Abstract
This study aimed to identify the prognostic subgroups of stage 4 high-risk neuroblastoma based on metastatic burden and explore their distinct clinical and genomic features. Patients aged ≥18 months with stage 4 and metaiodobenzylguanidine-avid neuroblastoma were enrolled. One hundred and thirty eligible patients were treated under the tandem high-dose chemotherapy scheme. Prognostic significance of metastatic burden measured by the modified Curie score was analyzed using a competing risk approach, and the optimal cut-point was determined. Metastasis-specific subgroups (cut-point: 26) were compared using clinicopathological variables, and differential gene expression analysis and gene set variation analysis (GSVA) were performed using RNA sequencing (RNA-seq). Metastatic burden at diagnosis showed a progressive association with relapse/progression. After applying the cut-point, patients with high metastatic burden showed >3-fold higher risk of relapse/progression than those with low metastatic burden. Moreover, patients with high metastatic burden showed smaller primary tumors and higher biochemical marker levels than those with low metastatic burden. In the genomic analysis, 51 genes were found to be differentially expressed based on the set criteria. GSVA revealed 55 gene sets, which significantly distinguished patients with high metastatic burden from those with low metastatic burden at a false discovery rate <0.25. The results indicated the prognostic significance of metastatic burden in stage 4 high-risk neuroblastoma, and we identified the distinct clinicopathological and genomic features based on metastatic burden. This study may aid in the better understanding and risk-stratification of stage 4 high-risk neuroblastoma patients.
Highlights
Few tumors have been recognized to show as many diverse clinical presentations and biological features as neuroblastoma (NB) [1]
Most of the patients (90%) showed an abdominal primary tumor; 22% of the patients had MYCN amplification (MNA) tumors, while 72% had tumors with unfavorable histology according to the International Neuroblastoma Pathology Classification (INPC)
This study suggested that patients with extensive NB with distinct clinical and biological features are prone to relapse/progression
Summary
Few tumors have been recognized to show as many diverse clinical presentations and biological features as neuroblastoma (NB) [1]. NB is characterized by heterogenous clinical behaviors, ranging from spontaneous regression to inexorable progression [2]. >50% of the children classified as high-risk show disease progression or relapse, despite intensive multimodal therapy. There is an urgent need to define the subgroups of high-risk NB with inferior outcomes [4]. An increasing number of metastatic compartments are related to poor outcome [6], and the extent of metaiodobenzylguanidine (mIBG)-avid disease is prognostic [5,8,9]. Whether metastatic burden at diagnosis has prognostic significance is controversial, and whether its prognostic impact persists in the context of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) remains unclear. The clinical behavior and underlying biology driving these prognostic differences must be elucidated
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