Stool DNA testing has emerged as a sensitive, noninvasive option for colorectal cancer (CRC) screening. A multi-target stool DNA test (MT-sDNA) has recently become available in the U.S. as the first FDA-approved molecular-based cancer screening test (“Cologuard” (Exact Sciences)). It is also approved by the Centers for Medicare & Medicaid Services and is incorporated into new screening guidelines by ACS, USPSTF, NCCN, and various other societies.

Stool DNA tests target signature genetic and/or epigenetic markers that continuously exfoliate from CRC and its precursors. In early comparison studies (Clin Gastroenterol Hepatol. 2012;10:272), stool assay of exfoliated molecular markers proved to be more sensitive than DNA testing on paired plasma for detection of colorectal neoplasia, and differences were most striking with early stage CRC and precancers. Such findings suggest that the mechanism of luminal exfoliation into stool may provide a biological advantage in early detection as it appears to occur sooner in the oncologic cascade than does vascular invasion into the circulation.

Average-Risk CRC Screening: The performance of the optimized MT-sDNA test (which assays a panel of 2 methylated genes, mutant KRAS, and hemoglobin) has been evaluated in multiple clinical studies. Case-control studies showed that CRC and precancers at greatest risk for progression could be detected with high sensitivity, that detection was unaffected by tumor stage or site within the colon, and that sensitivity for polyps increased in proportion to lesion size (Gastroenterology 2012;142:248, Clin Gastroenterol Hepatol 2013;11:1313). In subsequent cross-sectional validation studies from the screening setting (NEJM 2014; 370:1287, Mayo Clin Proc 2016;91:61), MT-sDNA achieved sensitivities for CRC of 92-100% at specificities (based on a denominator of patients with normal colonoscopy) of 90-93%; sensitivities for adenomatous or serrated polyps >1cm, >2cm, and >3cm were respectively 42-43%, 60-66%, and 67-82%. Neoplasm detection by MT-sDNA was significantly higher than by fecal blood testing in these studies.

Cumulative or “program” performance of MT-sDNA has been modeled. At the recommended testing frequency of every 3 years, MT-sDNA exhibits a higher benefit-to-risk ratio than the other endorsed CRC screening approaches and generates the fewest number of colonoscopies (i.e., highest program specificity) over a screening lifetime (JAMA 2016;315:2564). Furthermore, because polyps are slow-growing, it has been estimated that the program sensitivity of MT-sDNA for a cohort of advanced adenomas may exceed 90% by the 2nd or 3rd screening rounds (Dig Dis Sci 2015;60:623). Thus, over a lifetime of screening, regular use of MT-sDNA every 3 years has the potential to compare favorably with colonoscopy performed every 10 years in the detection of both CRC and those polyps at greatest risk for progression.

In the screening setting, effective neoplasm detection is based not only on test sensitivity but on patient compliance and test access as well. The user-friendly features of MT-sDNA have potential to enhance screening participation rates, and these include noninvasiveness, operator-independence, and avoidance of bowel preparation and diet/medication restrictions. Furthermore, unlike with colonoscopy which requires an average of two missed work days, MT-sDNA can be done from home with no missed work and access by mail is virtually unlimited. Early outcomes with MT-sDNA indicate that >40% of patients tested had not undergone CRC screening previously (based on questionnaire reports to Exact Sciences from first 100,000 test users). Further studies are needed to determine the uptake of this new test and its impact on CRC screening participation and long-term outcomes.

Dysplasia Surveillance in Inflammatory Bowel Disease (IBD): Patients with IBD are at increased risk for CRC. Although IBD patients are currently advised to undergo surveillance colonoscopy annually or every 2 years, only half comply with this rigorous regime. Complementary approaches are needed. In early case-control studies (APT 2013;37:546, Gastroenterology 2016;150:S48), stool DNA testing targeting a panel of informative methylated gene markers detected 90-100% of CRC and high grade dysplasia in IBD patients using colonoscopy and surgery as reference standards. Modeling suggests that stool DNA testing every 1-2 years followed by chromo-endoscopy if positive is more cost-effective than either chromo-endoscopy or white-light colonoscopy alone (Kisiel et al. Clin Gastroenterol Hepatol (in press)). A multi-center study of stool DNA for IBD surveillance is underway.

Extending Detection to Upper GI Neoplasms: Together, upper GI cancers account for roughly twice as many deaths as CRC does. Yet, they remain largely unscreened due, in part, to relatively lower single site prevalence and lack of cost-effective screening tools. Since all mucosal-based GI neoplasms exfoliate contents into a common excretory conduit, molecular stool testing allows the re-imagination of the GI tract as a single screen-able organ. Perceived in this way, it is the aggregate prevalence that counts and the value of a single screening intervention could theoretically be extended beyond the colon. While preliminary data suggest that tumors at all GI tract sites can be detected by stool DNA testing (Gastroenterology 2009; 136:2068), much technical optimization and substantial clinical testing are required to evaluate the feasibility and practicality of this intriguing approach.

In summary, stool DNA testing has potential to favorably affect detection accuracy, patient compliance, and access with general CRC screening. Early data suggest that this approach may have value as a complement to colonoscopy in the surveillance of IBD. And, potential future applications of stool DNA testing could include universal GI cancer screening.

Citation Format: David A. Ahlquist. Stool DNA detection of colorectal neoplasia. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA13.