Medical Policy
Fecal DNA Testing
for Colorectal Cancer
Effective Date: November 16, 2016;
Revised [5/08; 4/10; 4/12; 4/14; 1/16; 6/16]
Subject: Fecal DNA Testing for Colorectal Cancer
Overview: Fecal DNA testing screens for colorectal cancer based on the presence of specific, cancerassociated mutations in DNA extracted from stool samples.
Policy and Coverage Criteria:
Harvard Pilgrim considers fecal DNA testing medically necessary (e.g. Cologuard) for colorectal cancer
screening, according to USPSTF recommendations,1 once every three years for members:
 Aged 50 years until age 75 years; or
 Aged 76 years to 85 years upon individual consideration taking into account the member’s overall health
status and prior screening history.
Harvard Pilgrim considers all other forms of fecal DNA testing for colorectal cancer investigational and
experimental.
Exclusions: Harvard Pilgrim does not cover fecal DNA testing for members who have any symptoms of colon
cancer or for members who have had a colonoscopy where polyps were detected.
Supporting Information:
1. Technology Assessment: Fecal DNA testing is based on the principle that colorectal neoplasms shed DNA in
stool. The stool is tested against a panel of DNA markers associated with colorectal cancer genetic abnormalities.
The DNA is extracted from the stool and purified, amplified, and analyzed. If any of the genetic mutations are
identified, a more invasive test, such as colonoscopy, can be performed to look for lesions.
Cologuard is a fecal DNA test that achieved FDA approval in 2014. The Cologuard test combines fecal DNA testing
using a gene amplification technique to detect elevated levels of altered DNA and/or hemoglobin which may be
associated with cancer.
2. Literature Review: Onieva-Garcia et al (2015) conducted a systematic review to assess the available evidence
on the validity, diagnostic accuracy and clinical utility of the multitarget DNA test (Cologuard) for screening for
colorectal cancer. The authors concluded after reviewing 299 references that the Cologuard test is a valid
screening test for ruling out cancerous lesions but is suboptimal for ruling out precancerous lesions.
Heigh et al (2014) conducted a blinded prospective study to compare stool DNA testing with fecal
immunochemical testing for occult blood (FIT) to detect sessile serrated polyps (SSP) >/- 1 cm. A stool sample
was collected from 456 asymptomatic adults. The authors found that SSP >/- 1cm can be detected noninvasively
by stool assay of exfoliated DNA markers, especially mBMP3. FIT showed no value in SSP detection.
Imperiale et al (2014) compared a noninvasive, multitarget stool DNA test with a FIT in persons at average risk
for colorectal cancer. The DNA test included quantitative molecular assays for KRAS mutations, aberrant NDRG4
and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Colonoscopy showed that out of the 9989
participants, 65 had colorectal cancer and 757 had advanced precancerous lesions. DNA testing had a 92.3%
1
USPSTF Recommendation
sensitivity for detecting colorectal cancer compared to 73.8% with FIT. DNA testing had a 42.2% sensitivity for
detecting advanced precancerous lesions compared with 23.8% with FIT. DNA testing had a 69.2% rate of
detection of polyps with high-grade dysplasia compared to 46.2% with FIT. The rate of detection of SSP
measuring 1 cm or more were 42.4% for DNA testing and 5.1% for FIT. The authors concluded that in
asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly
more cancers than did FIT but had more false positive results.
A 2011 article by Kisiel et al. discussed next-generation stool DNA screening for CRC screening. The authors
noted the first generation stool DNA tests were found to be more sensitive than stool guaiac tests for CRC
detection or the combination of CRC and advanced adenomas. However, only about half of the screen-relevant
neoplasms were detected by the stool DNA testing in these studies. More recent tests promise substantially
improved performance characteristics, which may have significant impact on estimates of their value. Costeffectiveness estimates will need to be revised based on future clinical studies of next-generation stool DNA tests.
A review of stool-based screening tests by van Dam et al. (2010), evaluated evidence for traditional guaiac-based
testing, FIT, and stool DNA tests. The authors found while second generation DNA-based tests have potential
given their high specificity and sensitivity, additional studies are needed to further assess test performance and in
average-risk populations.
