This document addresses the use of tests that analyze human DNA in stool samples as a screening or diagnostic test for colorectal cancer.  This testing method, also known as fecal DNA testing, includes, but is not limited to, the following tests: PreGen-26™, PreGen Plus™ and ColoSure™ test.                                                                                                                   

Note:  Please see the following documents for additional information related to colorectal cancer:

• CG-SURG-01 Colonoscopy
• RAD.00029 CT Colonography (Virtual Colonoscopy) as a Screening or Diagnostic Test for Colorectal Cancer
• GENE.00001 Genetic Testing for Cancer Susceptibility

Investigational and Not Medically Necessary:

The analysis of DNA in stool samples, also known as fecal DNA testing, is considered investigational and not medically necessary as a screening or surveillance technique for colorectal cancer.

In 2004, Imperiale and colleagues reported on the results of a prospective trial of 5486 enrolled subjects at average risk for colon cancer.  Participants underwent fecal occult blood testing (FOBT), fecal DNA analysis and colonoscopy; colonoscopy is considered the gold standard.  Of the 5486 subjects enrolled, 4404 completed all aspects of the study and from this group, 2507 underwent comparative analysis.  The subgroup was chosen by including all subjects who were found to have adenocarcinoma (n=31) and a random selection of subjects with adenomas, polyps, or normal findings.  The sensitivity of fecal DNA analysis and FOBT for all cancers and adenomas with high grade dysplasia was 40.8% and 14.1%, respectively.  Specificity in subjects with a negative finding on colonoscopy was 94.4% for fecal DNA and 95.3% for FOBT. 

In an accompanying editorial by Woolf, caution is urged in interpreting the results of the Imperiale study.  For example, Woolf notes the wide confidence intervals around the sensitivity of fecal DNA, ranging from 35-68%, which preclude any firm estimates of the magnitude of benefit associated with fecal DNA testing. 

Further concerns regarding this study include the fact that it is not an "intent-to-treat analysis."  Approximately 20% of subjects were not evaluated (12% did not provide an adequate stool sample for DNA testing; 8% did not complete FOBT cards; 14% did not complete colonoscopy).  Missing data were not imputed.  The observed sensitivity for cancer of the Hemoccult II FOBT in this study was lower at 13% than reported in other studies.

Imperiale et al. also note in their Discussion section "the difference between our results [on Hemoccult sensitivity] and those of other reports is potentially important and deserves further study." And finally, the Hemoccult II FOBT tests were performed at each of the 81 study sites (including private-practice and university-based settings); quality control procedures were not described.  In contrast, the DNA test was conducted in a single laboratory.  Screening would require dissemination of the DNA test to more laboratories, which, as the authors note, could introduce greater variability in results.

Published, peer-reviewed, scientific literature on the ColoSure™ test is limited.  Itzkowitz and colleagues (2008) conducted a validation study on an improved stool DNA assay utilizing only two markers, hypermethylated vimentin gene (hV) and a two site DNA integrity assay (DY).  Using stool samples from forty-two participants with colorectal cancer (CRC) and 241 subjects with normal colonoscopy, the authors reported the sensitivity and specificity for CRC at 83% and 82% respectively.  While this test has been proposed as a screening tool for colorectal cancer, the population of individuals included in the study does not necessarily reflect the prevalence or spectrum of disease present in a screening environment (individuals with colon polyps or other abnormalities were excluded from the study).

In a randomized, multicenter trial, Ahlquist et al. (2008) compared fecal occult blood testing and multitarget DNA-based testing, followed by colonoscopy, for detecting colorectal cancer.  Evaluations were performed on 3764 of the 4482 average-risk individuals enrolled in the study.  The goal of the study was to:  (1) evaluate an older stool DNA test (SDT-1) with two occult blood tests (Hemoccult and HemoccultSensa); and (2) determine how well a newer stool DNA test (SDT-2) identified colon cancer compared with SDT-1 and the two occult blood tests.  The older DNA test (SDT-1) was a precommercial 23-marker assay, and SDT-2 targeted 3 broadly informative markers.  The authors reported that the newer DNA test was twice as effective at detecting cancer and serious precancerous polyps as either current blood stool sample tests or an older version of DNA testing.  While SDT-2 was able to identify more neoplasms than either of the occult blood tests, it is unclear whether this increased sensitivity is offset by a loss of specificity.  The value of this study is limited by the fact that SDT-2 was not performed on all subsets of participants.

