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For Colon Cancer Screening, Cologuard Test Offers A Solid New Option

This article is more than 9 years old.

Colon and rectal cancers are among the few malignancies about which most doctors agree on screening’s benefit for most people over age 50 years. Getting checked, one way or another, has even been deemed cost-effective. The question for colorectal cancer, if you choose to be screened, is how: what’s the best method?

It's March, colorectal cancer awareness month. And I’ll say up-front, I don’t think there’s a “right” answer for everyone. But I think it's worth considering the options, old and new. Starting with the latest:

In August 2014, the FDA approved a new, noninvasive test called Cologuard (Exact Sciences Corp, NASDAQ:EXAS). With a doctor’s prescription, you might prepare this test at home. This high-tech and sensitive test checks stool for blood and DNA abnormalities linked to colon cancer.

Last year the New England Journal of Medicine reported a study involving over 12,000 research subjects, nearly 10,000 of whom underwent both Cologuard testing and colonoscopy, at 90 institutions. In that study, which was sponsored by Exact Sciences, Cologuard predicted over 92 percent of colorectal cancers that were identified by colonoscopy. For pre-cancerous conditions, the sensitivity ranged from 42 to 69 percent (depending on the type of abnormality).

Among study participants with cancer, a polyp or another pre-cancerous condition in the lining of the colon or rectum, DNA testing predicted a higher proportion of abnormalities than did the blood assay alone. Those differences suggest that DNA analysis significantly adds value in terms of catching colorectal tumors.

It was results of this Deep-C trial that led the FDA to approve Cologuard last summer. The test costs $599 and, at present, is not covered by most private insurers. In October 2014, Medicare OK’d coverage with a reimbursement price of $492.72. Just this this week Anthem (BCBS) elected to cover it.

Why this matters: This year, nearly 143,000 people will be found with colorectal tumors, and 50,000 will die from these forms of malignancy in the United States. The IARC estimated that in 2012 approximately 694,000 men and women would die from these cancers worldwide. Over the past 20 years, the incidence of these tumors has declined in the United States. Deaths from the disease have dropped, too. Both effects are largely attributed to increased screening and removal of pre-malignant polyps.

The NCI lists several methods for screening. A few years ago, I reviewed new reports on what most doctors considered the two standard” methods in 2012: colonoscopy and testing the stool for trace amounts of blood (fecal occult blood testing, FOBT). The latter includes guaiac tests and what some doctors call hemoccult.

In 2015 many U.S. physicians, particularly internists and specialists in cities, favor colonoscopy. But that invasive procedure involves an unpleasant prep and does have some risks; it usually involves light anesthesia, and there is a very small chance of a perforation of tear. As I have said before, colonoscopy depends a lot on the skills of the doctor, usually a gastroenterologist, who does the procedure.

Colonoscopy remains essential for some. If you do have a pre-malignant polyp or early-stage cancer, there’s no way of removing it without a doctor actually inserting a scope and taking it out. One way of considering the value of Cologuard and other tests is if it’s worth doing them first – if preliminary negative screens can eliminate the need for some to have colonoscopy and, simultaneously, direct those at greater risk for having the procedure.

I asked Maneesh K. Arora, Chief Operating Officer at Exact Sciences, about possible resistance to Cologuard testing among gastroenterologists – doctors who often derive income from colonoscopies. “It varies,” he responded. “The GI community understands that a big proportion of the population refuses to get screened.” Many recognize this can be helpful, he said in a phone interview.

“The biggest challenge today is lack of commercial coverage," Arora said. "Coverage can be limiting," he considered.

“Changing the practice of medicine, even with great technology, is very hard. Because there is so much new information going to primary care physicians, it can be hard to keep up,” Arora considered. “But the key factor will be adoption by commercial payers,” he emphasized. “We believe that (coverage) will be the key driver for physicians. That plus education and awareness that it’s available. Many physicians don’t know about it yet.”

