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Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients.

ABSTRACT: Somatic mutations provide uniquely specific markers for the early detection of neoplasia that can be detected in DNA purified from plasma or stool of patients with colorectal cancer. The primary purpose of the present investigation was to determine the parameters that were critical for detecting mutations using a quantitative assay. A secondary purpose was to compare the results of plasma and stool DNA testing using the same technology.We examined DNA purified from the stool of 25 patients with colorectal cancers before surgery. In 16 of these cases, plasma samples also were available. Mutations in stool or plasma were assessed with an improved version of the BEAMing technology.Of the 25 stool DNA samples analyzed, 23 (92%) contained mutations that were present in the corresponding tumors from the same patients. In contrast, only 8 of the 16 (50%) plasma DNA samples analyzed had detectable levels of mutated DNA. We found that the DNA fragments containing mutations in both stool and plasma DNA typically were smaller than 150 bases in size. The sensitivity of the new method was superior to a widely used technique for detecting mutations, using single base extension and sequencing, when assessed on the same samples (92% vs 60%; P = .008, exact McNemar test).When assessed with sufficiently sensitive methods, mutant DNA fragments are detectable in the stool of more than 90% of colorectal cancer patients. DNA purified from stool provides a better template for mutation testing than plasma.

SUBMITTER: Diehl F

PROVIDER: S-EPMC2820386 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients.

Diehl Frank F Schmidt Kerstin K Durkee Kristine H KH Moore Kent J KJ Goodman Steve N SN Shuber Anthony P AP Kinzler Kenneth W KW Vogelstein Bert B

Gastroenterology 20080515 2

<h4>Background & aims</h4>Somatic mutations provide uniquely specific markers for the early detection of neoplasia that can be detected in DNA purified from plasma or stool of patients with colorectal cancer. The primary purpose of the present investigation was to determine the parameters that were critical for detecting mutations using a quantitative assay. A secondary purpose was to compare the results of plasma and stool DNA testing using the same technology.<h4>Methods</h4>We examined DNA pu ...[more]

PMID: 18602395

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Project description:Background & aimsPatients with chronic ulcerative colitis are at increased risk for colorectal neoplasia (CRN). Surveillance by white-light endoscopy (WLE) or chromoendoscopy may reduce risk of CRN, but these strategies are underused. Analysis of DNA from stool samples (sDNA) can detect CRN with high levels of sensitivity, but it is not clear if this approach is cost-effective. We simulated these strategies for CRN detection to determine which approach is most cost-effective.MethodsWe adapted a previously published Markov model to simulate the clinical course of chronic ulcerative colitis, the incidence of cancer or dysplasia, and costs and benefits of care with 4 surveillance strategies: (1) analysis of sDNA and diagnostic chromoendoscopy for patients with positive results, (2) analysis of sDNA with diagnostic WLE for patients with positive results, (3) chromoendoscopy with targeted collection of biopsies, or (4) WLE with random collection of biopsies. Costs were based on 2014 Medicare reimbursement. The primary outcome was the incremental cost-effectiveness ratio (incremental cost/incremental difference in quality-adjusted life-years) compared with no surveillance and a willingness-to-pay threshold of $50,000.ResultsAll strategies fell below the willingness-to-pay threshold at 2-year intervals. Incremental cost-effectiveness ratios were $16,362 per quality-adjusted life-year for sDNA analysis with diagnostic chromoendoscopy; $18,643 per quality-adjusted life-year for sDNA analysis with diagnostic WLE; $23,830 per quality-adjusted life-year for chromoendoscopy alone; and $27,907 per quality-adjusted life-year for WLE alone. In sensitivity analyses, sDNA analysis with diagnostic chromoendoscopy was more cost-effective than chromoendoscopy alone, up to a cost of $1135 per sDNA test. sDNA analysis remained cost-effective at all rates of compliance; when combined with diagnostic chromoendoscopy, this approach was preferred over chromoendoscopy alone, when the specificity of the sDNA test for CRN was >65%.ConclusionsBased on a Markov model, surveillance for CRN is cost-effective for patients with chronic ulcerative colitis. Analysis of sDNA with chromoendoscopies for patients with positive results was more cost-effective than chromoendoscopy or WLE alone.

Project description:BackgroundThe Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees.ObjectiveTo evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services.DesignComparative microsimulation modeling study using 2 independently developed models.Data sourcesDerived from literature.Target populationA cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied.Time horizonLifetime.PerspectiveThird-party payer.InterventionStool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies.Outcome measuresLife expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs.Results of base-case analysisAssuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be cost-effective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests.Results of sensitivity analysisNone of the results changed substantially when a cohort of persons aged 50 years was considered.LimitationNo pathways other than the traditional adenoma-carcinoma sequence were modeled.ConclusionStool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening.

Dataset Information

Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients.

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Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients.

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