Multitarget stool DNA screening test

A multi-target stool DNA screening test like Cologuard analyzes both DNA alterations and blood in the stool to detect the presence of colon cancer and precancers. With Cologuard, patients can provide a sample in the privacy of their own home.

Multitarget stool DNA (mt-sDNA) testing (trade name: Cologuard; Exact Sciences Corporation, Madison, Wisconsin) is a noninvasive screening test developed to detect biomarkers associated with colorectal cancer or precancerous lesions. Multitarget sDNA testing differs from other noninvasive colorectal cancer screening tests in that it looks for both abnormal DNA and hemoglobin in the stool, which can be released from cancerous and precancerous cells or from the underlying blood vessels, respectively. The test is approved by the Food and Drug Administration (FDA) for use in the United States in individuals 50 years or older who have no signs or symptoms of colorectal cancer and have an average risk of developing the disease.[1]

History

The first sDNA test was PreGen Plus, offered in 2003-2006. A second generation, Colosure, was offered from 2009-2011. These versions of sDNA test technology were not FDA approved. They are no longer available, but may be referred to by older clinical guidelines and some commercial insurance policies.

The ability of the test to detect colon cancer and precancerous lesions was investigated in a large clinical study involving over 10,000 patients at 90 clinical sites.[2] The study compared multitarget sDNA testing with colonoscopy, the current reference method for colorectal cancer screening,[3][4][5] and with fecal immunochemical testing (FIT; OC FIT-CHEK, Polymedco) for stool hemoglobin. Multitarget sDNA testing found 92% of colorectal cancers detected by colonoscopy, 42% of advanced adenomas and 69% of highest-risk precancerous lesions (high-grade dysplasia, which are the type most likely to develop into cancer).[2] The 92% sensitivity (or ‘true positive rate’) of cancer detection of multitarget sDNA was greater than FIT, which detected 74% of colorectal cancers, 24% of advanced adenomas, and 46% of the highest-risk precancerous lesions.[2] Multitarget sDNA testing missed 5 of 65 confirmed cases of colorectal cancer, while FIT missed 17 of the 65 cancer cases,[2] indicating that FIT missed 3 times more instances of colorectal cancer than multitarget sDNA and thus has a higher false-negative rate.

The specificity, or true-negative rate, of multitarget sDNA testing was 87%, while the true-negative rate for FIT was 95%.[2] The true-negative rate represents those instances where the multitarget sDNA test (or the FIT test) was negative and colonoscopy found no evidence of colorectal cancer or advanced precancerous lesions.

As of 2016 Cologuard was the only commercially available multitarget sDNA test. Following publication of a prospective clinical trial,[2] it was approved in August 2014 by the FDA as a screening test for non-symptomatic, average-risk adults 50 years or older.[1] The Cologuard test is also approved in the European Union.

Screening

Screening can detect precancerous lesions in the colon before they become cancerous, and can identify colorectal cancer in early stages when it is easier to treat.[3] The American Cancer Society[4] and many other organizations recommend colorectal cancer screening beginning at age 50 in general, and earlier in African Americans.[5] While evidence supports the effectiveness of screening for colorectal cancer and the availability of a variety of screening methods, only 59% of the US population aged 50 and older report have been screened as recommended. [6]

Barriers to screening include cost, lack of access to health care, low awareness, inadequate communication by health care providers, differences in patient and provider testing preferences and fear and embarrassment.[6] Many people are hesitant to undergo a colonoscopy (the primary and most frequently recommended screening method to which other colorectal cancer screening tests are compared[3][4][5]) because they fear it will be painful and/or they feel it is inconvenient, as it involves cumbersome bowel preparation and the need to take a day off from work.[7][8] Lack of awareness about noninvasive screening alternatives to colonoscopy also reduces compliance.[9] Noninvasive screening options significantly increases participation in colorectal cancer screening.[10][11]

Medical uses

The Cologuard multitarget sDNA test is a noninvasive test used to screen for colorectal cancer or precancerous lesions. A positive result should be followed by colonoscopy. It is available by prescription only. The American Cancer Society recommends screening with multitarget sDNA testing every 3 years, starting at age 50.[4]

Biology

The lining of the colon, or large intestine, sheds cells every day, some of which break apart and release DNA into the colon, which is passed in stool.[12][13] Some of the human DNA in the stool is altered, reflecting natural aging.

