Non-invasive Monitoring of Soft-tissue Sarcoma Response to Neoadjuvant Radiotherapy by Quantification of Circulating Tumor DNA (ctDNA) and Multiparametric MRI (mpMRI)

Abstract

Introduction: Soft-tissue sarcomas (STS) are a heterogenous group of rare, yet malignant tumors. Wide resection remains the cornerstone of treatment for localized STS. Current S3 guidelines recommend neoadjuvant radiotherapy for primary, high-grade tumors; however, therapy response for different histological subtypes and gradings has not been systematically investigated. This ongoing prospective study evaluates the response of various STS during the course of neoadjuvant radiotherapy using innovative, non-invasive methods. Through quantification of ctDNA, tumor activity and thus therapy response will be evaluated in correlation with imaging data. Materials and Methods: Liquid biopsies: Detection of circulating tumor DNA (ctDNA) in patient blood samples through targeted next-generation sequencing (NGS). Patient-specific exome sequencing allows the detection of individual structural variants (SVs) and point mutations. Circulating free DNA (cfDNA) is isolated from peritherapeutically collected patient plasma samples and ctDNA quantified therein. Bioinformatic analysis is performed using the MIRACUM Pipeline. Multiparametric MRI (mpMRI): Combination of conventional MRI sequences with diffusion-weighted imaging (DWI) and dynamic contrast enhancement (DCE). Multiparametric MRI is performed before, during, and after neoadjuvant radiotherapy. Accurate co-registration and correlation of mpMRI with the macroscopic, histologic, and immunohistochemical resected specimen allow an analysis of morphological changes during therapy. Results: Quantification of ctDNA mirrors the clinical course and tumor activity. Furthermore, we present imaging markers that allow the characterization of tumor masses for heterogenous STS and the evaluation of therapy response. Conclusion: Liquid biopsies can be used to detect the primary tumor and metastases, and to monitor the course of therapy. Quantification of ctDNA in combination with tumor mass characterization through co-registration of mpMRI and histopathology enables the evaluation of STS response to neoadjuvant radiotherapy. The participation and support of a wider group of oncologic surgeons are needed to validate these findings on a larger patient cohort to create future tumor- and patient-specific therapy concepts.