“We’re seeing wide-scale appeal,” Arora said. “Patients want it, physicians want it. But changing the practice of medicine is hard.”

How Cologuard works is like this: The patient receives a collection kit including a pint-sized container for collecting the stool; a tube into which a part is transferred, to check for blood in a separate part of the assay; and a small bottle of buffer to pour over and stabilize the main sample. The sealed containers all fit into a box of approximately 8 by 8 by 6.5 inches. It comes with a UPS label, ready for mailing to a central lab in Madison, WI.

The Cologuard test uses QuARTS (Quantitative allele-specific real-time target and signal amplification) technology. The company’s patented method is similar to PCR but affords greater specificity and assessment of methylated DNA, an epigenetic change that modulates gene expression. The Exact Sciences test yields a single read-out: The prescribing physician receives what’s essentially a positive or negative result and lets the patient know if colonoscopy is indicated.

For the multiplex DNA assay in the Exact Sciences lab, a probe pulls out human material from microbial and other genetic matter in stool. Then it uses QuARTS to amplify gene segments of interest, such as parts of the KRAS gene linked to colorectal cancers. Cologuard measures DNA methylation in two genes: NDRG4 and BMP3. Abnormal methylation of NDRG4 and BMP3, considered tumor suppressors, has been linked to colorectal tumors.

Cologuard also checks for miniscule amounts of blood by ELISA (enzyme-linked immunosorbent assay) for human hemoglobin. This part of the assay resembles other modern fecal immunochemical tests for blood in stool, but is potentially more accurate. An advantage over some older methods is that patients don’t need to modify their diets, such as by avoiding meat, beforehand. The Cologuard assay is highly-specific for human hemoglobin.

Dr. Aaron Sasson is a professor and surgeon at the University of Nebraska Medical Center in Omaha. His research and surgery focuses on gastrointestinal malignancies, including tumors of the colon and rectum.

“For colon cancer the value of screening is immense,” he said.  “It’s so hard to believe in this day and age that not everyone gets screened.”

“I can’t tell you how many times patients come to me with colon cancer or metastatic colon cancer and they ask, ‘how can I feel so good if I have cancer?’ And I tell them ‘well, you’ve probably had this for years.’ I think that if they had a colonoscopy five or six years ago, we might have avoided surgery and the need for chemotherapy,” Sasson said.

“We won’t cure cancer by doing this, but we would significantly, significantly reduce the burden if an extra 25 or 30 percent of the population got screened,” Sasson said.

“This kind of screening prevents cancer,” he emphasized. That’s because benign polyps tend to acquire genetic mutations and become frankly malignant over time, he explained. It usually takes four to seven years for a colon polyp to become cancerous, Sasson said. “It’s prevention, because we’re removing polyps before they become malignant,” he said.

“Screening, even by colonoscopy, isn’t perfect,” he admitted. Occasionally gastroenterologists fail to detect polyps. But the “miss” rate generally runs below 10 percent, he suggested. Some types of benign polyps, such as flat adenomas and those on the right side of the colon can be hard to visualize, Sasson said. “Detecting those is the new buzz for gastroenterologists.”

“I doubt there is anything in the immediate future that will obviate the need for colonoscopy, because it’s the only way we can visualize and remove polyps and small tumors,” he said.

Yet he does see a role for Cologuard. “It’s a way to capture patients who aren’t getting their colonoscopies,” Sasson said. A positive result will push some who are disinclined toward screening. “And it’s so sensitive that if you’re truly negative on Cologuard, you might not need a colonoscopy,” he added.

In Sasson’s view, Cologuard is far superior to hemoccult or stool guaiac tests, older methods in which patients or doctors apply small amounts of stool to a card before testing for hidden blood. “The problem is that having a negative hemoccult occult test doesn’t tell you very much. You could still have a non-bleeding cancer,” he said.  Cologuard’s testing of genetic material is relevant and helpful, he considered.

