Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 39, Issue 30, Pages 3377-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1200/JCO.21.00086
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Funding
- Annenberg Foundation
- Association Hubert Gouin Enfance et Cancer, France
- Federation Enfants Cancers Sante, Les Bagouz a Manon, Les amis de Claire
- SiRIC/INCa [INCa-DGOS-4654]
- PHRC [IC2007-09]
- Agence Nationale de la Recherche (Investissements d'Avenir program) [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program SiRIC [INCa-DGOS-4654]
- Neuroblastoma UK
- Cancer Research UK
- Department of Health
- Families against Neuroblastoma
- Solving Kids' Cancer
- Action Medical Research/Great Ormond Street Hospital Charity
- CCLG
- European Commission 5th Frame Work Grant (SIOPEN-R-NET EC) [QLRI-CT-2002-01768]
- Belgium: vzw Kinderkankerfonds
- Belgium: Kom op tegen Kanker
- Czech Republic: MH CZDRO
- Czech Republic: University Hospital Motol, Prague, Czech Republic
- Israel: Hayim Association-for Children
- Israel: Cancer in Israel, Ramat Gan
- Italy: Fondazione Italiana per la Lotta al Neuroblastoma O.N.L.U.S. c/o Istituto G. Gaslini
- Italy: Gaslini
- Italy: Genova
- Italy: Associazione Bianca Garavaglia O.N.L.U.S.
- Italy: Busto Arsizio
- Spain: Grant FIS [EC10/303]
- Spain: Asociacion Pablo Ugarte
- Spain: Cancercare Xavia
- Spain: Sumemos Muchas Manos
- Spain:Heath Institute Carlos III (ISCIII)
- Spain: FEDER (European Regional Development Fund) [PI17/01558, CIBERONC-CB16/12/00484]
- NEN Association [2017-PVR00157]
- Switzerland: Oncosuisse, Bern
- Swiss Cancer League, Bern
- Fond'action contre le Cancer, Lausanne
- FORCE Fondation Recherche sur le Cancer de l'Enfant, Ecublens
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Genetic alterations of ALK (clonal mutations and amplifications) in high-risk neuroblastoma patients are independent predictors of poorer survival. These data provide a rationale for the integration of ALK inhibitors in upfront treatment of high-risk neuroblastoma with ALK alterations.
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 (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 421; 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 En = 19], 26% [95% CI, 10 to 47], clonal ALKm En = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration En = 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. 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. (C) 2021 by American Society of Clinical Oncology
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