Abstract
PURPOSEEarlier detection of cancer recurrence using circulating tumor DNA (ctDNA) to detect molecular residual disease (MRD) has the potential to dramatically affect cancer management. We review evidence supporting the use of ctDNA as a biomarker for detection of MRD and highlight the potential impact that ctDNA testing could have on the conduct of clinical trials.METHODSWe searched the literature using MEDLINE (via PubMed) for articles from January 1, 2000, focusing on studies that assessed ctDNA as a predictor of cancer recurrence. Broadly focused searches on ctDNA and cancer were also performed to provide additional background information. www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing.RESULTSNumerous studies across different cancer types indicate that ctDNA-based MRD detection predicts recurrence with high sensitivity and specificity, and with lead times that precede standard imaging by up to 12 months. Recently, ctDNA testing has started being used to enroll MRD-positive patients at high risk of recurrence into trials, promising gains in statistical power that allow clinical utility to be demonstrated with smaller cohorts. Trials where ctDNA testing based-MRD detection is used to stratify patients into low or high-risk categories for treatment assignment are also ongoing. In addition, there is increasing evidence supporting the use of ctDNA dynamics or clearance as a surrogate end point, which could significantly reduce trial duration.CONCLUSIONctDNA-based trial enrichment across many cancers seems likely to become increasingly common for cost- and time-reduction benefits. Trial efficiency could also benefit from using ctDNA as a surrogate end point, leading to accelerated approval of new therapeutics. A clear demonstration of efficacy from trials that use ctDNA-based MRD detection to assign treatment could transform clinical practice.
Highlights
The presence of extracellular DNA in blood, referred to as cell-free DNA, was first reported in 1948.1 The first reports of tumor-specific mutations in cfDNA were published in 1994, when KRAS and NRAS mutations were observed in patients with pancreatic cancer and acute myelogenous leukemia.[2,3] Recent work indicates that for many cancers, there are genetic variants present in cfDNA that broadly overlap with variants found in tumor tissue.[4]
We review evidence supporting the use of circulating tumor DNA (ctDNA) as a biomarker for detection of molecular residual disease (MRD) and highlight the potential impact that ctDNA testing could have on the conduct of clinical trials
Numerous studies across different cancer types indicate that ctDNA-based MRD detection predicts recurrence with high sensitivity and specificity, and with lead times that precede standard imaging by up to 12 months
Summary
We searched the literature using MEDLINE (via PubMed) for articles from January 1, 2000, focusing on studies that assessed ctDNA as a predictor of cancer recurrence. Focused searches on ctDNA and cancer were performed to provide additional background information. Www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing Focused searches on ctDNA and cancer were performed to provide additional background information. www.clinialtrials.gov was searched to identify trials that incorporate ctDNA testing
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