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Targeted analysis of cell-free circulating tumor DNA is suitable for early relapse and actionable target detection in patients with neuroblastoma

Item Type:Article
Title:Targeted analysis of cell-free circulating tumor DNA is suitable for early relapse and actionable target detection in patients with neuroblastoma
Creators Name:Lodrini, M. and Graef, J. and Thole-Kliesch, T.M. and Astrahantseff, K. and Sprüssel, A. and Grimaldi, M. and Peitz, C. and Linke, R.B. and Hollander, J.F. and Lankes, E. and Künkele, A. and Oevermann, L. and Schwabe, G. and Fuchs, J. and Szymansky, A. and Schulte, J.H. and Hundsdoerfer, P. and Eckert, C. and Amthauer, H. and Eggert, A. and Deubzer, H.E.
Abstract:PURPOSE: Treating refractory or relapsed neuroblastoma remains challenging. Monitoring body fluids for tumor-derived molecular information indicating minimal residual disease supports more frequent diagnostic surveillance and may have the power to detect resistant subclones before they give rise to relapses. If actionable targets are identified from liquid biopsies, targeted treatment options can be considered earlier. EXPERIMENTAL DESIGN: Droplet digital PCR assays assessing MYCN and ALK copy numbers and allelic frequencies of ALK p.F1174L and ALK p.R1275Q mutations were applied to longitudinally collected liquid biopsies and matched tumor tissue samples from 31 patients with high-risk neuroblastoma. Total cell-free DNA (cfDNA) levels and marker detection were compared with data from routine clinical diagnostics. RESULTS: Total cfDNA concentrations in blood plasma from patients with high-risk neuroblastoma were higher than in healthy controls and consistently correlated with neuron-specific enolase levels and lactate dehydrogenase activity but not with 123I-meta-iodobenzylguanidine scores at relapse diagnosis. Targeted cfDNA diagnostics proved superior for early relapse detection to all current diagnostics in two patients. Marker analysis in cfDNA indicated intratumor heterogeneity for cell clones harboring MYCN amplifications and druggable ALK alterations that were not detectable in matched tumor tissue samples in 17 patients from our cohort. Proof-of-concept is provided for molecular target detection in cerebrospinal fluid from patients with isolated CNS relapses. CONCLUSIONS: Tumor-specific alterations can be identified and monitored during disease course in liquid biopsies from pediatric patients with high-risk neuroblastoma. This approach to cfDNA surveillance warrants further prospective validation and exploitation for diagnostic purposes and to guide therapeutic decisions.
Keywords:Cell-Free Nucleic Acids, Circulating Tumor DNA, Mutation, N-Myc Proto-Oncogene Protein, Local Neoplasm Recurrence, Neuroblastoma, Receptor Protein-Tyrosine Kinases / Genetics
Source:Clinical Cancer Research
Publisher:American Association for Cancer Research
Page Range:1809-1820
Date:1 May 2022
Official Publication:https://doi.org/10.1158/1078-0432.CCR-21-3716
PubMed:View item in PubMed

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