cfTrack: Exome-wide mutation analysis of cell-free DNA to simultaneously monitor the full spectrum of cancer treatment outcomes: MRD, recurrence, and evolution

Abstract

AbstractPurposeCell-free DNA (cfDNA) offers a non-invasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer.Experimental DesignThree simulation datasets were generated from 26 cancer patients to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n=76) from cancer patients (n=35) with six different cancer types were used for validating the performance of cancer monitoring during various treatments.ResultsWe present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across the known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fraction ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fraction ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.ConclusionOur results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.Translational RelevanceContinuous cancer monitoring is clinically necessary for cancer patients to detect minimal residual disease (MRD), recurrence, and progression, allowing for early intervention and therapy adjustment. Cell-free DNA (cfDNA) in blood has become an appealing option due to its non-invasiveness. Until now, cfDNA-based cancer monitoring methods have been focused on deep sequencing at a few known mutations, which are however insufficient when tumors evolve or new tumors emerge. We present the method, cfTrack, which for the first time uses whole-exome sequencing (WES) of cfDNA to track the full range of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancer. We demonstrate that, even with very low tumor fractions, cfTrack achieves sensitive and specific monitoring of tumor MRD/recurrence/evolution based on both simulation data and a cohort of cancer patients. These findings demonstrate the clinical utility of cfTrack.