“What I’d hate to see is people forgoing colonoscopy because there is Cologuard,” he added. “But there doesn’t have to be one answer. There are places where people don’t have access to great colonoscopy,” he considered. “Having other options available is worthwhile.”

“I’ve been avoiding having colonoscopy for 35 years” said Dan Meaney of Madison, NJ. He found out about Cologuard while watching his favorite program on TV, NBC’s Squawk Box. “I saw something about a company that was developing a DNA test for colon cancer, and that it was approved by the FDA,” he told me. “So I looked on-line, got the information and asked my primary care physician for a prescription.”

At 73 years, the retired computer scientist recalls a bad experience with sigmoidoscopy years ago. In the 1980s, through an executive health program, doctors advised him to get “scoped” because of what they mistakenly thought was a family history of colon cancer. “I was not thrilled with sigmoidoscopy. That was in the old days. There was no medication of any sort, no anesthesia or anything,” he said. “That’s the reason I avoided colonoscopy for so long.”

When Meaney first approached his general practitioner about Cologuard, the doctor admitted he hadn’t much prior experience with the test. That was in October 2014. “The doctor became interested when we discussed it.” When the Cologuard result came back as positive, indicating that he should have colonoscopy, Meaney agreed.

“So I followed up with a colonoscopy, which in this day and age was a lot easier than it was 30 years ago,” Meaney said. “They found and removed four benign polyps, so I guess Cologuard did its job.”

Even though his colonoscopy didn’t show cancer, Meaney is glad he went through with it because his doctors removed polyps that weren’t yet cancerous. About the Cologuard test, he says he would recommend that to a friend. “If it doesn’t turn out positive, you’re in luck,” he said. “Otherwise you’re constantly worrying. This gives you some confidence that you can avoid colonoscopy for some number of years.”

Meaney didn’t mind processing the Cologuard sample. “It’s no worse than those little strips they used to give you for blood testing in the stool,” he said. “It comes with a pre-packaged box and label. You put your stool in there and ship it out,” he said. “I felt comfortable because there’s no indication of what’s inside. I went to a UPS store, dropped it off and said good bye.”

“It was the DNA testing and science that drew me to the test,” Meaney said. “I can’t imagine in this day and age what they can do with the information.”

In sum, there appears to be an unusual consensus regarding colon cancer: that many deaths might be prevented by screening. The CDC and ACS report that over a third of adults over 50 years are not getting checked for colon cancer.

But it’s not just about saving lives; advanced colon and rectal cancers cause unpleasant symptoms like bleeding, intestinal obstruction and pain. And money: treatment of advanced disease, by surgery or chemotherapy and new biological drugs, is expensive. The NCI estimated that the U.S. will have spent $13.8 billion on colorectal cancer care in 2014.

Some emphasize that fecal blood testing is cheap and less risky than colonoscopy. Those are valid points, but many studies have shown that patients’ compliance with those tests is poor. Also, some tumors don’t bleed. I’m persuaded by recent data that the Cologuard test – though more costly – is far better at predicting a tumor or premalignant polyp than those simple methods, based on its capacity to look for colorectal-cancer associated DNA changes.

As for virtual colonoscopy, I just don’t see it as a reasonable method in 2015. Although these may be very good, similar to colonoscopy, in picking up tumors and polyps that have reached a certain size, once those have been imaged by a radiologist another doctor would still have to go in and remove those. Meanwhile, you’ve paid a few hundred dollars and been exposed to radiation. Yes, there are MRIs for colon imaging, but those cost more and have more false positives. And although Cologuard would also require a follow-up colonoscopy for patients with positive results, they won’t have been exposed to radiation. As things stand, Medicare and most insurance won’t cover the costs of virtual colonoscopy, and I’m not convinced that they should.

As for older invasive methods, like sigmoidoscopy, I don’t see a role for those anymore unless someone has particular disease of that region (in which case it wouldn’t be a screening test). In general, the same goes for barium enemas. Except for rare circumstances, they should be relegated to the annals of screening history.

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