Circulating tumor DNA as a noninvasive diagnostic biomarker for soft tissue sarcomas

• Applicants: Privatdozent Dr. David Johannes Braig; Professor Dr. Steffen Ulrich Eisenhardt
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; General and Visceral Surgery
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396168587

Soft tissue sarcomas are rare tumors of mesenchymal origin with a high mortality. After curative resection, about one third of patients experience distant metastases. Tumor follow-up captures only a portion of recurrences and is associated with a high cost and radiation burden. The situation is similar for metastatic sarcomas, where imaging provides only limited information about treatment response. Due to their rarity and diversity, no established diagnostic biomarkers exist for sarcomas so far. In the previously funded project, a proof-of-concept study succeeded in detecting free circulating tumor DNA (ctDNA) in the peripheral blood of sarcoma patients. ctDNA has tumor-specific mutation signatures, enabling highly sensitive and specific detection. Based on this, next-generation sequencing-based methods for ctDNA quantification have been developed. They can be automated in a diagnostic laboratory and are therefore suitable for clinical routine. These are based on subtype-specific gene panels and allow mutation diagnostics of tumor tissue and ctDNA. Establishment and validation was performed for myxoid liposarcomas (51 tumors) and synovial sarcomas (25 tumors). These subtype panels have a high sensitivity for detection of ctDNA (0.1% ctDNA). To further increase sensitivity and to be able to include sarcomas with complex karyotypes, exome sequencing of selected tumors was performed. Integration of these additional mutations into patient-specific panels allowed detection of ctDNA at <0.01% regardless of the histological subtype. ctDNA was quantified in plasma from selected patients. ctDNA concentrations correlated with tumor size, response to radio- and chemotherapy, and recurrence. In some patients, an increase in ctDNA was found even before tumor recurrence was detected by imaging, so that minimal residual disease (MRD) could be detected and the occurrence of recurrence could be predicted. In the proposed follow-up project, we would like to use prospectively collected plasma samples in a real-life study to determine the utility of ctDNA for the treatment of sarcoma patients. The possibilities of MRD and relapse diagnostics as well as determination of therapy response under chemo- and radiotherapy will be investigated comparatively to imaging. ctDNA diagnostic could detect MRD after putative curative resection, as well as recurrence, temporally prior to imaging. Therapeutic decisions, such as targeted adjuvant therapy or further diagnostics to localize recurrence, could be made earlier. In the case of disseminated disease, if there is no response to treatment, therapy can be adjusted in a timely manner. These advantages may lead to a survival benefit for patients in the future.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partners: Privatdozent Dr. Georgios Koulaxouzidis; Professor Dr. Andreas Leithner