Circulating tumor DNA (ctDNA) is a fragment of DNA that is shed from a tumor and circulates in the bloodstream. It is not associated with cells and should not be confused with cell-free DNA (cfDNA), which is a broader term that describes DNA that is freely circulating in the bloodstream but is not necessarily of tumor origin. ctDNA originates directly from the tumor or from circulating tumor cells (CTCs).
Although fragments of DNA are constantly shed into the bloodstream during cell death, the levels of cfDNA are at a relatively low level because of the rapid clearance by the liver, kidney, and spleen. Patients with cancer typically have significantly higher levels of cfDNA (compared to healthy patients) because tumors tend to have elevated cell turnover rates. It has been determined that the median circulating DNA concentration in the blood of patients with solid tumors is approximately three-fold higher than in healthy patients.
Normally, dead and dying cells are filtered and cleared from the bloodstream by phagocytes. However, this process is not as efficient for malignant cells and results in a release of ctDNA into the bloodstream. The rate of shedding of ctDNA into the circulation is dependent upon the location, size, and vascularity of the tumor and can lead to variability in levels across patients.
Clinically, the relative levels of ctDNA within a patient’s bloodstream have been demonstrated to correlate with tumor burden, increasing as the tumor enlarges and decreasing with response to therapy. The use of ctDNA as a liquid biopsy test has possible clinical utility for the monitoring and progression of tumors and the monitoring of treatment response. In addition, using ctDNA as a biomarker allows for a real-time determination of the tumor progression.
In June 2016, Roche’s ctDNA-based detection of epidermal growth factor receptor (EGFR) mutations in lung cancer patients was the first liquid biopsy assay to obtain FDA approval. The assay called the cobas® EGFR Mutation Test v2 is an automated test designed to detect the presence of mutations in the EGFR gene in metastatic non-small cell lung cancer (NSCLC). It is a high-specificity companion diagnostic for the cancer drug erlotinib, obviating the need for EGFR tissue testing when this blood test is positive.