Cancers, and to a lesser extent, precancerous lesions, shed abnormal cells and contribute altered DNA into the stool. Altered DNA may account for as much as 14% to 24% of the total recovered human DNA in the stool of colorectal cancer patients.[13] Cancers and precancerous lesions (polyps) that are ulcerated or rubbed by passing stool also may shed blood into the stool, which can be identified by a hemoglobin assay.[13]

Metrics

The test specifically looks for 3 types of stool biomarkers: 1) mutated human DNA; 2) aberrant human DNA methylation (hypermethylation); and 3) hemoglobin.[14][15] The resulting 11 biomarkers include 7 mutations in the KRAS gene (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) that have been detected in up to 35% of colorectal cancers[14] and are present to a lesser degree in adenomas. Cologuard also looks for aberrant methylation in the promoter regions of the ‘’NDRG4’’ gene (N-Myc Downstream-Regulated Gene 4) and ‘’BMP3’’ gene (Bone Morphogenetic Protein 3 gene), which are hypermethylated in colorectal cancer,[14][16][17] as well as hemoglobin.[13] Another DNA marker, the human beta-actin gene, acts as a reference gene and a measure of total human DNA.[18] Test results, even negative results, can only be generated if sufficient DNA was isolated and analyzed, which is determined by the measurement of human beta-actin DNA.[18]

The 3 marker types are each helpful screening tools, but are more powerful (finding more cancers) when considered together in an algorithm rather than individually.[18]

Procedure

No bowel preparation or dietary restriction is necessary before testing, as the test has no known interfering substances and does not rely on visualization of the colon.A single spontaneously passed stool sample is collected using a kit. The stool is collected into a container, which fits on a toilet seat. A sample for hemoglobin determination is captured with a small wand and placed into a separate sealed tube. A preservative buffer is added to the larger stool sample in the collection container, which is then sealed.

The tube and container are placed into a secure shipping box and shipped to a certified molecular biology laboratory for analysis, where the stool sample is processed for DNA extraction for testing. DNA amplification techniques (ie, polymerase chain reaction [PCR]) are used to identify the presence of ‘’KRAS’’ mutations and hypermethylated DNA, while the presence of hemoglobin from blood in the stool is determined using an enzyme-linked immunosorbent assay (ELISA). Results from the DNA and hemoglobin assays are then combined in a logistic algorithm that calculates a composite score dependent on the relative amounts of each biomarker.

Interpretation of results

A positive result could indicate the presence of a cancerous or precancerous lesion of the colon, warranting a diagnostic colonoscopy.[19] A negative result means that the composite levels of abnormal DNA and blood are below the threshold commonly seen with precancerous lesions and colorectal cancers. Patients with negative test results can continue with routine screening. If beta-actin DNA (the internal control) is insufficient, the test result is not reported as positive or negative[18] and the patient’s stool sample should be recollected to obtain a definitive screening result.

Limitations and risks

Multitarget sDNA testing is not recommended for patients with a history of colorectal cancer, or who have had a positive result from another screening method in the previous 6 months, those with a hereditary cancer syndrome[19] or those with a condition associated with a high risk of colorectal cancer, such as inflammatory bowel disease, chronic ulcerative colitis, Crohn’s disease, or those with a family history.[19] Tests on patients with diarrhea or blood in their urine or stool (eg, from bleeding hemorrhoids, bleeding cuts or wounds on their hands, rectal bleeding, or menstruation).

Colorectal cancer screening guidelines vary for people over 75.[3][19] Screening such people should be decided on an individualized basis in consultation with a health care provider. Cologuard test results should be interpreted with caution in older patients, as the rate of false-positive results increases with age.[19]

As with almost all screening tests, both false-negative and false-positive results can occur. It is possible that multitarget sDNA testing will give a negative result in an afflicted patient. Conversely, it is possible to receive a positive result when no cancer exists. In the clinical study of multitarget sDNA testing, 8% of people with cancer tested negative (false-negative), while 13% of people without cancer or advanced precancerous lesions (polyps greater than 1 cm or polyps containing features that predispose to cancer) tested positive (false-positive).[2] Any positive result should be followed by a diagnostic colonoscopy.

The performance of Cologuard was established in a cross-sectional study (i.e., at a single point in time).[2] Programmatic performance of Cologuard (benefits and risks with repeated testing over an established period of time) has not been studied. Performance has not been evaluated in adults who have been previously tested with Cologuard. Noninferiority or superiority of Cologuard programmatic sensitivity as compared to other recommended screening methods for colorectal cancer and advanced adenoma has not been established.[19]

Cost effectiveness and test interval

A 2016 study used modeling to demonstrate that this testing is cost effective. At an assumed average price of $600 per test and an assumed average cost of $1,500 for colonoscopies following a positive test, three-year sDNA screening costs $11,313 per quality adjusted life year (QALY) compared with no screening. By comparison, triennial cervical and biennial breast cancer screening have been reported to cost $15,500 and $30,000 per QALY, respectively, compared with no screening. The analysis further showed an incidence reduction of 57 percent and mortality reduction of 67 percent, compared to 65 and 73 percent, respectively, for decennial colonoscopy. This study used the Archimedes cost-effectiveness model. The authors conducted a five-arm screening study in a population of 200,000 virtual individuals. The model compared the clinical effectiveness of sDNA screening to colonoscopy performed at 10-year intervals and to no screening during a 30-year period.[20]

A 2016 study used the CISNET modeling data relied upon by the U.S. Preventive Services Task Force (USPSTF) when developing its draft guidelines. It concluded that sDNA screening on a three-year interval is equal or superior to screening with fecal blood tests on a two or three-year interval. The analysis further claimed that if used every three years, it generated greater than 90 percent of the life-years gained with screening colonoscopy in at least one of the models, in comparison with fecal blood tests every two-three years.[21]