According to the American Society for Gastrointestinal Endoscopy (ASGE) 2006 Colorectal Cancer Screening and Surveillance Guideline, "there are currently no studies demonstrating a reduction in colorectal cancer (CRC)-related mortality from fecal DNA testing, and the technique for the test has not been standardized. The use of this test is still in development and under study and, therefore, cannot be recommended at this time for CRC screening."  The Blue Cross Blue Shield Association (BCBSA) reached a similar conclusion in its 2006 TEC Assessment Special Report entitled "Fecal DNA Analysis for Colon Cancer Screening".  In this report the BCBSA states that there are several issues that need to be addressed before fecal DNA screening can be extensively recommended.  These issues include, but are not limited to: (1) determining if false-positive rates can be maintained appropriately low for a screening program; (2) determining which individuals should not be screened with fecal DNA testing; and (3) determining the optimal screening interval.

The American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology released their consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults (Levin, 2008).  The panel concluded that the data are sufficient to consider analysis of fecal DNA an acceptable option for colorectal cancer screening.  The guideline also provides extensive discussion of the pros and cons of this test.  The benefits of fecal analysis of DNA for colorectal cancer screening and surveillance include the fact that the test is noninvasive, causes no physical harm to the individual, appears to be accepted by both individuals and providers, is not dependent upon the detection of occult bleeding and requires only a single stool sample.  The limitations of the test (areas that require additional research) include, but are not limited to the following: (1) Test sensitivity is based on a panel of markers that appear to identify some, but not all colorectal cancers; (2) The cost of the test is significantly higher than the cost of other stool tests; (3) The interval at which the test should be performed is unclear; and (4) The uncertainty around how positive results without evidence of cancer or advanced lesions on follow-up should be interpreted and whether or not these individuals require an alternate plan for ongoing surveillance.  While fecal DNA analysis is a potentially useful tool for colorectal cancer screening and surveillance, due to the limitations noted above, this technology is considered investigational and not medically necessary at this time.

The U.S. Preventive Services Task Force guidelines for colon cancer screening were updated in 2008 stating that there is insufficient evidence to assess the benefits and harms of fecal DNA testing as a screening modality for all populations.

The National Cancer Institute (2008) acknowledges that genetic testing of stool samples is being studied as an alternative modality for colorectal cancer screening and concludes that additional studies are needed to determine whether this type of test accurately detects precancerous polyps or colorectal cancer in asymptomatic individuals.

In 2008, the Centers for Medicare and Medicaid Services (CMS) decided not to expand the colorectal cancer screening benefit to include coverage of the commercially available PreGen-Plus™ fecal DNA screening test.  CMS expressed a willingness to consider a request for reconsideration when the commercially available test has received approval from the Food and Drug Administration (FDA).

The National Comprehensive Cancer Network (NCCN) guideline on colorectal cancer screening (2009) states that fecal DNA test is an emerging non-invasive diagnostic tool for colorectal cancer screening that is currently under consideration.  However, the guideline does not include fecal DNA testing as one of the recommended screening modalities for colorectal cancer.

The American College of Gastroenterology (ACG) Guidelines for Colorectal Cancer Screening (2008) states that there is no rationale for the primary use of fecal DNA testing as a colorectal cancer detection test.  The disadvantages of fecal DNA testing include its high cost, the fact that there are no established data on which to determine an optimal interval for testing and a lack of clinical recommendations on how to respond to individuals who have positive DNA tests and negative colonoscopies.  The ACG considers fecal DNA testing at intervals less than every three years to be cost prohibitive (Rex 2009).

Description of Colorectal Cancer

According to the American Gastroenterological Association, colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in the United States.  This year, more than 50,000 Americans will die from colorectal cancer and approximately 131,600 new cases will be diagnosed.  Eighty to 90 million Americans (approximately 25 percent of the US population) are considered at risk because of age or other factors.  More women over the age of 75 die from colorectal cancer than from breast cancer.  Incidence increases with age, beginning around 40 years of age, and is higher in men than in women (60.4 in men versus 40.9 in women, per 100,000, per year).  Colorectal cancer survival is closely related to the clinical and pathological stage of the disease at diagnosis.  Approximately 65 percent of individuals present upon diagnosis with advanced disease.

Evidence exists indicating that reductions in colorectal cancer morbidity and mortality can be achieved through detection and treatment of early-stage colorectal cancers and the identification and removal of adenomatous colon polyps, the precursors of colorectal cancer.  Colorectal cancer screening tests have been shown to achieve accurate detection of early stage cancer and its precursors.

