Knowledge regarding the genomic changes in sarcoma is important for treatment decisions. Blood plasma of cancer patients has been shown to carry small amounts of fragmented circulating cell-free tumour DNA (ctDNA). The ctDNA represents in principle every cancer cell within the body. Using blood samples as a “liquid biopsy” allows new non-invasive means to obtain tumour material for molecular analyses of sarcoma (Namløs et al., Mol Aspects Med 2020). Liquid biopsies have received increased attention due to the obvious clinical implications for precision medicine. The presence and levels of ctDNA have been associated with a more aggressive cancer disease. Liquid biopsies can be collected in a diagnostic or prognostic setting or collected sequentially for real-time monitoring of treatment response and resistance to therapy and to monitor tumour evolution.
The karyotype complexity guides the analytical approach for molecular profiling of ctDNA in sarcomas.
Our group has several published and ongoing studies on liquid biopsies in sarcoma.
In a proof-of-concept study, we have shown that the levels of tumour-specific mutations in cfDNA can be correlated to clinical manifestation of metastatic disease in aggressive soft-tissue sarcoma, showing the potential of ctDNA to detect disease progression at an early stage (Namløs et al., BMC Cancer, 2017).
In CircSarc NoGIST, we detected, with high sensitivity, driver mutations in ctDNA of patients with localized and advanced GIST disease. All patients with metastatic disease had detectable ctDNA, and tumour burden was the most important detection determinant. It was shown that ctDNA could be used to capture the molecular heterogeneity of resistance within a tumour and monitor tumour evolution (Namløs et al., Mol. Cancer Ther., 2018).
In CircSarc GIST, liquid biopsies are used to monitor metastatic GIST patients during imatinib treatment. Following disease progression, we will monitor the level of mutations in ctDNA over time to detect the tumour evolution during treatment, and correlation with clinical response, as well as other clinical parameters.
In CircSarc STS, liquid biopsies are used to monitor patients with localised high-grade malignant soft tissue in the extremities and trunk that have been operated with wide or marginal surgical margins. The patients have been followed for 5 years, and more than 300 plasma samples have been collected during treatments and at controls. The aim of the study is to evaluate the clinical impact of ctDNA as a biomarker for disease monitoring in soft tissue sarcomas.
In CircSarc LPS-UPS, we have investigated the association between detection of ctDNA and clinical characteristics in a cohort of undifferentiated pleomorphic sarcomas and liposarcomas patients. Our results show that ultra-low pass whole genome sequencing (ULP-WGS) and digital droplet PCR (ddPCR) can be used to detect copy number changes in ctDNA, and detection seems to depend on disease aggressivity.
In STOP-GIST, a de-escalation study is performed to determine whether liquid biopsies can be used as a sensitive non-invasive method for early detection of recurrence in patients that have stopped imatinib treatment. We have recruited patients who have completed >5 years of imatinib treatment and have had all metastatic lesions surgically removed. A non-invasive blood sample may represent a new and sensitive method to monitor disease relapse in patients after treatment de-escalation.