CIRQUESARC - A national prospective observational study of Circulating tumor DNA and Quality of life in Sarcomas

IMPACT
One of the most significant barriers to improve sarcoma patient outcomes is the high levels of post-operative recurrences following primary treatment. The indication for neoadjuvant and adjuvant treatment in sarcomas is still controversial, and a better selection of patients would be a major improvement. Detectable circulating tumor DNA (ctDNA) after complete surgical remission could strongly indicate residual disease not detected by conventional imaging, and such patients would be expected to benefit from adjuvant chemotherapy.

CIRQUESARC is a national prospective observational biomarker study addressing the association between the plasma ctDNA levels with progressive disease or disease relapse in sarcoma patients.

BACKGROUND
Sarcomas are a heterogeneous group of malignant tumors derived from mesenchymal cells, accounting for 1–2% of all solid malignancies in adults. Presently the only curative treatment is surgical resection in combination with either chemotherapy, radiotherapy, or both. Despite adequate locoregional treatment, up to 25% of patients will develop metastatic disease.

No known biomarker exists to detect early relapse or progressive disease in sarcoma patients. Nor is there a promising biomarker that can help risk-stratify patients for more aggressive adjuvant treatment. However, despite promising data to use ctDNA as a potential biomarker in sarcoma patients, no larger prospective study has been conducted, and little is still known about which subtype of sarcomas that shed ctDNA into the circulation.

AIM
The primary aim is to investigate if the baseline plasma ctDNA levels or changes in the plasma ctDNA levels after treatment, are associated with disease progression, increased risk of relapse, or survival in patients with advanced/metastatic or high-grade localised sarcomas.

The secondary aims are to determine if the results from the baseline plasma ctDNA analysis and the tumor mutation profiling are comparable, and if there is a relationship between the plasma ctDNA levels and quality of life. Furthermore, we want to determine if the plasma ctDNA levels at first postoperative follow-up can be used as a prognostic marker and stratify patients according to relapse risk.

METHOD
To address these questions, we will include two different subsets of sarcoma patients in two separate studies:

Study 1 will include 55 patients with advanced/metastatic soft tissue sarcoma, osteosarcoma or Ewing’s sarcoma, referred for 1st line treatment with Doxorubicin based chemotherapy.

Study 2 will include 30 patients with high-grade localised soft tissue sarcoma, osteosarcoma or Ewing’s sarcoma, referred for radical surgery.

The ctDNA analysis will be performed by an already established diagnostics workflow using the TruSight Oncology 500 (TSO500) ctDNA, Illumina assay.

EXPECTED OUTCOME
The goal of the CIRQUESARC study is to find a noninvasive circulating biomarker with three different purposes: 1. Detect recurrent disease at an earlier stage than CT, so that patients can benefit from a curative surgical strategy; 2. Detect progressive disease at an earlier stage than CT, so that patients can benefit from new therapeutic adjustments and reduce unnecessary toxicities; and 3. Improve postoperative risk stratification.

If the CIRQUESARC study finds evidence pointing towards a relationship between the postoperative plasma ctDNA levels and high relapse risk, we will proceed with a randomised phase 2 study examining the use of adjuvant therapy and intensified CT surveillance in this subgroup of patients.

Image

Joanna Vitfell-Rasmussen

MD, PhD student

Department of cancer treatment, Herlev and Gentofte Hospital