Eradicating Colon Cancer: A Lofty Goal
Eradicating colon cancer is a lofty goal — but a credible one if a high-performance, noninvasive screening tool were available. Such a test is undergoing validation studies to earn Food and Drug Administration (FDA) approval. It can detect all types of colorectal cancer and precancer and does not necessarily require a health care visit.
As a clinician and researcher, David Ahlquist, M.D., is daily reminded of the profusion of needless personal tragedies that result from colorectal cancer — a curable disease when detected early; and a preventable disease when precursor lesions are found.
In a previous study to uncover highly prevalent anemia among Yupik Eskimos in Alaska, he and his team uncovered nearly universal chronic gastrointestinal (GI) bleeding caused by stomach ulceration from an infection (Helicobacter pylori). At that time, he also learned that native Alaskans have the world's highest rate of colorectal cancer and among the worst prognosis from this cancer because there's no effective screening.
"Most native peoples in Alaska live so remotely, colonoscopy is simply not practical, and fecal blood testing is ineffective because nearly everybody's positive," says Dr. Ahlquist who would later circle back with a new approach to screening.
At the dawn of his career, Dr. Ahlquist hit the research trailhead that led him to a big idea — to prevent colorectal cancer by developing an effective screening program. After years of relentless research, Dr. Ahlquist's team developed a screening approach using a stool DNA test. In a recent large multicenter study, the stool DNA test detected 85 percent of cancers and 64 percent of precancerous polyps from throughout the colon.
Colon Cancer Stats
Because the test is so user-friendly and can be mailed in, Dr. Ahlquist believes it will increase screening rates in those who are unable to access or choose not to seek a primary health care visit. Thus, it is tailor-made for remote access populations, and Dr. Ahlquist's team is about to return to Alaska to evaluate its effectiveness among its native peoples. With more than 600,000 annual deaths worldwide from colon cancer, the potential benefit of the stool DNA test is enormous.
Fecal Pap smear
Think of Dr. Ahlquist's invention as a molecular "fecal Pap smear."
"The Pap smear has gone a long way toward eliminating cervical cancer because it detects precancerous changes that can be treated before cancer develops," says Dr. Ahlquist. "Colorectal cancer is entirely preventable if a screening test that detects precancer is regularly applied in the same way as cervical Pap smears are. Based on our data, the stool DNA test has a higher sensitivity than the Pap smear. The idea is that if you miss a precancer on the first screening, chances are it will be detected on subsequent tests while it is still in a treatable stage."
The stool DNA test works on the principle of exfoliation — it detects DNA in cells shed into the colon from the surface of cancer and precancer. The test targets a panel of DNA markers for all types of colorectal cancer and precancer with exquisite accuracy. Yet this remarkably sophisticated, high-performance molecular assay is extraordinarily simple for the patient. There is no bowel preparation, no diet or medication restrictions, and no uncomfortable procedure. In addition, there's no need for a prerequisite visit to your health care provider.
Hitting the research trailhead
A college mentor, Samuel Schwartz, M.D., a University of Minnesota scientist, unwittingly launched Dr. Ahlquist on his quest when he assigned a project to develop a test that quantifies blood in gastric juice. Throughout Dr. Ahlquist's medical school and residency training at Mayo, the two worked on developing and validating the HemoQuant test, the first quantitative in vitro assay for hemoglobin in stool (N Engl J Med 1985). However, fecal blood tests produce too many false negatives and positives. They don't differentiate between bleeding from cancer and from benign causes, such as hemorrhoids, and they don't detect precancers.
Paul J. Limburg, M.D., who now leads Mayo's chemoprevention research efforts, was instrumental in demonstrating the feasibility of capturing cells that slough off lesions and recovering them from the stool by using magnetic beads with an attached antibody. The concept was patented in 1999 — one of many patents from Dr. Ahlquist's team.
Here the trail began a steep climb. The test worked well for left-sided cancers, but cells from right-sided cancers burst.
"We had layer upon layer of studies that looked at many proteins, but bacteria in stool broke them down," says Dr. Ahlquist. "We eventually found that DNA is more stable in stool."
Undaunted by a lack of technology to test the concept, the lab along with collaborators from industry and academia set about developing what they needed and, in 2000, published the first paper demonstrating the feasibility of a multitarget assay panel to screen for both cancer and precancers from the colon by detection of altered DNA (Gastroenterology 2000).
Paralleling Dr. Ahlquist's research, a company called Exact Sciences was developing technologies that could make the stool DNA test more effective and efficient. In 2009, Mayo Clinic entered into a collaborative agreement that included the license of the technology to Exact Sciences. As part of this license agreement, Mayo Clinic will receive royalties that will be reinvested to support Mayo's mission.
"The more we can link critical resources and technology around important clinical questions, the more meaningful the outcomes will be," says Dr. Ahlquist. "It made sense to commercialize in order to fund the large studies necessary to validate the stool test, to educate the public and to produce a practical high-throughput tool to deliver to patients."
Working with Exact Sciences as senior scientific advisor, Dr. Ahlquist collaborates on a number of research and development projects to meet Mayo's highest ethical and quality-control standards.
Detecting right-sided cancers
In May 2010, Fareeda Taher Nazar Hussain, a student in Dr. Ahlquist's lab who now attends Mayo Medical School, presented exciting data demonstrating the detection of serrated colorectal polyps with the stool DNA test. Whereas common adenomatous polyps mushroom out from the lining of the colon making them easy to spot with an endoscope, serrated polyps are typically flat, located on the right side of the colon and much harder to find. Historically, serrated polyps have been excluded from screening studies, yet they account for up to 35 percent of colon cancers.
In a stool assay, the lab targeted two genetic markers (mutant BRAF and methylated vimentin genes) present in serrated polyps and yielded remarkably high detection rates: 71 percent of serrated polyps were detected by the stool DNA test compared with just 7 percent by conventional fecal blood tests.
The refined stool DNA test takes eight hours to process and is now being partially automated. A buffer added to the sample kit boosts DNA preservation, and improved technology has increased test sensitivity and specificity. It's being evaluated in a large clinical trial to begin this year that is expected to take 12 to18 months to complete. The results will be submitted to the FDA and, if approved, Exact Sciences plans to commercialize the product and make it widely available.
"I am extremely grateful to all who have contributed so generously to make this research possible and bring this promising new screening approach to fruition," says Dr. Ahlquist. Dr. Ahlquist would like to acknowledge his many research fellows and the critical support from the National Institutes of Health, Mayo Clinic, Exact Sciences, Richard M. Schulze Family Foundation, and "wonderfully gracious individual benefactors such as Charles Oswald and Eugene and Eva Lane."
More information about Mayo Clinic's DNA stool testing is available on the Mayo Clinic News Blog.
— April 2011