Finding a place for Cologuard in the CRC screening algorithm

In August 2014, the Food and Drug Administration (FDA) approved Cologuard, a noninvasive, multitarget stool screening test for colorectal cancer (CRC). The test is an automated assay for tumor-specific DNA changes, including aberrant methylated BMP3 and NDRG4, a mutant form of KRAS, β-actin, and hemoglobin.

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 compared 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 included the following:

  • 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 percent 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 centimeter or more were 42.4 percent and 5.1 percent, respectively.
  • Specificities for Cologuard and FIT were 90 percent and 95 percent, respectively.

Despite Cologuard's superiority in trials — and its proven ability to perform equally well on both sides of the colon — questions remain regarding Cologuard's role in the colorectal screening algorithm, says Seth R. Sweetser, M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota.

"We know that Cologuard performs well as a one-time screening test for colorectal neoplasia in average-risk individuals. It has high sensitivity for cancer but is less sensitive for advanced polyps. So one question that needs to be addressed is how it would perform in a programmatic fashion, that is, in a longitudinal screening program," he explains. "A screening interval of three years has been recommended after a negative Cologuard test, so the test would be performed three times over 10 years. In theory, the sensitivity of Cologuard should be higher than that of other noninvasive screening tests when applied over time within a screening program."

Exact Sciences, the Wisconsin-based manufacturer of Cologuard, is undertaking a study to determine the most appropriate screening interval and how well Cologuard actually performs over time. The study will follow 2,000 enrolled participants for three years.

Questions addressed

Other questions concerning Cologuard will be addressed by Mayo Clinic investigators, including:

What patient and provider factors influence test selection for CRC screening? Why choose Cologuard over colonoscopy or vice versa?

David A. Ahlquist, M.D., a gastroenterologist at Mayo Clinic's campus in Minnesota and co-developer of Cologuard, has looked at patient factors affecting test selection. He found that those who choose colonoscopy are uncomfortable with the idea of missed polyps, whereas those who prefer Cologuard are averse to the invasiveness and test prep associated with colonoscopy. But according to Dr. Sweetser, test preference is more nuanced and reflects provider attitudes, too, and how information is presented to patients. A study will use surveys and questionnaires to look at provider-patient factors in CRC screening test selection.

How should patients who have a positive Cologuard and negative colonoscopy be evaluated?

"There is an algorithm in place to evaluate such patients based on expert opinion and the best information available, but we need more evidence-based information to develop a better algorithm," Dr. Sweetser says. "There is a small chance that Cologuard can pick up an upper gut malignancy; in theory, it could detect gastric, pancreatic or esophageal cancer, leading to a positive fecal test but negative colonoscopy.

"The New England Journal of Medicine study found a 10 percent false-positive rate, so how do we evaluate these patients? Do we need to look elsewhere in the gut? This is the most pressing question, which raises a lot of anxiety among both patients and providers. A comprehensive evaluation of these patients over time will better inform us."

Cologuard availability

Cologuard is currently available at Mayo Clinic's campus in Minnesota and will soon be available at Mayo's campuses in Jacksonville, Florida, and Scottsdale, Arizona. A rollout is 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.

How to order Cologuard. Exact Sciences.