Currently, there are several acceptable options for the screening of colorectal cancer.  The Fecal Occult Blood Test (FOBT) is a simple exam used to look for blood from bleeding polyps in the stool.  Sigmoidoscopy involves the use of an instrument called a sigmoidoscope that is used to look for polyps and cancer in the lower portion of the colon, known as the sigmoid colon.  Colonoscopy is a similar procedure but is uses a colonoscope to inspect the entire colon for polyps and cancer.  During both of these scope procedures, any polyps found can be removed and tumors biopsied.  There are other tests available for CRC screening, however the current gold standard for an average-risk individual (those without any factors which increase their risk of CRC) at age 50 is to receive an annual FOBT with sigmoidoscopy every five years or colonoscopy every ten years.  Both these screening methods are believed to be equivalent as screening tools and the choice of screening method is a matter left to the discretion of the doctor in consultation with the individual.  For individuals with higher than average risk for CRC, more frequent screening schedules are recommended.

Description of Technology

Fecal DNA testing is a simple process that involves collection of fresh stool samples that are then sent to the laboratory for analysis.  Analysis of DNA in stool samples has been proposed as a screening and diagnostic tool for detection of colorectal cancer.  The premise for this type of testing is based upon the knowledge that colorectal cancer cells and precursor polyps contain mutated DNA, referred to as microsatellites, which are shed into the colon and may be detected in fecal matter.  Like any other cells, colorectal cancer cells slough off from the main tumor body and are expelled from the body in feces.  Exact Sciences, Inc. (Maynard, MA) invented two different DNA tests that demonstrated the ability to identify several common microsatellite DNA mutations known to exist in colorectal cancer cells.  One test, PreGen-26™, detected a mutation in a gene called BAT-26.  Mutations in BAT-26 have been associated with colorectal cancers arising in individuals with Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), which is a common cause of colorectal cancer that runs in families.  The second test, PreGen-Plus™, was is a single test that identified the presence of 23 different microsatellite mutations known to be associated with colorectal cancer, including mutations in BAT-26.  Additionally, 21 other point mutations in other genes associated with colorectal cancer were included in this test (APC, K-ras, and p53).  Finally, this test was designed to detect long DNA fragments, which have been specifically associated with cells called non-apoptotic colonocytes, which are common in colorectal cancer.  In October 2007 PreGen Plus™ was the subject of an FDA letter which stated that the PreGen-Plus™ assay is a medical device and therefore requires premarket approval or clearance.  PreGen-26™ and PreGen-Plus™ are no longer being marketed in the United States. 

In 2008, Laboratory Corporation of America (LabCorp), Burlington, NC began marketing ColoSure™, a single-marker lab-based fecal DNA test that utilizes a methylation-specific PCR and gel electropheresis technique to identify abnormal changes in the vimentin gene.  ColoSure™ determines if the vimentin gene is "turned on."  The vimentin gene is turned off (hyper-methylated) in about 72-77% of people with colon cancer.  According to information on the LabCorp web site, ColoSure™ is not intended to replace a colonoscopy in individuals who are willing to undergo the procedure and while it may be used adjunctively or in individuals noncompliant with screening recommendations, it is not a primary screening tool for individuals at increased risk for developing disease.  ColoSure™ is available thru DNADirect and as a laboratory-developed test, is not subject to FDA regulation.

Proposed Benefits

It has been proposed that fecal DNA testing may be an alternative to FOBT as a screening test for colorectal cancer.  While colonoscopy is considered the gold standard screening technique, many individuals are unwilling to undergo this procedure.  The data suggest that fecal DNA testing has a greater sensitivity than FOBT testing, and therefore, may be a screening option for individuals who are unwilling or unable to undergo a colonoscopy.  Additional benefits of fecal analysis of DNA include the fact that the test is non-invasive, only one sample is needed and no bowel preparation is required.  However, the individual is required to collect a bowel movement, pack it, refrigerate it and then mail it to a laboratory.  How well individuals accept and comply with fecal DNA testing has not yet been determined.

Possible Risks

The data suggest that the sensitivity of fecal DNA testing is less than the gold standard of colonoscopy.  Therefore, if fecal DNA testing is the only screening method used, there is an increased likelihood of missing colon cancer.  Missed cancers could progress into more serious disease before identification, leading to poorer prognosis and worsened health outcomes.

DNA (also known as deoxyribonucleic acid): The basic material responsible for coding genetic information in a cell.

Multi-target Assay panel (i.e., PreGen-plus™): A type of laboratory test that incorporates several tests for detecting different substances into one single test.

