The broad application of stool DNA testing in longitudinal screening programs is to prevent CRC through high precancer detection. In an invited lecture at the ASCO meeting, Dr. Ahlquist said this claim is “not too bold and not hyperbole.”
Stool DNA testing detects tumor-specific DNA alterations in cells that are continually being shed into the stool from precancerous and cancerous lesions. The test detects lesions on both sides of the colon with equal accuracy and reveals flat or serrated polyps likely to be missed by both fecal occult blood tests and colonoscopy. Stool DNA testing is noninvasive, involves no diet or medication restrictions, does not require bowel preparation and is done at home using a stool sample.
“It is user-friendly, affordable and offers individuals unlimited access by mail,” Dr. Ahlquist said.
The test is being developed by Exact Sciences, a molecular diagnostics company in Madison, Wis.
Dr. Ahlquist and colleagues published the results of a multicenter, blinded study that measured the new test’s effectiveness in the February issue of Gastroenterology (Ahlquist DA et al. 2012 142:248-256). The study included 678 individuals, 253 of whom had CRC and 130 who had advanced adenomas. The investigators found that the test detected 85% of nonmetastatic CRCs and 64% of adenomas 1 cm or larger. Lesions were detected in the proximal and distal colons with equal accuracy, 87% and 83%, respectively, for cancerous lesions and 55% and 53%, respectively, for adenomas 1 cm or larger.
Dr. Ahlquist noted that this detection sensitivity rate increases over time with repeated tests, much in the way that cervical cancer screening becomes more beneficial as it is employed sequentially over time. Additionally, detection sensitivity increased as adenoma size increased: 64% for adenomas 1 cm or larger, 77% for those larger than 2 cm, 86% for those larger than 3 cm and 92% for those larger than 4 cm. (Less than one-third of adenomas smaller than 1 cm were identified).
“This is most important,” he said. “As a polyp grows, the risk for transformation to cancer increases, and the sensitivity of this test increases in proportion.”
Stool Test Versus Plasma-based DNA Test
Dr. Ahlquist and colleagues also recently compared the stool DNA test with a commercially available plasma test for methylated Septin 9 (SEPT9); they found the stool DNA test to be superior (Ahlquist DA et al. Clin Gastroenterol Hepatol 2012;10:272-277). The stool DNA test detected 82% of large adenomas and 87% of CRC, whereas the plasma test detected 14% and 60%, respectively. False-positive rates were almost four times higher for the plasma test (7% vs. 27%, respectively).
Final validation of the stool DNA test’s accuracy is under way in a multicenter study, the results of which should support FDA approval, Dr. Ahlquist said.
“The data are very impressive. I’m surprised and delighted at how good the test is,” said Richard Goldberg, MD, physician-in-chief at The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Institute of Ohio State University Medical Center, in Columbus.
“I was a bit surprised that the methylation was so good because of the heterogeneity of CRC evolution,” added Dr. Goldberg, who chaired the ASCO meeting’s steering committee.
Dr. Ahlquist noted, “We did deep sequencing of the CpG island and found within the island there were certain base sequences that were never methylated in normal tissue but highly methylated in cancerous and precancerous lesions. We redesigned the capture and the primer sequences to yield a very specific approach. One of the criteria we applied was no methylation—zero—in normal tissue.”
Dr. Ahlquist added that an optimized multimarker panel includes DNA screening plus fecal immunochemical testing for hemoglobin. In a case–control study of 78 cases and 278 matched controls presented in an industry seminar at the 2011 annual meeting of the Association for Molecular Pathology, the assay showed 98% sensitivity for cancer and 64% sensitivity for adenomas greater than 1 cm at a specificity of 91%.
The assay also will be affordable, Dr. Ahlquist said.
“The goal has been for this to be an everyman’s test. I would like to see it cost less than $300,” he said. “And this will be just the tip of the submerged iceberg,” he added. “The reduction in false-positives and the effect of cancer prevention are all enormous downstream cost burdens that could be lightened with this approach.”
Dr. Goldberg noted that, if the test pans out and is used as a substitute for widespread screening, the cost savings would be substantial.
“This is potentially a very exciting development,” Dr. Goldberg said.
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