In a Children’s Oncology Group (COG) study reported in the Journal of Clinical Oncology, Berko et al identified the spectrum and clinical significance of clonal and subclonal pathogenic alterations in high-risk neuroblastoma.
Study Details
The study involved use of a focused high-risk neuroblastoma sequencing panel including ALK, NRAS, KRAS, HRAS, BRAF, PTPN11, TP53, and ATRX genes for ultra-deep sequencing. The panel was applied to 242 pretherapy tumors from patients in the phase III COG ANBL0532 study.
Key Findings
ALK-activating mutations were identified in 52 tumors (21.5%; 30 clonal and 22 subclonal alterations), and 8 tumors (3.3%) showed ALK amplification. Event-free survival was significantly poorer among patients with any ALK-aberrant tumor vs wild-type ALK (5-year rates of 34.9% vs 50.6%, hazard ratio [HR] = 1.556, P = .0203). Overall survival was also poorer in patients with any ALK-aberrant tumor (5-year rates of 37.7% vs 66.3%, HR = 1.992, P = .0007).
Both 5-year event-free survival and 5-year overall survival were poorer among patients with tumors harboring activating ALK mutations at ≥ 5% variant allele frequency (VAF) vs those with ALK wildtype tumors; 5-year event-free survival was 33.2% vs 50.6 (HR = 1.539, P = .0518), and 5-year overall survival was 37.7% vs 66.3% (HR = 1.966, P = .0041).
RAS pathway mutations were identified in 19 tumors (7.9%; 4 clonal, 15 subclonal). Both 5-year event-free survival and 5-year overall survival were poorer among patients with VAF ≥ 5% vs those with RAS wildtype; 5-year event-free survival was 28.6% vs 46.8% (HR = 2.508, P = .0444), and 5-year overall survival was 19.1% vs 60.0% (HR = 3.021, P = .0168).
The investigators concluded: “Ultra-deep sequencing of high-risk [neuroblastomas] demonstrates that oncogenic aberrations are more prevalent at diagnosis than previously recognized. ALK and RAS pathway aberrations confer inferior outcomes in patients treated with contemporary therapy, emphasizing the need for novel therapeutic approaches.”
Yael P. Mossé, MD, of the Children’s Hospital of Philadelphia, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute and others. For full disclosures of the study authors, visit ascopubs.org.
