Stool Multitarget DNA Test More Sensitive, But Less Specific Than Fecal Immunochemical Test for Colorectal Cancer Screening in Persons at Average Risk
In a study reported in The New England Journal of Medicine, Imperiale et al found that a noninvasive, multitarget stool DNA test—including assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, β-actin, and hemoglobin—was significantly more sensitive but significantly less specific than the fecal immunochemical test in detecting colorectal cancer in persons at average risk for the disease.
Study Details
The study included 11,016 asymptomatic subjects aged 50 to 84 years enrolled between June 2011 and November 2012 at 90 sites in the United States and Canada who were considered to be at average risk of colorectal cancer and who were scheduled to undergo screening colonoscopy. Enrollment was weighted toward persons aged ≥ 65 years to increase the prevalence of cancer in the study population.
Subjects were excluded if they had a history of colorectal neoplasia, digestive cancer, or inflammatory bowel disease, had undergone colonoscopy within the previous 9 years or a barium enema, computed tomographic colonography, or sigmoidoscopy within the previous 5 years, had positive results on fecal blood testing within the previous 6 months, had undergone colorectal resection for any reason other than sigmoid diverticula, had overt rectal bleeding within the previous 30 days, or had a personal or family history of colorectal cancer.
The multitarget stool DNA test consists of molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and β-actin (a reference gene for DNA quantity) and an immunochemical assay for hemoglobin. Quantitative measurements of each marker were incorporated into a validated logistic-regression algorithm, with a value of ≥ 183 indicating a positive result. For the fecal immunochemical test, stool samples with hemoglobin > 100 ng/mL buffer were considered positive. The same stool sample was used for fecal immunochemical testing and DNA testing.
Study Exclusions
Of the 11,016 subjects who could be evaluated, 689 had DNA tests excluded (including 474 with stool samples that could not be evaluated and 213 due to technical failure), 304 had colonoscopy excluded (including 194 who had negative results but incomplete exams and 71 who underwent biopsy but had no pathology result due to no tissue or loss of specimen), and 34 had fecal immunochemical tests excluded (due to insufficient hemoglobin sample).
Increased Sensitivity, Decreased Specificity
Of the 9,989 subjects included in the analysis, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps ≥ 1 cm) on colonoscopy; 2,893 (29.0%) had nonadvanced adenomas.
Sensitivity for detecting colorectal cancer was 92.3% with DNA testing vs 73.8% for fecal immunochemical testing (P = .002) and sensitivity for detecting advanced precancerous lesions was 42.4% vs 23.8% (P < .001). Rates of detection of polyps with high-grade dysplasia (69.2% vs 46.2%, P = .004) and serrated sessile polyps ≥ 1 cm (42.4% vs 5.1%, P < .001) were significantly greater with DNA testing.
Specificities for DNA testing vs fecal immunochemical testing were 86.6% vs 94.9% (P < .001) among subjects with nonadvanced or negative findings and 89.8% vs 96.4% (P < .001) among those with negative findings on colonoscopy.
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 fecal immunochemical testing.
The investigators concluded, “In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did [fecal immunochemical testing] but had more false positive results.”
Thomas F. Imperiale, MD, of Indiana University School of Medicine, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Exact Sciences. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
