10552 Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. 5-year survival rates for high-risk NB are < 50% despite intense multimodality treatment. Recent studies revealed that as opposed to diagnostic samples, relapsed NB tumors have a significantly higher mutational burden as a result of clonal evolution. This poses a challenge for the development of personalized therapies and warrants molecular profiling at relapse. However, tumor samples are not always accessible at relapse. Our study evaluates the feasibility of using cell-free DNA (cfDNA) to noninvasively characterize tumor profiles at relapse to identify targetable genetic variants. Methods: Tumor specimens, plasma and matched control samples from 10 patients with high-risk stage 4 NB were collected during multimodality treatment. Samples were analyzed using the MSK-IMPACT platform, a targeted deep sequencing assay to interrogate the exons and selected introns of 410 actionable genes. Tumor samples were collected from surgeries performed either at diagnosis, disease progression, or relapse. Plasma samples were collected at a time of disease progression, at an average 395 days (range of 47-1597 days) from tumor collection. Matched control samples were used to filter germline variants. Results: We detected somatic mutations and copy number alterations in tumor tissues and cfDNA of 10/10 and 6/10 patients, respectively. These included recurrent NB drivers such as MYCN amplification and ATRX mutations. In 4 patients, cfDNA also revealed somatic variants that were not detected in the original tumor specimens, including potentially targetable mutations in NRAS, MLL2, CIC and IDH2 that were recently reported to be enriched in the relapse setting, as well as ARID1B mutation that is associated with poor prognosis. Conclusions: This study suggests that it is feasible to noninvasively profile the dynamic genetic heterogeneity of NB by plasma cfDNA analysis. Such analysis can potentially supplement tumor profiling especially in the relapse setting to guide treatment plans. Our findings call for incorporation of cfDNA analysis in clinical trials to further evaluate its utility for clinical management of NB patients.