Prevalence of ctDNA in early screen-detected breast cancers using highly sensitive and specific dual molecular barcoded personalised mutation assays

<p>Breast screening has low sensitivity in many patients, and circulating biomarkers may be useful adjuncts to mammography. Circulating tumour DNA (ctDNA) has been studied as a potential biomarker in primary breast cancer (BC)1 and patient-specific mutation panels for detection of cancer recurrence and monitoring of residual disease via ctDNA has potential.2 The role of ctDNA in the detection and monitoring of asymptomatic, screen-detected BC remains unclear, since these patients generally have earlier-stage disease. Here, we report the first study to investigate the prevalence of ctDNA in an unbiased breast screening setting comparing women with early stage 1 and stage 2 BC, detected on incidental routine mammograms. We used a newly developed sequencing technology (Ion Ampliseq™ HD; Thermo Fisher Scientific, Waltham, MA) that uses dual unique molecular identifiers or barcodes to cluster ‘families’ of the same molecule for ctDNA detection. This provides a sensitivity equivalent to digital droplet polymerase chain reaction (PCR) (confident detection of three molecules of ctDNA in 10 000 human haploid genome equivalents) with >99% specificity for single nucleotide variants, hotspots, indels, copy number variations, and fusions.3 With the exception of one study of 12 hepatobiliary cancers in advanced patients,4 this is also the first report of the use of this technology.</p>