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ALK Mutations and Amplifications are Independent Predictors of Poorer Survival in High-Risk Neuroblastoma

In a study that examined whether the presence of an ALK alteration was associated with a poor prognosis in a large patient series treated in the prospective European high-risk neuroblastoma study (HR-NBL1), the International Society of Paediatric Oncology European Neuroblastoma Study Group (SIOPEN) found that ALK alterations are independent predictors of poorer survival. Dr. Gudrun Schleiermacher of the Institut Curie in Paris, France and colleagues wrote on 11 June 2021 in the Journal of Clinical Oncology that their data provide a rationale for integration of ALK inhibitors in upfront treatment of high-risk neuroblastoma with ALK alterations.

Neuroblastoma is the most frequent solid, extracranial malignancy in children. It exhibits wide clinical and genetic heterogeneity. High-risk neuroblastoma is defined as metastatic disease over the age of 12 months or MYCN-amplified disease at any age. It is associated with long-term survival rates of only 50%.

Several recurrent genetic alterations have been described in neuroblastoma. MYCN amplification is a strong biomarker associated with rapid tumour growth. Other copy-number alterations occur over more extensive chromosome regions, with segmental chromosome alterations being associated with a poor outcome. Recurrent mutations have been described in the RAS-MAPK pathway, ATRX and ARID1A genes, and TERT rearrangements.

ALK mutations are the most frequent mutations in neuroblastoma, occurring in both familial and sporadic cases, with somatically acquired ALK mutations observed in 6-12% of sporadic neuroblastomas in all risk groups. ALK can also be activated by genomic focal amplification, described in 1-2% of neuroblastomas, almost exclusively with MYCN amplification, or, more rarely, following structural rearrangements. 

Genetic alterations of ALK are associated with poorer survival in the overall neuroblastoma population. However, their prognostic role in high-risk neuroblastoma has been less well studied. The authors wrote in the study background that ALK alterations are an important molecular target, given the role of ALK as a driver oncogene in neuroblastoma and its actionability with small molecule therapies.

In order to determine the frequency of ALK mutations and amplifications, their correlation with clinical characteristics, and their prognostic impact in high-risk neuroblastoma, the study team analyzed a large series of 1,092 diagnostic neuroblastoma samples from patients treated in the prospective European study.

Genomic ALK amplification was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification. ALK amplification was associated with a significantly poorer overall survival (OS), 5-year OS 28% in cases with ALK amplification (95% confidence interval [CI] 15 to 42) and 51% in cases with no ALK amplification (95% CI 47 to 54), p < 0.001, particularly in cases with metastatic disease. 

ALK mutations 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 mutation and MYCN amplification (p < 0.001).

Among 571 cases with known ALK amplification and mutation status, a statistically significant difference in OS was observed between cases with ALK amplification or clonal ALK mutation versus subclonal ALK mutation or no ALK alterations; 5-year OS 26% in case of ALK amplification (95% CI 10 to 47], 33% in case of clonal ALK mutation (95% CI 21 to 44], 48% in case of subclonal ALK mutation (95% CI 26 to 67), and 51% in case of no alteration (95% CI 46 to 55), respectively, p = 0.001.

In a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR] 2.87; p < 0.001), ALK amplification (HR 2.38; p = 0.004), and clonal ALK mutation (HR 1.77; p = 0.001) were independent predictors of poor outcome.

The authors concluded that ALK amplification or clonal mutation was associated with inferior prognosis in patients with high-risk neuroblastoma and both were independent prognostic variables in multivariate analysis. They commented that this is the first study to report the highly prognostic significance of ALK amplification in high-risk neuroblastoma. Importantly, the prognostic significance of ALK alterations included a subgroup of study patients treated with the current standard of care for high-risk neuroblastoma including anti-GD2 immunotherapy.

The data contribute to the rationale for future clinical studies introducing ALK targeted treatment in the frontline setting together with chemotherapy and immunotherapy. Distinct prognostic impact of different ALK alterations needs to be considered.

The study was supported by numerous governmental and funds from the non-profit organisations.  

Reference

Bellini A, Pötschger U, Bernard V, et al. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). Journal of Clinical Oncology; Published online 11 June 2021. DOI: 10.1200/JCO.21.00086

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