2015-02-24 03:31:15 UTC


Feb. 19, 2015

Cologuard, the multitarget stool DNA test used in the Deep-C study, now offers a very viable colorectal cancer screening alternative.

Steven H. Itzkowitz, MD, FACP, FACG, AGAF

Steven H. Itzkowitz, MD, FACP, FACG, AGAF

Professor of Medicine and Oncological Sciences; Director, GI Fellowship Program, The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, NYC, NY

Ideally, a cancer screening test should be non-invasive, safe, easy to perform, operator-independent and inexpensive. And, it should be accurate enough to detect early stage cancers and important precancerous lesions. While we have come to accept colonoscopy as the most sensitive screening test for colorectal neoplasia, colonoscopy does not meet many of these criteria. Colonoscopy has an alleged 95 percent sensitivity for detecting CRC. But how does this reconcile with studies from the U.S., Canada and Germany showing a minimal impact of colonoscopy in reducing right-sided colon cancer incidence and mortality? And how does the interval of 10 years accommodate the variable natural history of CRC, such as interval CRCs?

I am a staunch advocate of colonoscopy as a screening test — after all, I do it for a living! I’ve spent the last decade developing and implementing novel patient navigation approaches to get traditionally underserved patients to complete screening colonoscopy. I have been involved in the ongoing efforts of the New York Citywide Colon Cancer Control Coalition (C5), which helped transform screening colonoscopy rates of 42 percent in 2003 to 61 percent in 2007, while eliminating ethnic disparities.1

But, colonoscopy has its drawbacks, including: a paucity of endoscopists in many regions and high patient costs in some plans; a substantial gap in colonoscopy usage among uninsured individuals; and considerable operator dependence (thus the enormous national effort to improve colonoscopy quality). Colonoscopy can miss neoplasms, and it has a small but measurable rate of complications. Limitations from the patient’s perspective include: aversion to the bowel prep, loss of time from work/caretaking, and need for an escort. Many patients referred for screening colonoscopy have multiple serious co-morbidities and are taking numerous medications, especially anticoagulants, adding risk to colonoscopy as a routine screening test.

So, here’s the dilemma: colonoscopy may be the best test, but at least one-third of screen-eligible individuals are not getting colonoscopy or any other CRC screening test. In NYC, with considerable capacity and systems in place, screening colonoscopy rates seem to be plateauing at approximately 69 to 70 percent. Many screen-eligible folks don’t like the idea of colonoscopy because of embarrassment, machismo, fear of complications, fear of potential findings, use of sedation, medical mistrust, fatalism or inconvenience. Most medical societies have embraced the ambitious goal of the American Cancer Society and CDC to reach “80 percent by 2018” for CRC screening by any available method.2 So, given how prevalent and treatable CRC is if found early, how can we reach these people?

Cologuard, the multitarget stool DNA test used in the Deep-C study,3 now offers a very viable screening alternative. Unlike other stool-based CRC screening tests that detect only occult blood in the stool, Cologuard detects abnormal DNA and fecal hemoglobin. This is an important advance for several reasons. First, DNA is amplifiable, so even the very small amounts of human DNA in stool can be detected using sensitive PCR techniques. Second, many cancers, and most adenomas, do not bleed sufficiently/consistently to be detected by hemoglobin alone. By contrast, DNA is continuously shed from neoplasms into the lumen due to aberrant cell death. Also, DNA comes from epithelial cells. Since the epithelial layer of adenomas is thrown into extensive invaginations (tubules), the effective surface area of a 2 cm adenoma is actually 200 times larger than it appears through the scope.4 And, as a polyp grows, the ability to detect it by Cologuard increases substantially.3 Third, sessile serrated polyps (important precursors of CRC that are frequently located in the proximal colon and overlooked due to their subtle colonoscopic appearance) essentially never bleed but often express hypermethylated DNA. Cologuard detected 45 percent of sessile serrated polyps ≥1 cm compared to 5 percent detection by FIT.3 Fourth, FIT and guaiac FOBTs are poor at detecting proximal CRC.5,6 Cologuard, however, detects cancers equally well in the proximal and distal colon. For the first time, we now have a noninvasive test that works well in the proximal colon. This can be a useful adjunct to sigmoidoscopy and colonoscopy.

