Where Will Cologuard Fit Into CRC Screening?

Nick Mulcahy

August 15, 2014

This week, a stool DNA test (Cologuard, Exact Sciences) was approved for colorectal cancer (CRC) screening by the US Food and Drug Administration, but where will the new test fit in?

The noninvasive test joins a litany of options that clinicians can now offer individuals eligible for screening.

Although the screening "gold standard" in the United States is colonoscopy, many adults avoid the invasive procedure.

Until now, the most commonly used noninvasive alternatives have been based solely on analyses of blood in the stool. Cologuard is also based on stool DNA, and has been shown to be significantly more sensitive.

Specifically, in its pivotal clinical trial, Cologuard was significantly more sensitive than the Fecal Immunochemical Test (FIT, Polymedco) in detecting CRCs (92% vs 74%; P = .002) and advanced precancerous lesions (adenomas and sessile serrated polyps) (42% vs 24%; P < .001).

But on the downside, Cologuard was significantly worse than FIT at correctly identifying patients who were negative for CRC or advanced lesions (87% vs 95%; P < .001).

The great hope for Cologuard is that it will engage patients who skip CRC screening because they want to avoid the discomfort and time required for colonoscopy.

"There is potential to reach patients who have not been screened and would prefer a noninvasive option," said Daniel Chung, MD, from the Massachusetts General Hospital Cancer Center in Boston, in an email to Medscape Medical News.

"Many people don't get screened because they've come to equate CRC screening with colonoscopy," said Thomas Imperiale, MD, from Indiana University and the Regenstrief Institute in Indianapolis, who is a Cologuard investigator, also in an email.

"The reason that gastroenterologists will like Cologuard is that it will bring more patients into screening," Kevin Conroy, chief executive officer of Exact Sciences in Madison, Wisconsin, told Medscape Medical News.

Another clinician went as far as to suggest, in an editorial published this week in JAMA (2014;312:601-602), that Cologuard might someday eclipse both colonoscopy and sigmoidoscopy as the initial screening test of choice in the United States.

"Stool DNA testing has the potential to reduce colorectal cancer mortality substantially while sharply reducing the number of routine colonscopies," summarized Allan Brett, MD, from University of South Carolina in Columbia.

However, it remains to be seen whether there will be widespread uptake of the new stool DNA test.

In fact, in their 90-site, 10,000-patient Cologuard study, Dr. Imperiale and his colleagues acknowledge that currently available data "cannot determine which test or strategy is better or preferred" (N Engl J Med. 2014;370:1287-1297).

Without such data, clinicians and patients will decide for themselves how Cologuard fits their needs.

One thing is certain: patients who have a positive test result with Cologuard must proceed to colonoscopy.

Detecting vs Preventing Colon Cancer

Cologuard is a hemoglobin assay like FIT, but also contains a DNA test that targets various gene mutations, including those of KRAS.

Like stool DNA tests before it, Cologuard detects cancer better than it detects adenomas and sessile serrated polyps.

That is a shortcoming of the new stool test if you are attempting to prevent colon cancer, not just detect it, Dr. Chung pointed out.

Colonoscopy remains the modality that is most likely to detect precancerous polyps.

"In 2014, a well-performed colonoscopy remains the modality that is most likely to detect precancerous polyps in the colon," he said.

The adenoma is the "real target of a screening program whose goal is to prevent colon cancer," Dr. Chung explained in a previous editorial (Ann Intern Med. 2008;149:509-510).

"Like all noninvasive tests, Cologuard does not perform particularly well in detecting colonic polyps," he told Medscape Medical News this week. "It detected only 17% of all nonadvanced adenomatous polyps. However, it performed better in identifying advanced adenomas, with a sensitivity of 42%. Of all polyps, advanced adenomas are the lesions that are most likely to progress to invasive cancer."

However, colonoscopy is not as successful a screening strategy as it could be; only about 60% of eligible Americans get screened for CRC. "Compliance with colorectal cancer screening remains suboptimal," noted Dr. Chung.

Better noninvasive options are needed and could help "close this gap," he added.

Giving people a choice "seems to increase participation in CRC screening," said Dr. Imperiale. In a previous study, when people were given the option of fecal occult blood testing (FOBT) or colonoscopy, screening rates increased (Arch Intern Med. 2012;172:575-582), he reported.

It is recommended that screening with Cologuard take place every 3 years. However, the performance of the test was established in a "cross-sectional" study, which means it was evaluated at a single point in time.

Nevertheless, Dr. Imperiale believes that the combination of the time interval and the noninvasive nature of the Cologuard test should improve the uptake of CRC screening.

"My sense is that Cologuard every 3 years would have better uptake than sigmoidoscopy every 5 years or FOBT annually," stated Dr. Imperiale.

For the moment, Cologuard seems to be the top performing noninvasive test. "Cologuard appears to detect more advanced adenomas and advanced serrated polyps than FIT," Dr. Chung observed. And, "there are no other stool DNA tests available now," he pointed out.

Previous stool-based DNA tests have suffered from "only fair sensitivity" for the detection of CRC, and "low sensitivity" for detecting advanced adenomas, Dr. Imperiale's team note in their 10,000-patient Cologuard study.

Practicalities and Cost

Cologuard test kit

To order a test kit, clinicians must register on the Cologuard Web site; a company representative will then contact them to complete the process.

When a physician places an order, the kit will be mailed directly to the patient. Each kit includes a pouch and a prepaid shipping box so the patient can send a stool sample to the Exact Science lab in Wisconsin.

It takes 2 weeks or more for the Cologuard results to be reported to the physician. Exact Sciences issues a only a "positive" or "negative" finding. A positive result "may indicate the presence of a cancer or advanced adenoma" and "should be followed by a colonoscopy," according to the company.

The test is not for everyone. In the major clinical trial, the investigators excluded adults with a history of digestive cancer or inflammatory bowel disease, and anyone with a personal or family history of CRC.

The test costs $599, according to CEO Conroy.

That is "expensive" and "will limit use," said David A. Johnson, MD, from the Eastern Virginia Medical School in Norfolk, in an email to Medscape Medical News.

He pointed out that Medicare currently reimburses a practice $64 for a sigmoidoscopy done in a facility and $215 for a colonoscopy.

Dr. Chung hesitated to call Cologuard too costly, although in 2008, he described the cost of the first stool DNA assay ($795) as "expensive." Instead, he called for cost-effectiveness studies of Cologuard.

"Some of the factors that will come into play are the false-positive rate of the test and the frequency with which the test is recommended," Dr. Chung said.

Dr. Chung, Dr. Brett, and Dr. Johnson have disclosed no relevant financial relationships. Dr. Imperiale is a Cologuard investigator. Mr. Conroy is an employee of Exact Sciences.


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