Circulating tumor DNA in Ewing sarcoma

Purpose: The application of the tumor specific genomic fusion sequence as non-invasive biomarker for therapy monitoring in Ewing sarcoma (EwS) has been evaluated. Experimental Design: EwS xenograft mouse models were used to explore detectability in small plasma volumes and correlation of genomic <i>EWSR1-FLI1</i> copy numbers with tumor burden. Furthermore, 234 blood samples from 20 EwS patients were analyzed before and during multimodal treatment. <i>EWSR1</i> fusion sequence levels in patients' plasma were quantified using droplet digital PCR and compared to tumor volumes calculated from magnetic resonance imaging (MRI) or computed tomography (CT) imaging studies. Results: Kinetics of <i>EWSR1</i> fusion sequence copy numbers in the plasma are correlated with changes of the tumor volume in patients with localized and metastatic disease. The majority of patients showed a fast reduction of cell free tumor DNA (ctDNA) during initial chemotherapy. Recurrence of increasing ctDNA levels signalized relapse development. Conclusions: Genomic fusion sequences represent promising non-invasive biomarkers for improved therapy monitoring in Ewing sarcoma. Until now, response assessment is largely based on MRI and CT imaging, implying restrictions on closely repeated performance and limitations on the differentiation between vital tumor and reactive stromal tissue. Particularly in patients with prognostic unfavorable disseminated disease, ctDNA is a valuable addition for the assessment of therapy response.

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