Dataset Information

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 = 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 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.

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.

SUBMITTER: Bellini A

PROVIDER: S-EPMC8791815 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Bellini Angela A Pötschger Ulrike U Bernard Virginie V Lapouble Eve E Baulande Sylvain S Ambros Peter F PF Auger Nathalie N Beiske Klaus K Bernkopf Marie M Betts David R DR Bhalshankar Jaydutt J Bown Nick N de Preter Katleen K Clément Nathalie N Combaret Valérie V Font de Mora Jaime J George Sally L SL Jiménez Irene I Jeison Marta M Marques Barbara B Martinsson Tommy T Mazzocco Katia K Morini Martina M Mühlethaler-Mottet Annick A Noguera Rosa R Pierron Gaelle G Rossing Maria M Taschner-Mandl Sabine S Van Roy Nadine N Vicha Ales A Chesler Louis L Balwierz Walentyna W Castel Victoria V Elliott Martin M Kogner Per P Laureys Geneviève G Luksch Roberto R Malis Josef J Popovic-Beck Maja M Ash Shifra S Delattre Olivier O Valteau-Couanet Dominique D Tweddle Deborah A DA Ladenstein Ruth R Schleiermacher Gudrun G

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20210611 30

<h4>Purpose</h4>In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied <i>ALK</i> genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact.<h4>Materials and methods</h4>Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine <i>ALK</i> amplification statu ...[more]

PMID: 34115544

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Project description:A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Project description:IntroductionBetween 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features.Materials and methodsThis SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021.ResultsOf the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant).ConclusionThis prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.

Dataset Information

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

Purpose

Materials and methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Purpose

Materials and methods

Results

Conclusion

Publications

Frequency and Prognostic Impact of &lt;i&gt;ALK&lt;/i&gt; Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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