Cost effectiveness of different CRC screenings was evaluated by Lansdorp-Vogelaar et al. in a 2011 review. Part
of the review focused on the whether the newly developed screening test like FIT, stool DNA testing, CT
colonography, and capsule endoscopy are cost-effective when compared with the established CRC screening
tests. Fecal DNA testing was not found to be cost-effective.
In a study by Imperiale et al., patients were screened with fecal DNA testing, fecal occult blood testing and
colonoscopy. Results showed fecal DNA testing had a higher sensitivity at detecting colorectal cancers than fecal
occult blood testing. Further evidence supporting fecal DNA testing for colorectal cancer in low-risk patients is
limited. Cost analysis by Song et al. showed fecal DNA testing cost effective every five years compared to no
screening, but not cost effective when compared to current screening methods of fecal occult blood testing and
colonoscopy. Parekh et al. found improved cost effectiveness for fecal DNA, but fecal occult blood testing and
fecal immunochemical testing continue to be the more cost effective screenings. In March 2008, a joint guideline
released by the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the
American College of Radiology highlighted that colon cancer prevention should be the primary focus of screening
tests. The tests most effective for detecting colorectal cancer and potentially cancerous polyps are the more
invasive tests such as colonoscopy and sigmoidoscopy. Stool based tests like fecal occult blood tests and fecal
DNA tests are primarily designed to detect the presence malignancies.
4. Professional/Governmental Groups:
American College of Gastroenterology Colorectal Cancer Screening Guidelines 2008:
Annual Hemoccult Sensa and fecal DNA testing every 3 years are alternative cancer detection tests.
http://s3.gi.org/physicians/guidelines/CCSJournalPublicationFebruary2009.pdf
CMS:
The CologuardTM - Multitarget Stool DNA (sDNA) Test (effective October 9, 2014)
Screening stool or fecal DNA (deoxyribonucleic acid, sDNA) testing detects molecular markers of altered DNA that
are contained in the cells shed by colorectal cancer and pre-malignant colorectal epithelial neoplasia into the
lumen of the large bowel. Through the use of selective enrichment and amplification techniques, sDNA tests are
designed to detect very small amounts of DNA markers to identify colorectal cancer or pre-malignant colorectal
neoplasia. The CologuardTM - multitarget sDNA test is a proprietary in vitro diagnostic device that incorporates
both sDNA and fecal immunochemical test techniques and is designed to analyze patients’ stool samples for
markers associated with the presence of colorectal cancer and pre-malignant colorectal neoplasia.
Effective for dates of service on or after October 9, 2014, The CologuardTM test is covered once every three
years for Medicare beneficiaries that meet all of the following criteria:
 Age 50 to 85 years, and,
 Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower
gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal
immunochemical test (iFOBT)), and,

At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal
cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history
of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis
colorectal cancer).
C.
Nationally Non-Covered Indications
All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or
otherwise specified above remain nationally non-covered. Non-coverage specifically includes:
(1) All screening sDNA tests, effective April 28, 2008, through October 8, 2014. Effective for dates of service on
or after October 9, 2014, all other screening sDNA tests not otherwise specified above remain nationally noncovered.
https://www.cms.gov/medicare-coverage-database/details/ncddetails.aspx?NCDId=281&ncdver=5&bc=AAAAgAAAAAAAAA%3d%3d&
A 2007 AHRQ Technology Assessment evaluating cost-effectiveness of stool DNA testing for CRC found: “the
science is promising for the use of DNA stool-based technology in the future. However, the current evidence
suggests that this test is not a cost-effective screening tool if the cost were to remain as high as $350.”
https://www.cms.gov/determinationprocess/downloads/id52TA.pdf
Codes:
CPT:
81528 - Oncology (colorectal) screening, quantitative real-time target and signal amplification of 10 DNA markers
(KRAS mutations, promoter methylation of NDRG4 and BMP3) and fecal hemoglobin, utilizing stool, algorithm
reported as a positive or negative result
References:
1. American Academy of Family Physicians. CCLinical preventive service recommendation: colorectal cancer.
http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectalcancer-screening2 . Accessed July 14, 2016.
2. Burt, RW., Cannon, JA., David, DS., et al. National Comprehensive Cancer Network. Colorectal caner
screening. J Natl Compr Canc Netw. 2013; 11(12):1538-75.