Stool samples: A sample of fecal matter collected from an individual and used for the detection of various health conditions, including colorectal cancer.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services are Investigational and Not Medically Necessary:
For the procedure code listed below, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Ahlquist DA, Sargent DJ, Loprinzi CL, et al. Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med 2008; 149(7):441-450.
2. Gryfe, R. Clinical implications of our advancing knowledge of colorectal cancer genetics: Inherited syndromes, prognosis, prevention, screening and therapeutics. Surg Clin N Am. 2006; 86(4):787–817.
3. Imperiale TF, Ransohoff DF, Itkowitz SH, et al. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average risk population.  N Eng J Med. 2004; 351(26):2704-2714.
4. Itzkowitz S, Brand R, Jandorf L, et al. A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol. 2008; 103(11):2862-2870.
5. Itzkowitz SH, Jandorf L, Brand R. Improved Fecal DNA Test for Colorectal Cancer Screening. Clin Gastroenterol Hepatol. 2007; 5(1):111-117.
6. Song K, Fendrick AM, Ladabaum U. Fecal DNA testing compared with conventional colorectal cancer screening methods: a decision analysis. Gastroenterology. 2004; 126(5):1270-1279.
7. Woolf SH.  Editorial.  A smarter strategy? - Reflections on fecal DNA screening for colorectal cancer.  N Eng J Med. 2004; 351(26):2755-2758.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Society for Gastrointestinal Endoscopy (ASGE). ASGE Guideline: Colorectal cancer screening and surveillance. Gastrointestinal Endoscopy. 2006; 63(4):5446-5457.  Available at: http://www.asge.org/WorkArea/showcontent.aspx?id=3334.  Accessed on February 8, 2011.
2. Blue Cross Blue Shield Association. Special report. Fecal DNA analysis for colon cancer screening. TEC Assessment, 2006; 21(6). Available at: http://blueweb.bcbs.com/global_assets/special_content/tec_assessments/VOL21/21_06.pdf  Accessed on February 8, 2011.
3. Centers for Medicare and Medicaid Services. Manual System. Screening DNA Stool Test for Colorectal Cancer. Pub. 100-02, Transmittal: 93.  July 25, 2008.  Available at:  http://www.cms.hhs.gov/transmittals/downloads/R93BP.pdf  Accessed on February 8, 2011.
4. Institute for Clinical Systems Improvement. Healthcare Guidelines: Colorectal Cancer Screening. Released 05/2010. Available at: http://www.icsi.org/guidelines_and_more/gl_os_prot/preventive_health_maintenance/colorectal_cancer_screening
   /colorectal_cancer_screening_6.html  Accessed on February 8, 2011.
5. Levin B, Lieberman DA, McFarland B, et al. 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. CA Cancer J Clin. 2008. 58(3):130-160.  Available at: http://caonline.amcancersoc.org/cgi/content/full/CA.2007.0018v1. Accessed on February 8, 2011
6. National Cancer Institute (NCI). Colorectal Cancer (PDQ^®): Screening (health professional version). Summary of Evidence. Last modified 01/28/2011. Available at:  http://www.cancer.gov/.   Accessed on February 8, 2011. 
7. National Comprehensive Cancer Network^® (NCCN) Clinical Practice Guidelines in Oncology™. © 2011. National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org.  Accessed on February 8, 2011.
   • Colorectal cancer screening. (v2.2011). Revised October 22, 2010.
8. Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009;104(3):739-750.
9. U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 149(9):627-637. Available at: http://www.guideline.gov/content.aspx?id=13133&search=screening+for+colorectal+cancer+2008.   Accessed on February 8, 2011.
10. Whitlock EP; Lin JS; Liles E; et al. Screening for Colorectal Cancer: A Targeted, Updated Systematic Review for the U.S. Preventive Services Task Force.  Ann Intern Med. 2008; 149: 638 – 658.  Available at: http://www.annals.org/cgi/reprint/149/9/638.pdf  Accessed on February 8, 2011.
11. Winawer S, Fletcher R, Rex D, et al. American Gastroenterological Association. Colorectal cancer screening and surveillance: clinical guidelines and rationale – Update based on new evidence. Gastroenterology 2003; 124(2):544-560.

1. American Gastroenterological Association. Colorectal Cancer Detection and Prevention. Available at: http://www.gastro.org/. Accessed on February 8, 2011.
2. National Cancer Institute. Colorectal Cancer (PDQ^®): Screening. Last modified 04/30/2010. Available at: http://www.cancer.gov. Accessed February 8, 2011.

Colorectal Cancer Screening
ColoSure™
PreGen-26™
PreGen-Plus™
Stool DNA Analysis

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.