Abstract 2431: Enrichment of targetable mutations in the relapsed neuroblastoma genome

Neuroblastoma (NB) is a pediatric tumor responsible for 15% of pediatric cancer deaths. Patients with relapsed high-risk disease have less than a 5% chance of survival despite intensive cytotoxic chemotherapy regimens. Personalized therapies targeted against driver oncogenes may improve patient outcomes. However, genetic analyses of tumors biopsied at diagnosis generally harbor few, if any, targetable mutations [Pugh et al. Nat Gen 2013]. A recent study comparing the genetic profiles of tumors from 23 NB patients before and after disease relapse showed that relapsed tumors have a higher percentage of targetable mutations, particularly in the ALK/RAS/MAPK pathway [Eleveld et al. Nat Gen 2015]. We performed a retrospective study to further define the genetic landscape of diagnostic and relapsed NB. A total of 151 NB samples from 11 institutions were submitted for targeted sequencing of 236 genes commonly mutated in cancer using the FoundationOne assay; 40 at diagnosis, 67 at disease relapse, and 38 during primary therapy (i.e. second look surgery). Three patients were biopsied at both diagnosis and disease relapse. Patients were included in the study based solely on the availability of FoundationOne data. We identified 38 unique genes with known oncogenic mutations in this cohort. Of these, ALK was the most prevalent, with mutations occurring in 13.8% of patients, and there was a higher frequency of known oncogenic ALK mutations in relapsed disease (17% of patients) than at diagnosis (7.7% of patients). Further, there were more unique genes with known oncogenic mutations or gene amplifications in relapsed disease (25 mutated, 7 amplified) than at diagnosis (14 mutated, 2 amplified). Patients with relapsed disease were more likely to have at least one known mutation or gene amplification (60% vs. 41% of patients, P = 0.07). ALK mutations in NB are targetable with available therapies, and of the 37 other mutated genes detected, 13 are “potentially actionable”, falling within pathways that are targetable by drugs which are either currently available or in clinical trials. Patients with relapsed disease displayed a greater likelihood of having potentially actionable mutations (34% vs. 21% of patients). Of the 144 unique patients in this study, 21 were reported to have received targeted therapy based on the sequencing results and 14 outcomes were reported: while 10 patients showed progressive disease, one patient had a complete response, one had a partial respons