pone.0285580.g002.tif (441.92 kB)

Timeline of the prospective study protocol.

figure

posted on 2023-11-01, 17:37 authored by Alexander Runkel, David Braig, Balazs Bogner, Adrian Schmid, Ute Lausch, Anika Boneberg, Zacharias Brugger, Anja Eisenhardt, Jurij Kiefer, Thomas Pauli, Melanie Boerries, Hannah Fuellgraf, Konrad Kurowski, Peter Bronsert, Jutta Scholber, Anca-Ligia Grosu, Philipp Rovedo, Fabian Bamberg, Steffen Ulrich Eisenhardt, Matthias Jung

Background

Wide resection remains the cornerstone of localized soft-tissue sarcomas (STS) treatment. Neoadjuvant radiation therapy (NRT) may decrease the risk of local recurrences; however, its effectiveness for different histological STS subtypes has not been systematically investigated. The proposed prospective study evaluates the NRT response in STS using liquid biopsies and the correlation of multiparametric magnetic resonance imaging (mpMRI) with histopathology and immunohistochemistry.

Methods

Patients with localized high-grade STS, who qualify for NRT, are included in this study.

Liquid biopsies

Quantification of circulating tumor DNA (ctDNA) in patient blood samples is performed by targeted next-generation sequencing. Soft-tissue sarcoma subtype-specific panel sequencing in combination with patient-specific exome sequencing allows the detection of individual structural variants and point mutations. Circulating free DNA is isolated from peritherapeutically collected patient plasma samples and ctDNA quantified therein. Identification of breakpoints is carried out using FACTERA. Bioinformatic analysis is performed using samtools, picard, fgbio, and the MIRACUM Pipeline.

mpMRI

Combination of conventional MRI sequences with diffusion-weighted imaging, intravoxel-incoherent motion, and dynamic contrast enhancement. Multiparametric MRI is performed before, during, and after NRT. We aim to correlate mpMRI data with the resected specimen’s macroscopical, histological, and immunohistochemical findings.

Results

Preliminary data support the notion that quantification of ctDNA in combination with tumor mass characterization through co-registration of mpMRI and histopathology can predict NRT response of STS.

Clinical relevance

The methods presented in this prospective study are necessary to assess therapy response in heterogeneous tumors and lay the foundation of future patient- and tumor-specific therapy concepts. These methods can be applied to various tumor entities. Thus, the participation and support of a wider group of oncologic surgeons are needed to validate these findings on a larger patient cohort.