Multitarget Stool DNA Testing for Colorectal-Cancer Screening

New England Journal of Medicine (Impact Factor: 55.87). 03/2014; 370(14). DOI: 10.1056/NEJMoa1311194
Source: PubMed


An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening.

We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings.

Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P=0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT.

In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; number, NCT01397747.).

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    • "Increasing the performance of non-endoscopic screening methods as well as making them more acceptable to the individual are the primary benefits of genomic, epigenomic , and other molecular early detection markers. The stool DNA test in the recent New England Journal of Medicine paper detailed above [12] uses a panel of nine different markers (two hypermethylation markers and seven KRAS point mutations in addition to an FIT. Several groups are working on molecular markers that can be found in blood, including proteins such as carcinoembryonic antigen, mutated genes such as KRAS [16]; hypermethylated genes such as SEPT9 (encoding septin 9) [17]; and microRNA [18]. "

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    • "They evaluated 21 mutations in APC, Kras, and P53 genes on asymptomatic subjects (n = 4404) tested already for FOBT (Imperiale et al., 2004), and they recently evaluated KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin on very large number of individuals (n = 9989) tested for FIT (Imperiale et al., 2014). Inclusion of a very large number of asymptomatic subjects shows the potential of sensitivity gain for molecular testing (Imperiale et al., 2004, 2014). With these inclusion criteria, the authors simulated a real situation of screening and applied powerful statistical tools to evaluate the true performance of the test used. "
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    • "The benefit of using stool samples to identify colonic neoplasms has recently been demonstrated. Following promising results in the identification of neoplasms in patients with inflammatory bowel disease [71], methylation of BMP3 and NDRG4 were taken forward for use in conjunction with an immunochemical assay for haemoglobin and the detection of KRAS mutations, using bactin as a reference gene to establish DNA levels, for the detection of colorectal tumours [72]. Using an algorithm to calculate a score based upon these measurements, this stool-based approach offered superior sensitivity to the faecal immunochemical test in the detection of tumours (92% vs 74%) and advanced precancerous lesions (42% vs 24%), at the expense of a reduction in specificity (87% vs 95%). "
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