Screening compliance

A 2016 study looked at the longitudinal adherence of colorectal cancer screening among more than 150,000 average-risk subjects over a 10-year period and found that only three in a thousand people (0.3 percent) undertook annual colorectal cancer screening using either the fecal immunochemical test (FIT) or fecal occult blood test (FOBT).[22]

References

  1. 1 2 "FDA approves first non-invasive DNA screening test for colorectal cancer [press release]". Food and Drug Administration. August 11, 2014. Retrieved 30 June 2015.
  2. 1 2 3 4 5 6 7 8 Imperiale, TF; Ransohoff, DF; Itzkowitz, SH; et al. (2014). "Multitarget stool DNA testing for colorectal-cancer screening". N Engl J Med 370 (14): 1287–1297.
  3. 1 2 3 4 U.S. Preventative Services Task Force (2008). "Screening for colorectal cancer: U.S. Preventative Services Task Force recommendation statement". Ann Intern Med 149 (9): 627–637.
  4. 1 2 3 4 Smith, RA; Manassaram-Baptiste, D; Brooks, D; et al. (2015). "Cancer screening in the United States, 2015: a review of current American cancer society guidelines and current issues in cancer screening". CA Cancer J Clin 65 (1): 30–54.
  5. 1 2 3 Rex, DK; Johnson, DA; Anderson, JC; et al. (2009). "American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]". Am J Gastroenterol 14 (3): 739–750.
  6. 1 2 Colorectal Cancer Facts & Figures 2014-2016. Atlanta, GA: American Cancer Society. 2014.
  7. ↑ Levin, B; Lieberman DA, DA; McFarland, B; et al. (2008). "Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology". Gastroenterology 134 (5): 1570–1595.
  8. ↑ Wexner, SD; Beck, DE; Baron, TH; et al. (2006). "A consensus document on bowel preparation before colonoscopy: prepared by a task force from the American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES)". Gastrointest Endosc 61 (7): 894–909.
  9. ↑ Gimeno Garcia, AZ; Hernandez Alvarez Buylla, N; Nicolas-Perez D, D; Quintero, E (2014). "Public awareness of colorectal cancer screening: knowledge, attitudes, and interventions for increasing screening uptake". ISRN Oncol 2014: 425787.
  10. ↑ Inadomi, JM; Vigan, S; Janz, NK; et al. (2012). "Adherence to colorectal cancer screening: a randomized clinical trial of competing strategies". Arch Intern Med 172 (7): 575–582.
  11. ↑ Senore, C; Inadomi, J; Segnan, N; et al. (2015). "Optimising colorectal cancer screening acceptance: a review". Gut 64 (7): 1157–1177.
  12. ↑ van der Flier, LG; Clevers, H (2009). "Stem cells, self-renewal, and differentiation in the intestinal epithelium". Annu Rev Physiol 71: 241–260.
  13. 1 2 3 4 Osborn, NK; Ahlquist, DA (2005). "Stool screening for colorectal cancer: molecular approaches". Gastroenterology 128 (1): 192–206.
  14. 1 2 3 Berger, B; Ahlquist, DA (2012). "Stool DNA screening for colorectal cancer neoplasia: biological and technical basis for high detection rates". Pathology 44 (2): 80–88.
  15. ↑ Ahlquist, DA; Zou, H; Domanico, M; et al. (2012). "Next-generation stool DNA test accurately detects colorectal cancer and large adenomas". Gastroenterology 142 (2): 248–256.
  16. ↑ Jemal, A; Siegal, R; Xu, J; Ward, E (2012). "Cancer statistics". CA Cancer J Clin 60 (5): 277–300.
  17. ↑ Melotte, V; Lentjes, MH; van den Bosch, SM; et al. (2009). "N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer". J Natl Cancer Inst 101 (13): 916–927.
  18. 1 2 3 4 Lidgard, GP; Domanico, MJ; Bruinsima, JJ; et al. (2013). "Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia". Clin Gastroenterol Hepatol 11: 1313–1318.
  19. 1 2 3 4 5 6 Exact Sciences. [1.pdf?t=1435352862350 "Cologuard Physician Brochure"] (PDF). Retrieved 30 June 2015.
  20. ↑ Berger, BM; Shroy, PC; Dinh, TA. "Screening for Colorectal Cancer Using a Multitarget Stool DNA Test: Modeling the Effect of the Intertest Interval on Clinical Effectiveness.". Clinical Colorectal Cancer. Epub ahead of print. PMID 26792032.
  21. ↑ Berger, BM; Parton, M; Levin, B (2016). "USPSTF Colorectal Cancer Screening Guidelines: An Extended Look at Multi-Year Interval Testing". American Journal of Managed Care 22 (2): 77–81. PMID 26881323.
  22. ↑ Cyhaniuk, A; Coombes, M (2016). "Longitudinal Adherence to Colorectal Cancer Screening Guidelines". American Journal of Managed Care 22: 295–300.

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