Circulating DNA is a mixture of DNA from normal and tumor cells.The majority of studies analyses the clinical potential of tumor specific mutations which are detectable in a fraction of patients. In contrast, the total cell-free DNA (cfDNA) can be analyzed in all patients and a normal upper limit provided for standardization. Studies suggest that levels of total cfDNA are higher in CRC than healthy controls and associated with a poor prognosis in metastatic disease. This indicates a strong clinical potential calling for statistical validation. The aim was to perform a systematic review and meta-analysis of the prognostic value of total cfDNA in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy.
A systematic literature search of PubMed and Embase was performed by two independent investigators (KGS and AKB). Eligibility criteria were; total cfDNA analysis, mCRC, prognostic value during palliative treatment. The PRISMA guidelines were followed, and meta-analysis applied on both aggregate data extraction and individual patients' data provided by the authors when applicable. Primary endpoint was overall survival (OS).
A total of 11 patient cohorts were identified, including a total of 1158 patients. The majority of data were based on patients with late-line disease, but also a cohort of 86 patients in second-line, and study in the first-line settings, with similar results. Seven studies used qPCR methods, two BEAMing technology and two digital droplet PCR. The baseline median levels of cfDNA was similar in the presented studies, and all individual studies reported a clear prognostic value in favor of patients with lowest levels of baseline cfDNA. The meta-analysis revealed a combined estimate of favorable overall survival hazard ratio (HR) in patients with levels below the median cfDNA (HR = 2.46, 95% CI 2.17-2.75, p
The total cfDNA levels are high in patients with mCRC and bear strong prognostic information, which should be tested prospectively by using a pre-defined cut-off value. Total cfDNA can be measured in a simple pre-treatment blood sample and potentially aid in clinical decision-making.
Clinical trial identification
Legal entity responsible for the study
Novo Nordisk Foundation
All authors have declared no conflicts of interest.