3. Canadian Task Force on Preventive Health Care. Recommendations on screening for colorectal cancer in
primary care. CMAJ. 2016; 188(5):340-8.
4. Dong SM, Traverso G, Johnson C, Geng L, Favis R, Boynton K, Hibi K, Goodman SN, D'Allessio M, Paty P,
Hamilton SR, Sidransky D, Barany F, Levin B, Shuber A, Kinzler KW, Vogelstein B, Jen J. Detecting colorectal
cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst. 2001 Jun 6;93(11):858-65.
5. Hayes, Inc. Medical Technology Directory. Fecal DNA Testing for Colorectal Cancer Screening and Monitoring.
Hayes Inc. Lansdale, PA, February 7, 2007.
6. Heigh, RI., Yab, TC., Taylor, WR., Hussain, FT., Smyrk, TC., Mahoney, DW., Domanico, MJ., Berger, BM.,
Lidgard, GP., Ahlquist, DA. Detection of colorectal serrated polyyps by stool DNA testing: comparison with
fecal immunochemical testing for occult blood (FIT). PLoS One. 2014; 9(1):e85659.
7. Imperiale TF, Ransohoff DF, Itzkowitz SH, Turnbull BA, Ross ME; Colorectal Cancer Study Group. Fecal DNA
versus fecal occult blood for colorectal-cancer screening in an average-risk population. N Engl J Med. 2004
Dec 23;351(26):2704-14.
8. Imperiale, TF., Ransohoff, DF., Itzkowitz, SH., Levin, TR., Lavin, P., Lidgard, GP., Ahlquist, DA., Berger, BM.
Multitarget stool DNA testing for colorectal-cancer screening. N Eng J Med. 2014; 370(14):1287-97.
9. Kisiel, JB., Ahlquist, DA. Stool DNA screening for colorectal cancer: opportunities to improve value with n ext
generation tests. J Clin Gastroent. 2011; 45(4): 301-8.
10. Lansdorp-Vogelaar, I., Knudsen, AB., Brenner, H. Cost-effectiveness of colorectal cancer screening. Epidemiol
Rev. 2011; 33(1): 88-100.
11. Levin B, Lieberman DA, McFarland B, et al. Screening and Suveillance for the Early Detection of Colorectal
Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer, and the American College of Radiology. CA: A Cancer Journal for
Clinicians. 2008; 58: 130-160.
12. Lin, JS., Piper, M., Perdue, LA., et al. Screening for Colorectal Cancer: A systematic review for the U.S.
Preventive Services Task Force. Evidence Synthesis no. 135. AHRQ Publication No. 14-05203-EF-1. Rockville,
MD: AHRQ:2016.
13. Onieva-Garcia, MA., Llanos-Mendez, A., Banos-Alvarez, E., Isabel-Gomez, R. A systematic review of the
clinical validity of the Cologuard genetic test for screening colorectal cancer. Rev Clin Esp. 2015; [Epub ahead
of print]
14. Parekh M, Fendrick AM, Ladabaum U. As tests evolve and costs of cancer care rise: reappraising stool-based
screening for colorectal neoplasia. Ailment Pharmacol Ther. 2008, 27(8): 697-712.
15. Pox, C. Colon cancer screening: which non-invasive filter tests? Dig Dis. 2011; 29 Suppl 1: 59-9.
16. Song K, Fendrick AM, Ladabaum U. Fecal DNA testing compared with conventional colorectal cancer
screening methods: a decision analysis. Gastroenterology. 2004 May;126(5):1270-9.
17. U.S. Preventative Services Task Force (USPSTF). Final Recommendation Statement: Colorectal Cancer:
Screening. U.S. Preventive Services Task Force. June 2016.
http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorectalcancer-screening2
18. Van Dam, L., Kuipers, EJ., van Leerdam, ME. Performance improvements of stool-based screening tests. Best
Pract Res Clin Gastroenterol. 2010; 24(4): 479-92.
19. Wilt, TJ., Harris, RP., Qaseem, A. High value care task force of the American College of Physicians. Screening
for cancer: advice for high-value care from the American College of Physicians. Ann Intern Med. 2015;
162(10):718-25.