CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Anne Paxton
November 2016—When a Hollywood producer forecasts box office receipts, or a public health official contemplates action against a deadly but preventable cancer, there’s one hypothetical that might make both shudder: What if you held a screening and nobody came?
Fortunately, in colorectal cancer screening, no such scenario exists. Each year tens of millions of people are screened preventively or diagnostically with a fecal immunochemical test or a colonoscopy—frequently with the government or health plans signing the reimbursement checks. Still, in the past decade, about 35 percent of those who are eligible for screening in the U.S. have remained unscreened.
With the Food and Drug Administration’s approval last April of Epi proColon, the first plasma test to detect the colon cancer marker methylated SEPT9 DNA, hopes are high that the percentage of people who shirk CRC screening will begin to fall.
Dr. Heichman
“We know there are populations that are going to refuse a colonoscopy and refuse a stool-based fecal test. They’re not comfortable sending bowel movements in the mail, they’re not comfortable with preparation and everything you need for a colonoscopy, or they’re afraid of the procedure,” says Karen A. Heichman, PhD, vice president and director of the PharmaDx program at ARUP Laboratories. A minimally invasive liquid-biopsy approach might be the solution. “Epi proColon is the first blood-based test with the potential to reach those patients who were never going to get screened for colon cancer.”
New U.S. Preventive Services Task Force screening guidelines, published June 21 in JAMA (2016;315[23]:2564–2575), give a Grade A recommendation to CRC screening of average-risk, asymptomatic adults between ages 50 and 74. “Though the guidelines do not recommend specific screening tests by name, but rather by methods,” says Nicholas Potter, PhD, FACMG, a member of the advisory board of Epi proColon manufacturer Epigenomics, “they acknowledged that there was a significant number of screening options, some new, that could be utilized, and they did not state a preference. That’s important because what many people believe, and this is supported in the peer-reviewed literature, is that more options can help drive increased compliance through what is called ‘the best test is the one that gets done’ approach.”
As it had done with Exact Sciences’ Cologuard, a stool-based FIT and fecal DNA test approved by the FDA in August 2014, the FDA has also required Epigenomics to design and complete a post-market “real-world” study of effectiveness over time, says Dr. Potter, executive vice president of clinical affairs at Molecular Pathology Laboratory Network, Maryville, Tenn. “It’s very hard to frame the concept of cost and cost-effectiveness to the health care system for some of these tests in the absence of longitudinal data. You need it because, in any programmatic screening endeavor, if you lose patients within the screening interval—whether it’s annual, biannual, or once every 10 years—you obviously lose the effectiveness of your gains in programmatic sensitivity from testing people multiple times.”
ARUP Laboratories has been at the center of the new blood test’s development. A group led by Dr. Heichman devised a laboratory-developed test for methylated SEPT9 DNA based on the original assay design that Epigenomics used. The LDT was on the market for several years, as was a similar one that Quest Diagnostics developed. “That LDT was really the basis for the assay that went to the FDA, so we’ve been involved with this for a long time,” Dr. Heichman says. ARUP is transitioning from its LDT to Epi proColon now that the FDA has approved Epigenomics’ assay.
SEPT9 works as a marker because septin 9 hypermethylation occurs in the vast majority of CRC adenoma and tumor tissues that have been tested.
Historically, CRC testing is based on the fecal immunochemical test, an assay that has distinct advantages. “The specimen can be collected at home, the test is inexpensive, and if people have a positive test, they are referred for colonoscopy,” Dr. Heichman notes. But stool-based testing has failed to gain traction. “People don’t relish the fecal test. There’s definitely an unmet need to get more people screened.”
When Epigenomics submitted its premarket approval application to the FDA in 2013, the clinical information supporting the application included a study, led by Dr. Potter, showing that Epi proColon had a 68 percent sensitivity and an 80 percent specificity for cancer detection using colonoscopy as the comparator (Potter NT, et al. Clin Chem. 2014;60[9]:1183–1191). A study comparing FIT with SEPT9 showed Epi proColon had 73 percent sensitivity at 82 percent specificity, demonstrating “non-inferiority” to FIT as a CRC test (Johnson DA, et al. PLOS One. 2014;9[6]:e98238).
Initially, the FDA response to the Epi proColon application was less than encouraging. “The 2014 vote of the Molecular and Clinical Genetics Advisory Committee was 9–0 on the safety issue with one abstention, 5–6 with regard to effectiveness, and 5–4 with one abstention as to whether the benefits outweighed the risk,” Dr. Potter says.
The 5–6 effectiveness vote prompted the FDA to issue a “not approvable” letter and request that Epigenomics perform an additional study to determine how the test might perform in real-life situations with regard to adherence and uptake, he explains. After this study (known as ADMIT, or Adherence to Minimally Invasive Testing, publication forthcoming) was completed, the data were submitted to the FDA and reviewed, and Epi proColon won approval.
How Epi proColon compared with already existing screening methods, most notably FIT, was a key question in the FDA’s review, says Dr. Potter, who was part of the team that presented the data to the FDA. “Their question was, with a 68 percent sensitivity for detection of cancer at an 80 percent specificity, basically what you’re telling us is you have a molecular test which is no better than FIT for cancer detection, but with an inferior specificity.”
“In essence they weren’t really sure, in the absence of any true effectiveness data, whether compliance or adherence could be increased by offering a blood test, and whether this would provide a substantial long-term benefit.” That was why the FDA required the ADMIT trial before the recent approval of Epi proColon, Dr. Potter says.
“A lower specificity for Epi proColon means the potential for more colonoscopy referrals, and that’s always a concern,” Dr. Potter says. “Colonoscopy is not without risk—statistically it has 0.68 percent risk for an adverse outcome—and the use of Epi proColon compared to other noninvasive screening options is expected to result in additional colonoscopies.” But since the additional patients should be screened anyway, “the use of Epi proColon shouldn’t increase the risk above the standard of care.”