Early detection of molecular disease progression by whole-genome circulating tumor DNA in advanced solid tumors

Purpose: Treatment response assessment for patients with advanced solid tumors is complex and existing methods of assessment require greater precision for early disease assessment. Current guidelines rely on imaging, which has limitations such as the long time required before treatment effectiveness can be determined. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to detect disease progression early in the treatment course. Methods: 97 patients with advanced cancer were enrolled, and blood was collected before and after initiation of a new treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to identify molecular progression or response in a binary manner. Study endpoints were agreement with first follow-up imaging (FUI) and stratification of progression-free survival (PFS). Results: Patients with early molecular progression had shorter PFS (n=14; median 62d) compared to others (n=78; median 263d, HR 12.6 [95% confidence interval 5.8-27.3], log-rank P<10-10, 5 excluded from analysis). All cases with molecular progression were confirmed by FUI and molecular progression preceded FUI by a median of 40d. Sensitivity for the assay in identifying clinical progression was 54%, median 24d into treatment and specificity was 100%. Conclusions: Molecular progression, based on ctDNA data, detected disease progression for cases on treatment with high specificity approximately 6 weeks before follow-up imaging. This technology may enable early course change to a potentially effective therapy, avoiding side effects and cost associated with cycles of ineffective treatment.