Eve; Baulande, Sylvain; Ambros, Peter F.; Auger, Nathalie; Beiske, Klaus; Bernkopf, Marie; Betts, David R.; Bhalshankar, Jaydutt; Bown, Nick; de Preter, Katleen; Clément, Nathalie; Combaret, Valérie; Font de Mora, Jaime; George, Sally L.; Jiménez, Irene; Jeison, Marta; Marques, Barbara; Martinsson, Tommy; Mazzocco, Katia; Morini, Martina; Mühlethaler-Mottet, Annick; Noguera, Rosa; Pierron, Gaelle; Rossing, Maria; Taschner-Mandl, Sabine; Van Roy, Nadine; Vicha, Ales; Chesler, Louis; Balwierz, Walentyna; Castel, Victoria; Elliott, Martin; Kogner, Per; Laureys, Geneviève; Luksch, Roberto; Malis, Josef; Popovic-Beck, Maja; Ash, Shifra; Delattre, Olivier; Valteau-Couanet, Dominique; Tweddle, Deborah A.; Ladenstein, Ruth; Schleiermacher, Gudrun;
• Is Part Of: Journal of clinical oncology. Volume 39:Issue 30(2021)
• Page Start: 3377
• Page End: 3390
• Publication Date: 2021-10-20
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.21.00086
• Languages: English
• ISSNs: 0732-183X

Abstract

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 = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS: Genomic ALK amplification ( ALK a) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALK a was associated with a significantly poorer overall survival (OS) (5-year OS: ALK a [n = 41] 28% [95% CI, 15 to 42]; no- ALK a [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALK 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 ALK m and MNA ( P < .001). Among 571 cases with known ALK a and ALK m status, a statistically significant difference in OS was observed between cases with ALK a or clonal ALK m versus subclonal ALK m or no ALK alterations (5-year OS: ALK a [n = 19], 26% [95% CI, 10 to 47], clonal ALK m [n = 65] 33% [95% CI, 21 to 44], subclonal ALK m (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), ALK a (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .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.