Cologuard, the multitarget stool DNA test used in the Deep-C study, now offers a very viable screening alternative.

In the Deep-C study, Cologuard demonstrated impressive point sensitivities of 92 percent for CRC and 69 percent for adenomas with high-grade dysplasia.3 And, for essentially all parameters, Cologuard outperformed a commonly used commercial FIT, with the exception that Cologuard specificity was lower. The specificity of Cologuard for individuals with normal colonoscopies was 90 percent; i.e., 10 percent false-positives. Of note, because DNA undergoes methylation with normal aging, there are more false positives in older age groups. Actually, only 6 percent of individuals 50 to 65 years old had a false positive Cologuard.3 If Cologuard is performed every three years, the programmatic specificity and sensitivity should be even higher. Cancers of the upper GI tract cancer rarely cause a false positive Cologuard, based on preliminary studies (www.fda.gov).

Perhaps the greatest benefit of Cologuard comes from the patient’s perspective (Table). The provider orders the test directly with the lab. The collection kit is mailed from the lab to the patient’s home. The patient collects the stool in a container conveniently mounted on the toilet and mails it back to the lab using a prepaid air-bill. Parenthetically, this makes Cologuard easy to administer in remote or low-resource parts of the country. It is safe, and the patient does not have to deal with bowel prep, dietary/medication restrictions, work absence, escort or returning the test to the clinic. The three-year interval recommended by CMS, informed by a review of screening effectiveness from an unpublished modeling exercise, may be preferred to the annual FIT interval. Compared to not screening, the $600 cost, modeled at three-year intervals, is cost-effective (unpublished data).

We do not yet know how Cologuard compares to colonoscopy as a primary screening tool. In the Deep-C study, all patients who performed the Cologuard test also underwent colonoscopy, regardless of whether the Cologuard was positive or negative. Will patients with a negative Cologuard avoid doing colonoscopy? Of note, if Cologuard is negative, there is only a 0.06 percent chance that there is cancer.3 Will Cologuard be used by patients previously unwilling to undergo any CRC screening, as seen with earlier sDNA based tests?7 Will endoscopists faced with a positive Cologuard be more careful when performing a screening colonoscopy, especially in seeking proximal neoplasia?

Now that Cologuard has been approved by FDA and CMS, I am greatly looking forward to seeing how it will add to our important fight against what is arguably the most preventable cancer. As Yogi Berra said: “The future ain’t what it used to be.”

Dr. Itzkowitz is on the scientific advisory board and receives research consulting fees and research support from Exact Sciences Corporation. He is also co-chair of the NYC Citywide Colon Cancer Control Coalition.


1. Richards CA, Kerker BD, Thorpe L, Olson C, Krauskopf MS, Silver LS, Weber TK, Winawer SJ. Increased screening colonoscopy rates and reduced racial disparities in the New York Citywide campaign: an urban model. Am J Gastroenterol 2011;106:1880-86.

2. National Colorectal Cancer Roundtable 80% by 2018 fact sheet; 2014.


3. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370:1287-97.

4. Berger BM and Ahlquist DA. Stool DNA screening for colorectal neoplasia: biological and technical basis for high detection rates. Pathology 2012;44:80-8.

5. Morikawa T, Kato J, Yamaji Y, Wada R, Mitsushima T, Shiratori Y. A comparison of the immunochemical fecal occult blood test and total colonoscopy in the asymptomatic population. Gastroenterology. 2005;129(2):422-8

6. Ahlquist DA, Sargent DJ, Loprinzi CL, Levin TR, Rex DK, Ahnen DJ, Knigge K, Lance MP, Burgart LJ, Hamilton SR, Allison JE, Lawson MJ, Devens ME, Harrington JJ, Hillman SL. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med. 2008;149(7):441-50

7. Berger BM, Schroy PC 3rd, Rosenberg JL, Lai-Goldman M, Eisenberg M, Brown T, Rochelle RB, Billings PR. Colorectal cancer screening using stool DNA analysis in clinical practice: early clinical experience with respect to patient acceptance and colonoscopic follow-up of abnormal tests. Clin Colorectal Cancer 2006;5:338-43.

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