Novel Stool DNA Test May Enhance Colon Cancer Screening

Fran Lowry

March 19, 2014

An investigational multitarget stool DNA test for screening colorectal cancer detects significantly more cancers than the currently available fecal immunochemical test (FIT), researchers report.

But it does so at the cost of more false-positive results.

"This new test is the most sensitive noninvasive test for detecting colorectal cancer," said lead study author Thomas F. Imperiale, professor of medicine at the Indiana University School of Medicine in Indianapolis.

Dr. Thomas Imperiale

"The advantages are that it could be done less frequently than annually. We are going to have to have computer simulation analyses tell us what an appropriate interval would be," he told Medscape Medical News in a telephone interview.

"The new test is very good at detecting curable-stage cancers. If there is a downside, it's that the specificity is not as good as FIT. That's the way it goes with diagnostic tests. The more sensitive they are, usually the less specific they are," he said.

The study was published online March 19 in the New England Journal of Medicine.

The test, known as Cologuard, is produced by Exact Sciences and was codeveloped by the Mayo Clinic. It consists of quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. The test is currently under review at the US Food and Drug Administration; the company is scheduled to appear before the Molecular and Clinical Genetics Panel of the Medical Advisory Committee on March 27.

Noninvasive Alternative to Colonoscopy

Despite widespread recommendations and the availability of several screening tests, a substantial proportion of the American population does not get screened. The noninvasive nature of this stool DNA test might make colorectal cancer screening more acceptable, Dr. Imperiale said.

He and his team evaluated 9989 asymptomatic people 50 to 84 years of age who were considered to be at average risk for colorectal cancer and who were scheduled to undergo a screening colonoscopy.

All participants provided a stool specimen before routine bowel preparation for colonoscopy.

On colonoscopy, colorectal cancer was identified in 65 participants — a prevalence of 0.7%. Of these, 60 had stage I to III cancers. In addition, advanced precancerous lesions were identified in 757 (7.6%) participants.

Stool DNA testing identified 60 of the 65 participants with cancer, for a sensitivity of 92.3%, including 56 of the 60 participants with stage I to III cancers, for a sensitivity of 93.3%.

DNA testing sensitivity did not vary significantly by cancer stage or location in the colon, Dr. Imperiale reported.

DNA testing also identified 321 of the 757 advanced precancerous lesions, 27 of the 39 (69.2%) participants with high-grade dysplasia, and 42 of the 99 (42.4%) participants with sessile serrated polyps 1 cm or larger.

The sensitivity of the DNA test increased as lesion size increased, and was higher for distal advanced precancerous lesions than for proximal lesions (54.5% vs 33.2%).

Age did not affect its sensitivity for detecting cancer.

For the 9167 participants who had colonoscopy findings other than colorectal cancer or advanced precancerous lesions, such as nonadvanced adenomas or negative results, the specificity of the DNA test was 86.6%.

For the 4457 participants with negative colonoscopy results, the specificity of the DNA test was 89.8%. In this subgroup, specificity was 94.0% for participants younger than 65 years and 87.1% for those 65 years and older.

For colorectal cancer, overall sensitivity was significantly better with DNA testing than with FIT (92.3% vs 73.8%; P = .002).

The sensitivity of DNA testing was also better than of FIT for advanced precancerous lesions (42.4% vs 23.8%; P < .001).

However, for people with nonadvanced or negative findings on colonoscopy, specificity was worse with DNA testing than with FIT (86.6% vs 96.4%; P < .001).

To detect 1 cancer, 154 people would need to be screened with colonoscopy, 166 with DNA testing, and 208 with FIT.

Number of False-Positives With Stool DNA Concerning

Results with this stool DNA test are "encouraging", said Douglas Robertson, MD, chief of gastroenterology at the White River Junction Veterans Affairs (VA) Medical Center in Vermont and associate professor of medicine at the Dartmouth Medical School in Hanover, New Hampshire.

He and his colleague, Jason A. Dominitz, MD, from the VA Puget Sound Health Care System and the University of Seattle, coauthored an accompanying editorial.

"The test is showing progress in terms of being able to detect cancer, but it remains to be seen how it will function in real-world clinical practice," Dr. Robertson told Medscape Medical News.

Dr. Douglas Robertson

"Ultimately, one of the dictums of colorectal cancer screening is that the best test is the one that gets done," he noted.

Another concern is the false-positive rate. The more frequently the test returns a false-positive result, the more colonoscopy exams will be required, he explained.

The interval with which this test would be applied in clinical practice is also not clear, Dr. Robertson said. "It probably can't be applied every year because the false-positive rate would be pretty high and you might end up doing colonoscopies on everybody over time anyway," he said.

"These are real-world practical issues that still need to be sorted out with stool DNA testing," he said. "It's exciting because the test clearly is functioning better than FIT, but how it will translate into clinical outcomes in practice we don't yet know."

Dr. Robertson said the results of this study could help to inform the US Preventive Services Task Force (USPSTF) as it re-evaluates recommendations for colorectal cancer screening.

"Right now, the USPSTF recommends 3 tests: colonoscopy, sigmoidoscopy, and stool testing with FIT. The last time they looked at the data, they didn't think there was enough support for fecal DNA testing so they did not endorse or recommend its use. This study might change that. Before, fecal DNA technology picked up about 50% of the cancers; now, in a similar study years later and with a newer version of the test, fecal DNA is detecting more than 90% of cancers," he explained.

"It is definitely working better than it used to; there's no question about that, Dr. Robertson said. "Whether the USPSTF will recommend it as an option remains to be seen."

The study was supported by Exact Sciences Inc. Dr. Imperiale has disclosed no relevant financial relationships. Dr. Robertson reports being on the advisory board of Pill Cam Colon (Given Imaging).

N Engl J Med. Published online March 19, 2014. Abstract, Editorial

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