An FDA advisory panel unanimously recommended approval of a noninvasive, multitarget DNA stool test as an option for colorectal cancer screening.

Patients at average risk for colon cancer who would benefit from colonoscopy may soon have an additional screening option.

In March, the Molecular and Clinical Genetics panel of the FDA's Medical Devices Advisory Committee voted unanimously to recommend approval of Cologuard, an in vitro DNA diagnostic test that detects molecular markers of altered DNA shed by cancerous and precancerous cells into a patient's stool during digestion.

Manufactured by Exact Sciences Corp. of Madison, WI, Cologuard detects methylated target DNA (NDRG4,BMP3), specific DNA point mutations (KRAS), and total human DNA (β-actin). It also analyzes the level of hemoglobin present in the stool sample and combines all of the information.

“We use a logistic-regression algorithm, which takes quantitative data from each component assay and generates a qualitative score, so physicians are given a positive or negative result,” says David Ahlquist, MD, a gastroenterologist at Mayo Clinic in Rochester, MN, and co-inventor of Cologuard. “If a test is positive, a patient is advised to have a colonoscopy.”

Cologuard does not require dietary restrictions or bowel preparations and a kit is designed to make it simple for patients to collect samples at home and mail them to a laboratory for analysis.

The FDA panel determined that Cologuard is safe and effective, and that its benefits outweigh its risks. The decision was based on data from the Deep-C trial, published March 19 in The New England Journal of Medicine, which compared Cologuard to fecal immunochemical testing (FIT). FIT detects occult blood.

The study evaluated 9,989 patients who had had screening colonoscopy, which identified colorectal cancer in 65 patients and advanced precancerous lesions in 757 patients.

Stool samples were collected from each patient and analyzed with the Cologuard DNA test and FIT. The DNA test identified 60 of the 65 cancers (92.3% sensitivity), whereas FIT identified 48 (73.8% sensitivity). The DNA test was also more sensitive than FIT in detecting advanced precancerous lesions (42.4% vs. 23.8%), polyps with high-grade dysplasia (69.2% vs. 46.2%), and serrated sessile polyps measuring 1 cm or larger (42.4% vs. 5.1%).

However, the DNA test had lower specificity than FIT among patients with negative colonoscopy results (89.8% vs. 96.4%) and among those with non-advanced precancerous lesions (86.6% vs. 94.9%). This translates into false-positive results of 10.2% to 13.4% vs. 3.6% to 5.1%.

“The implications of these observed point-in-time differences in false-positive rates between tests will need to be considered in the context of programmatic application,” notes Ahlquist. “Because the DNA test is so sensitive, it may be done every 3 years rather than annually, yielding a cumulative false-positive rate comparable to or less than that of FIT.”

The FDA is expected to follow the recommendations of the panel, which has requested post-approval analysis to review performance, screening intervals, and follow-up care.

Ahlquist believes Cologuard could boost low colorectal screening rates. “Because it's noninvasive and user friendly, we hope it will increase participation rates across the country and will be an important step toward a substantial reduction in cancer incidence and mortality,” he says.