Analytical evaluation of tumor-naive ctDNA molecular response detection through baseline informed comprehensive genomic profiling with matched white blood cell analyses

Liquid biopsies can provide an improvement over existing diagnostic modalities to detect, characterize and monitor cancer across the care continuum. Circulating tumor DNA (ctDNA) dynamics have been shown to identify cancer progression earlier than can be achieved with imaging-based assessments, however, can be limited due to low tumor burden together with the biological background associated with germline and clonal hematopoietic (CH) alterations in cell-free DNA. PGDx elio® plasma complete™ (EPC) is a pan-solid tumor hybrid capture, next-generation sequencing (NGS) comprehensive genomic profiling test for the identification of single nucleotide variants (SNVs), insertions and deletions (indels), copy number amplifications, translocations, microsatellite instability (MSI), and blood tumor mutation burden (bTMB) across 521 genes. To optimize EPC for the sensitive and specific detection and quantification of limited ctDNA levels, patient-matched white blood cells (WBCs) were sequenced and a baseline informed bioinformatic approach was implemented, aggregating the tumor-specific mutational signature across the panel. To demonstrate the analytical performance of this strategy, noncancerous donor plasma samples (n=29, 25 ng each) and four contrived reference models were analyzed across seven tumor content levels, with five replicates of each model evaluated at each level (n=140, 25 ng each). These studies demonstrated 100% specificity (116/116) with a limit of detection (95%) of 0.05% tumor and limit of quantification of 0.15% tumor (<20% median CV). Taken together, these data demonstrate that through the integrated analysis of cfDNA and matched white blood cell DNA, with a tumor-naïve approach, EPC can achieve increased sensitivity for the accurate detection and quantification of ctDNA required for the assessment of molecular response in patients with metastatic solid tumors.