{"id":27186,"date":"2021-06-24T07:35:00","date_gmt":"2021-06-24T07:35:00","guid":{"rendered":"http:\/\/bb77c86c6a29a88b3ca0caf2865cdcb7"},"modified":"2024-11-03T15:14:52","modified_gmt":"2024-11-03T15:14:52","slug":"alk-mutations-and-amplifications-are-independent-predictors-of-poorer-survival-in-high-risk-neuroblastoma","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/alk-mutations-and-amplifications-are-independent-predictors-of-poorer-survival-in-high-risk-neuroblastoma\/","title":{"rendered":"ALK Mutations and Amplifications are Independent Predictors of Poorer Survival in High-Risk Neuroblastoma"},"content":{"rendered":"

In a study that examined whether the presence of an ALK<\/em> 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<\/em> 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<\/em> Oncology<\/em> that their data provide a rationale for integration of ALK inhibitors in upfront treatment of high-risk neuroblastoma with ALK<\/em> alterations.<\/p>\n

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<\/em>-amplified disease at any age. It is associated with long-term survival rates of only 50%.<\/p>\n

Several recurrent genetic alterations have been described in neuroblastoma. MYCN<\/em> 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<\/em> and ARID1A<\/em> genes, and TERT<\/em> rearrangements.<\/p>\n

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

Genetic alterations of ALK<\/em> 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<\/em> alterations are an important molecular target, given the role of ALK<\/em> as a driver oncogene in neuroblastoma and its actionability with small molecule therapies.<\/p>\n

In order to determine the frequency of ALK<\/em> 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.<\/p>\n

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

ALK<\/em> 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<\/em> mutation and MYCN<\/em> amplification (p < 0.001).<\/p>\n

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

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

The authors concluded that ALK<\/em> 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<\/em> amplification in high-risk neuroblastoma. Importantly, the prognostic significance of ALK<\/em> alterations included a subgroup of study patients treated with the current standard of care for high-risk neuroblastoma including anti-GD2<\/sub> immunotherapy.<\/p>\n

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<\/em> alterations needs to be considered.<\/p>\n

The study was supported by numerous governmental and funds from the non-profit organisations.  <\/p>\n

Reference<\/h4>\n

Bellini A, P\u00f6tschger U, Bernard V, et al.<\/em> Frequency and Prognostic Impact of ALK<\/em> Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)<\/a>. Journal of Clinical Oncology<\/em>; Published online 11 June 2021. DOI: 10.1200\/JCO.21.00086<\/p>\n

Source<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

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 […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-27186","post","type-post","status-publish","format-standard","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27186","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=27186"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27186\/revisions"}],"predecessor-version":[{"id":45971,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/27186\/revisions\/45971"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=27186"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=27186"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=27186"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}