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

By Andrew A. Davis, Wade T. Iams, David Chan, Michael S. Oh, Robert W. Lentz, Neil Peterman, Alex Robertson, Abhik Shah, Rohith Srivas, Timothy Wilson, Nicole Lambert, Peter George, Becky Wong, Haleigh Wood, Jason Close, Ayse Tezcan, Ken Nesmith, Haluk Tezcan, Young Kwang Chae

Posted 24 Jul 2019
medRxiv DOI: 10.1101/19002550

PurposeTreatment 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. Methods97 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). ResultsPatients 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%. ConclusionsMolecular 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. Translational RelevanceTools for early assessment of treatment response in advanced solid tumors require refinement. We performed baseline and early serial assessments of WG ctDNA to predict treatment response prior to standard of care clinical and radiographic assessments. Our results demonstrated that the blood-based prediction reliably identified molecular progression, approximately 6 weeks before imaging, with very high specificity and positive predictive value across multiple tumor and treatment types. Patients with molecular progression had significantly shorter progression-free survival compared with non-progressors. In addition, a large quantitative decrease in tumor fraction ratio was associated with significant durable benefit. Collectively, these findings demonstrate that cancer-related changes in the blood precede clinical or imaging changes and may inform changes in management earlier in the treatment course to improve long-term patient outcomes and limit cost.

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