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Circulating tumour DNA (ctDNA) detection of molecular residual disease (MRD)in solid tumours correlates strongly with patient outcomes and is being adoptedas a new clinical standard. ctDNA levels are known to correlate with tumorvolume, and although the absolute levels vary across indication and histology,its analysis is driving the adoption of MRD. MRD assays must detect tumor whenimaging cannot and, as such, require very high sensitivity to detect the lowlevels of ctDNA found after curative intent therapy. The minimum threshold is0.01% Tumour Fraction but current methods like Archer and Signatera are limitedby detection sensitivity resulting in some patients receiving a false negativecall thereby missing out on earlier therapeutic intervention. Multiple vendorsare increasing the number of somatic variants tracked in tumour-informed andpersonalized NGS assays, from tens to thousands of variants. Most recently,assays using other biological features of ctDNA, e.g methylation orfragmentome, have been developed at the LOD required for clinical utility.These uniformed, or tumour-naive and non-personalised assays may be moreeasily, and therefore more rapidly, adopted in the clinic. However, this rapiddevelopment in MRD assay technology results in significant challenges inbenchmarking these new technologies for use in clinical trials. This is furthercomplicated by the fact that previous reference materials have focused onsomatic variants, and do not retain all of the epigenomic features assessed bynewer technologies. In this Comments and Controversy paper, we detail what isknown and what remains to be determined for optimal reference materials of MRDmethods and provide opinions generated during three-years of MRD technologybenchmarking in AstraZeneca Translational Medicine to help guide the communityconversation.

Next-generation MRD assays: do we have the tools to evaluate them properly?