In August 2014, the Food and Drug Administration (FDA) approved Cologuard, a noninvasive, multitarget stool DNA screening test for colorectal cancer (CRC). For the first time, the Centers for Medicare & Medicaid Services (CMS) simultaneously proposed national coverage for the test as part of a pilot FDA-CMS parallel review program.
"The decision to seek FDA approval was a big one; most tests are not FDA approved, but we felt it was important to take this revolutionary new tool to the highest and most rigorous level," says David A. Ahlquist, M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, who co-developed Cologuard with Wisconsin-based Exact Sciences.
The test is an automated assay for tumor-specific DNA changes, including aberrant methylated BMP3 and NDRG4, a mutant form of KRAS, beta-actin, and hemoglobin. Unlike other fecal tests, which need to be performed annually, Cologuard can be used every three years because of its high accuracy.
FDA approval was based on data from a pivotal prospective trial involving nearly 10,000 average-risk, asymptomatic patients at 90 centers in the United States and Canada. The trial, called DeeP-C, compared the safety and efficacy of Cologuard and the fecal immunochemical test (FIT) — the most commonly used fecal occult blood test —with colonoscopy. Study results were published in the March 2014 issue of The New England Journal of Medicine.
The study's primary performance measures were Cologuard CRC sensitivity and Cologuard advanced neoplasia specificity. Major findings include:
- Sensitivity of Cologuard for CRC was 92.3 percent overall and 94 percent for the earliest and most curable cancer stages — on a par with colonoscopy. In contrast, sensitivity of FIT for CRC was 73.8 and 70 percent, respectively.
- Detection rates for polyps with high-grade dysplasia were 69.2 percent with Cologuard versus 46.2 percent with FIT; detection rates for serrated sessile polyps measuring 1 cm or more were 42.4 percent and 5.1 percent, respectively.
- Specificities for Cologuard and FIT were 90 and 95 percent, respectively, for patients with negative findings on colonoscopy.
Dr. Ahlquist says the specificity of Cologuard should be higher than that of other screening tests when applied over time within a screening program. For example, false positives would average 3 or 4 a year with Cologuard done every three years compared to 5 a year with FIT performed annually.
Of primary importance is Cologuard's high sensitivity for CRC. "That sensitivity is essential because you may only get one shot at detecting colorectal cancer," Dr. Ahlquist says. "The sensitivity for polyps with high-grade dysplasia is 70 percent, but we have additional opportunities with them because they grow slowly. By the second screen, the cumulative sensitivity is 92 percent, and it is even higher with the third screen. That may be equal to or better than colonoscopy performed every 10 years."
The ideal CRC screening test
Cologuard was developed to provide a new choice in CRC screening tests because research shows that patients who are offered alternatives are more likely to comply with screening, says John B. Kisiel, M.D., a gastroenterologist at Mayo's Rochester campus who was actively involved in Cologuard research and development. "Our overarching mission was to develop a new test that is highly sensitive for cancers and noncancers that is not affected by the location of the tumor in the colon," he explains.
Since 1980, the incidence of right-side colorectal adenocarcinomas has gradually increased; today, they account for half of all colon tumors in the U.S. and 60 percent of those in Olmsted County, Minnesota. Yet current screening methodologies are biased toward left-side tumors. Large case-control and cohort studies in Canada, the U.S. and elsewhere have found that screening colonoscopy is less effective in lowering mortality and incidence of right-side CRC. Cologuard, on the other hand, performs equally well on both sides of the colon.
Dr. Kisiel says the ideal test should also:
- Be easy to use
- Require no bowel prep or medication or dietary restrictions
- Be widely available
Cologuard, which is mailed to patients at home and requires only a stool sample, meets all these requirements. "Although colorectal cancer is almost entirely preventable, it is the second-leading cause of cancer mortality in adults in the United States, mainly because 1 in 3 people who are eligible for screening don't participate. Colonoscopy, the most widely used screening method, is expensive and requires bowel prep, sedation and time off work, both for patients and a friend or family member to drive them home, and people are simply reluctant to undergo it. We tried to eliminate as many of those barriers as possible," he says.
Cologuard also eliminates problems of operator variability. As Dr. Ahlquist points out, "Many studies demonstrate that polyp detection can vary as much as sixfold among endoscopists within the same center. With Cologuard, there is no operator, and no statistically significant difference in reporting among different labs, so the test may actually encourage colonoscopists to do a better job."
As for cost-effectiveness, at $599 — of which Medicare is expected to pay $502 — Cologuard is more expensive than FIT, but less than colonoscopy. Cost-effectiveness analysis was performed by an independent third party and has been studied by a number of payor organizations. Drs. Kisiel and Ahlquist say pricing in other countries will be flexible, depending on the cost of screening practices there.
Cologuard in IBD patients
Cologuard is not intended to replace diagnostic colonoscopy or surveillance colonoscopy in high-risk patients, including those with inflammatory bowel disease (IBD). Yet surveillance colonoscopy in patients with (IBD) is fraught with problems. One is the unreliability of random biopsies, which sample only a small fraction of the colon mucosal surface. Even targeted biopsies using enhanced imaging techniques such as chromoendoscopy can miss lesions obscured by background inflammation.
There is also little data on the ideal frequency for performing surveillance exams and little evidence to demonstrate their effectiveness. Several meta-analyses have found no reduction in CRC deaths with surveillance colonoscopy. "The practice is endorsed because it may find cancers at an earlier stage, but it is invasive, and most patients don't comply very well, even those with access to good health care. The surveillance compliance rate is half what it should be," Dr. Kisiel says.
In a 2013 study published in Alimentary Pharmacology & Therapeutics, Drs. Kisiel, Ahlquist and colleagues demonstrated the feasibility and effectiveness of DNA stool testing for the detection of colorectal neoplasia associated with IBD. The belief is that a noninvasive test like Cologuard will lead to much higher rates of compliance. Based on data from fecal blood testing, compliance rate to subsequent colonoscopy after a positive screening test is around 90 percent.
Cologuard is currently available at Mayo Clinic's campus in Minnesota and will be available at the campuses in Jacksonville, Florida, and Scottsdale, Arizona, in the first quarter of 2015. A rollout is also in progress for many other large health care organizations and systems. Private practice physicians can register directly with the manufacturer.
For more information
Imperiale TF, et al. Multitarget stool DNA testing for colorectal-cancer screening. The New England Journal of Medicine. 2014;370:1287.
Kisiel JB, et al. Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2013;37:546.
How to order Cologuard. Exact Sciences Corporation.