Authors: Yves Konigshofer, PhD; Andrew Anfora, PhD; Omo Clement, PhD; and Krystyna Nahlik, PhD. LGC Clinical Diagnostics. Introduction Liquid biopsy methods developed for circulating tumor DNA (ctDNA) analysis in solid tumors are transforming clinical practice, allowing for non-invasive detection and assessment of earlier stages of disease, monitoring for resistance to therapy, and post-treatment monitoring for minimal residual disease (MRD) and recurrence of cancer. The presence of minimal residual disease may be prognostic in that is has been found to correlate with worse patient outcomes, so early and accurate measurement is crucial. ctDNA-based assays allow for the detection of MRD at earlier time points than standard clinical and imaging surveillance, and could allow for treatment modification based on real-time assessment of the tumor genomic landscape.

Part 1 of 2 Background Measurable Residual Disease (MRD) monitoring – for purposes of this blog – will be the act of looking for somatic variants in a liquid biopsy sample by analyzing circulating cell-free DNA (ccfDNA). This is done to monitor the disappearance of a metastatic solid tumor during treatment and to follow any future reemergence of that cancer. Analyzing ccfDNA assumes that circulating tumor DNA (ctDNA) will be present, and the median ctDNA frequency in patient samples across cancers seems to be around 0.5 to 1 %. Thus, the median variant allele frequencies (VAFs) of the somatic variants will start around this range, and the goal of MRD monitoring is to be able to detect them at much lower VAFs. This can be challenging and if we are going to design an assay for MRD monitoring, then we need to be aware of them and overcome them.