Frequency and Prognostic Significance of Genetic Abnormalities in a Subgroup of Patients With Intermediate-Risk Neuroblastoma: A SIOPEN Study.

Abstract

Intermediate-risk neuroblastoma patients older than 18 months, with non-<i>MYCN</i> amplified, International Neuroblastoma Risk Group Staging System localized, unresectable or International Neuroblastoma Staging System stage 3 tumors, and unfavorable histology have inferior outcomes compared with other intermediate-risk patients. This study aimed to identify genetic prognostic biomarkers within this rare subgroup. We conducted a large, international study including chromosomal copy number in all cases, next-generation DNA sequencing in most, and telomere maintenance mechanisms and gene expression in a subset, and correlated results with patient survival. Among 98 tumors, 9/98 (9.2%) had oncogene amplifications (<i>CDK4/MDM2/TERT</i> coamplification (n = 1), <i>CDK4/MDM2</i> coamplification (n = 4), <i>CDK4</i> (n = 2), <i>TERT</i> (n = 1), and <i>MYC</i> (n = 1)), while 63/98 (64.3%) had typical segmental chromosomal aberrations (tSCAs). Patients with tumors with oncogene amplification had the worst 5-year event-free survival (EFS; 0%; <i>P</i> < .0001 log-rank test) and 5-year overall survival (OS; 44.4% [95% CI, 21.4 to 92.3]; <i>P</i> < .01 log-rank test). Patients with tumors harboring tSCAs had inferior EFS compared with those with numerical chromosomal aberrations only (51.7% [95% CI, 40.6 to 65.8] <i>v</i> 93.3% [95% CI, 81.5 to 100]; <i>P</i> < .01). Patients with p53 pathway tumor alterations (n = 10) had worse EFS than those without (0% <i>v</i> 61.1% [95% CI, 50.3 to 74.3]; <i>P</i> < .0001, log-rank test) and worse OS (26.7% [95% CI, 8.9 to 80.3] <i>v</i> 80.9% [95% CI, 71.8 to 91.3]; <i>P</i> < .001 log-rank test). Multivariable analysis identified tSCAs as an independent prognostic variable for EFS and oncogene amplification or p53 pathway abnormalities as independent prognostic variables for EFS and OS. Oncogene amplification and/or p53 pathway abnormalities and/or typical SCAs identify patients with intermediate-risk neuroblastoma with inferior outcome for whom intensified or alternative treatments should be considered.