Although current screening efforts have reduced colorectal cancer (CRC) incidence and mortality, CRC remains the second-leading cause of cancer deaths in the United States. Worldwide, incidence rates are rising sharply.
"We have a mandate to improve effectiveness of screening by better use of existing tools and by creating better tools," says David A. Ahlquist, M.D., of Mayo Clinic in Rochester, Minn. "If one had to start all over, the ideal screening test would be noninvasive and affordable; require no bowel prep, medication restriction or diet change; and would detect neoplasms on both sides of the colorectum with high accuracy."
A new multimarker test for stool DNA (sDNA) developed by Mayo Clinic in collaboration with Exact Sciences Corp. of Madison, Wis., meets those requirements. No special preparation or restrictions are needed, it can be performed on mailed-in samples, eliminating the need for an office visit, and it has proved highly accurate at detecting premalignant polyps and early-stage colorectal cancer.
The sDNA test is an automated assay for tumor-specific DNA changes, including methylated BMP3 and NDRG4, a mutant form of KRAS, the β-actin gene, and hemoglobin. In three blinded case-control studies, each involving more than 1,000 patients, that have been published or presented in the past year, detection rates for the critical screening targets have been remarkably high. Sensitivity for:
Detection rates increase with size and progression risk of polyps. Sensitivity was 64 percent for both adenomatous and serrated polyps greater than 1 cm, 77 percent for those greater than 2 cm, and 92 percent for polyps larger than 4 cm. Of critical importance, detection is not affected by location or stage.
Dr. Ahlquist says cumulative sensitivity can approach 100 percent after a few checks if the test is applied programmatically every three years. "The point sensitivity of the Pap test for precancerous dysplasia is about 50 percent, yet the Pap test has nearly eliminated cervical cancer in women regularly screened. The point sensitivity of the sDNA test is better than that of the Pap. Our hope is that sDNA tests will help eradicate colon cancer if regularly applied over time," he says.
In a head-to-head comparison, sDNA also proved far superior to a plasma test for SEPT9, identifying 82 percent of adenomas ranging from 1 to 5 cm compared with 14 percent detected by SEPT9. The stool DNA test identified patients with curable-stage CRC with 90 percent sensitivity, whereas SEPT9 had 50 percent sensitivity. False-positives were 7 percent and 27 percent, respectively.
"Our findings are entirely consistent with the biology of marker release," Dr. Ahlquist says. "Cancerous and precancerous cells are shed into the stool and detected by the stool DNA test long before tumors progress to invade the bloodstream for detection by plasma SEPT9 screening. Biology favors the stool test; I am very confident about that."
Unlike colonoscopy and fecal blood testing, the sDNA test is not operator dependent; it is a standardized automated procedure with results interpreted by a computer. The test is also performed less frequently than fecal blood testing — the most commonly used noninvasive option — thereby providing more opportunities for increasing compliance and reducing costs.
An optimized sDNA assay recently underwent a study involving more than 12,000 patients across multiple centers in the United States and Canada. Data from that study will be reviewed by the Food and Drug Administration in early 2013, and if approved, the test will become available shortly thereafter. Because of its developmental role, Mayo Clinic will be one of the first centers to offer it.
Mayo researchers are also actively involved in developing other applications for sDNA testing, including the detection of cancer and precancerous lesions in patients with inflammatory bowel disease and cancers and precancers above the colon. "We are actively pursuing development of a single test that will someday screen the entire GI tract," Dr. Ahlquist says.