Abstract
Simple SummaryCurrently, patients with high-risk neuroblastoma are uniformly treated with maximum therapy. This study investigated a high-risk subgroup characterized by the presence of the amplified MYCN oncogene in the tumor regardless of the stage. In contrast to the corresponding high-risk subgroup consisting of patients with metastases and age at diagnosis over 18 months, the investigated subgroup had generally a superior survival chance. However, the detection of mutations of specific genes in the tumor tissue (RAS and p53 pathway including ALK) had a strong, negative impact. These genes should be therefore also investigated in the future. Complete surgical removal of the primary tumor proved to be beneficial for high-risk neuroblastoma patients assigned to the high-risk category solely by MYCN amplification.Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.
Highlights
Neuroblastoma is considered as high-risk if the calculated 5-year event-free survival is below 50% for de novo patients
Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001)
Studies on outcome of high-risk neuroblastoma patients commonly report two categories, i.e., those diagnosed as stage 4 over the age of 18 months and those assigned to high risk due to other criteria
Summary
Neuroblastoma is considered as high-risk if the calculated 5-year event-free survival is below 50% for de novo patients. The SIOPEN group reported an improved survival for stage 4 patients who responded to induction chemotherapy and had complete macroscopical excision of the primary tumor (plus high-dose chemotherapy, local radiotherapy and immunotherapy) [14] In another smaller study, stage 4 patients with poor response to induction chemotherapy had no outcome benefit from a higher extent of primary tumor resection [15]. Telomere maintenance may result from various genomic alterations, including MNA [21] It has remained unclear, whether mutations in the pre-defined set of genes related to the RAS-/p53-pathway [19] impact clinical outcomes of the subgroup of children with MNA but otherwise low- or intermediate-risk characteristics.
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