Abstract 2431: Enrichment of targetable mutations in the relapsed neuroblastoma genome
| العنوان: | Abstract 2431: Enrichment of targetable mutations in the relapsed neuroblastoma genome |
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| المؤلفون: | Kaitlyn R. Rubnitz, Shakeel Modak, Vincent A. Miller, Olivia M. Padovan-Merhar, Yael P. Mosse, Brian Weiss, Siraj M. Ali, Meaghan Granger, Pichai Raman, John M. Maris |
| المصدر: | Cancer Research. 76:2431-2431 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Genetics, Cancer Research, Oncology, Biology, Genome, Relapsed Neuroblastoma |
| الوصف: | 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 response, and two had stable disease after targeted therapy. Our data confirm recent evidence suggesting that NBs undergo substantial mutational evolution during therapy, and as a result, relapsed disease is more likely to be driven by a targetable oncogenic pathway. These data support the conclusion that biopsy of relapsed NB has the potential to benefit the patient. Prospective clinical trials to match sequencing results to targeted therapies are required. Citation Format: Olivia M. Padovan-Merhar, Pichai Raman, Kaitlyn R. Rubnitz, Siraj M. Ali, Vincent A. Miller, Yael P. Mosse, Meaghan P. Granger, Brian D. Weiss, John M. Maris, Shakeel Modak. Enrichment of targetable mutations in the relapsed neuroblastoma genome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2431. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::71a4d52f0e52f7b9de68f946d6092c77 https://doi.org/10.1158/1538-7445.am2016-2431 |
| رقم الأكسشن: | edsair.doi...........71a4d52f0e52f7b9de68f946d6092c77 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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