Impact of Genomic and Clinical Factors on Outcome of Children ≥18 Months of Age with Stage 3 Neuroblastoma with Unfavorable Histology and withoutMYCNAmplification: A Children's Oncology Group (COG) Report

Abstract

PURPOSE: Patients ≥18 months of age with INSS Stage 3 unfavorable histology (UH), MYCN-non-amplified (MYCN-NA) tumors have favorable survival rates compared to other high-risk neuroblastoma populations. The impact of select clinical and biological factors on overall (OS) and event-free survival (EFS) were evaluated. PATIENTS AND METHODS: Patients enrolled on COG A3973 (n=34), ANBL0532 (n=27), and/or biology protocol ANBL00B1 (n=72) were analyzed. Tumors with available DNA (n=65) and RNA (n=42) were subjected to whole exome sequencing (WES) and RNAseq. WES analyses and gene expression profiling were evaluated for their impact on survival. Multivariate analyses of EFS/OS using significant factors from univariate analyses were performed. RESULTS: 5-year EFS/OS for patients treated with high-risk therapy on A3973 and ANBL0532 were 73.0±8.1%/87.9±5.9% and 61.4±10.2%/73.0±9.2%, respectively (p=0.1286 and p=0.2180). In the A3973/ANBL0532 cohort, patients with CONCLUSION: Patients ≥18 months of age at diagnosis who had tumors with UH and MYCN–NA INSS Stage 3 neuroblastoma assigned to high-risk therapy had an 81.6±5.3% 5-year OS. Less than PR to induction therapy and chromosome 11q loss/LOH are independent predictors of inferior outcome and identify patients who should be eligible for future high-risk clinical trials.

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma

“…Analyses of data from ANBL00B1 indicate that 1p and/or 11q SCAs can identify groups of patients with inferior outcomes 1 . SCA status was informative in 12−18 month olds with Stage M disease with MYCN ‐ NA tumors and those ≥18 months with Stage L2 disease, a finding recently validated through analyses of data from high‐risk trials (A3973, ANBL12P1, ANBL0532) 4 . Retrospective studies have supported the prognostic strength of SCAs including loss of 1p and 11q as well as loss of 3p and 4p and gain of 1q, 2p, and 17q 21,22 .…”

“…16,17 ANBL0532). 4 Retrospective studies have supported the prognostic strength of SCAs including loss of 1p and 11q as well as loss of 3p and 4p and gain of 1q, 2p, and 17q. 21,22 These SCAs are especially important in subgroups with otherwise favorable features.…”

“…While survival of patients with high‐risk disease has improved over time as treatment has evolved (Figure 1), 3‐year EFS remains just over 50% 3 . Survival rates of patients with L2, MYCN nonamplified tumors with unfavorable histology are superior to those of other high‐risk patients, however they are still classified as high risk because outcomes remain unsatisfactory, particularly among patients whose tumors harbor an SCA at 11q 4 …”

“…In Europe, these patients are treated according to an intermediate‐risk paradigm. The finding that 11q loss may help to risk‐stratify this group of patients 4 has led to plans to include 11q status among integral biomarkers in a trial under development that will assign patients at lower recurrence risk to less toxic therapy, while assigning those at greater risk to more intensive treatment. This approach aligns with our overall goal to improve cure rates for higher risk patients, while avoiding overtreatment for patients with lower risk disease.…”

“…3 Survival rates of patients with L2, MYCN nonamplified tumors with unfavorable histology are superior to those of other high-risk patients, however they are still classified as high risk because outcomes remain unsatisfactory, particularly among patients whose tumors harbor an SCA at 11q. 4…”