Stool DNA testing more sensitive, less specific than FIT

Multitarget stool DNA testing detected significantly more cancer than fecal immunochemical testing (FIT) but had more false-positive results in asymptomatic persons at average risk for colorectal cancer, a study found.

Researchers in North America enrolled asymptomatic persons between the ages of 50 and 84 years who were considered to be at average risk for colorectal cancer and who were scheduled to undergo screening colonoscopy from June 2011 through November 2012 in a cross-sectional study at 90 sites. Enrollment was weighted toward persons 65 years of age or older in order to increase the prevalence of cancer. All participants provided a stool specimen and underwent screening colonoscopy within 90 days.

The study was funded by the manufacturer of a stool DNA test and was designed by the authors. Data were gathered by a contract research organization.

The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. An algorithm was used to generate results, with values of 183 or more considered to be positive. FIT values of more than 100 ng Hg/mL of buffer were considered to be positive.

Results appeared in the March 19 New England Journal of Medicine.

Of 9,989 participants, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions, defined as advanced adenomas or sessile serrated polyps measuring 1 cm or more in the greatest dimension. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P=0.002), a difference of nearly 20 percentage points, the authors noted.

DNA testing detected 42.4% of advanced precancerous lesions and FIT detected 23.8% (P<0.001). DNA testing detected 69.2% of high-grade dysplasia and FIT detected 46.2% (P=0.004). DNA detected 42.4% of serrated sessile polyps measuring 1 cm or more and FIT detected 5.1% (P<0.001).

Specificity with DNA testing was 86.6% of participants with nonadvanced or negative findings, and FIT was 94.9% (P<0.001). Specificity with DNA testing was 89.8% among those with negative results on colonoscopy and 96.4% among those with negative results on FIT (P<0.001).

The numbers of persons who would need to be screened to detect 1 cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT.

The researchers noted that sensitivity of the DNA test exceeded the performance of the FIT overall and in important subsets of lesions, including adenomas measuring 2 cm or more and large, sessile serrated polyps that may account for up to one-third of colorectal cancers. DNA testing was associated with a relative increase of 27% in the rate of detection of stage I to III colorectal cancers and a relative increase of 78% in the rate of detection of advanced precancerous lesions compared to FIT. But, the authors continued, the specificity of FIT (94.9% to 96.4%) was superior to that of the DNA test (86.6% to 89.8%), with false-positive rates of 3.6% to 5.1% and 10.2% to 13.4%, respectively.

An editorial commented that the stool DNA test is clearly an improvement over its predecessors and that the results of this study will help the U.S. Preventive Services Task Force reevaluate screening tests.

“Only through a better understanding of other key factors, such as the screening interval, adherence, cost, and diagnostic evaluation of positive results, can we determine the appropriate place for stool DNA testing on the screening menu,” the editorial noted.