Medical Policy



Subject: Analysis of Fecal DNA for Colorectal Cancer Screening
Document #: GENE.00008 Current Effective Date:    03/29/2017
Status: Revised Last Review Date:    02/02/2017

Description/Scope

This document addresses the use of tests that analyze human DNA in stool samples as a screening test for colorectal cancer. Cologuard™ (Exact Sciences Inc., Madison), also known as fecal DNA testing, provides qualitative detection of colorectal neoplasia associated DNA markers and detects occult hemoglobin in human stool using fecal immunohistochemical testing.                                                                                                                   

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

Position Statement

Medically Necessary:

Cologuard, a fecal DNA test, is considered medically necessary once every 3 years as a screening technique for individuals at average risk for colorectal cancer in whom colorectal cancer preventive screening is indicated.

When previous screening has been undertaken using an alternative method, then the initial Cologuard test is considered medically necessary as a screening technique for individuals at average risk for colorectal cancer based on the preceding test's designated next appropriate screening interval. 

Investigational and Not Medically Necessary:

The Cologuard test is considered investigational and not medically necessary when the criteria above are not met and for all other indications including post colorectal cancer diagnosis surveillance.

All other methods for the analysis of DNA in stool samples are considered investigational and not medically necessary.

Rationale

Screening of Individuals at Average-risk for Colorectal Cancer

Colorectal cancer (CRC) screening consists of the systematic identification and evaluation of asymptomatic individuals for CRC or adenomatous polyps. The goal of CRC screening is twofold: to reduce CRC mortality by identifying cancer at an early, curable stage and to reduce the incidence of CRC by detecting and removing precursor lesions (for example, adenomas or preinvasive adenomatous polyps) (NCCN, 2016). Individuals are stratified into screening groups depending upon their risk of CRC. According to the National Comprehensive Cancer Network (NCCN), individuals considered to be at average risk of developing CRC are those age 50 years or older with no family history of CRC, no personal history of adenoma, sessile serrated polyps or CRC, and no inflammatory bowel disease (NCCN, 2016).

Several options are currently available for CRC screening including colonoscopy, flexible sigmoidoscopy, immunochemical-based testing, CT colonography and fecal-based testing. This document addresses the use of fecal DNA tests to screen individuals for CRC.

Fecal DNA tests are designed to identify signs of CRC by detecting alterations in exfoliated DNA in stool samples. Fecal DNA testing has included the PreGen-26™, PreGen-Plus™, ColoSure™ and Cologuard™ tests. However, at the time of the most recent review, only the Cologuard test is available in the United States.

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. 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 42 participants with 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 CRC, 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 multi-target DNA-based testing, followed by colonoscopy, for detecting CRC. 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 Hemoccult Sensa); 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.

Ahlquist and colleagues (2012a) evaluated the colorectal neoplasm detection rate by a next-generation stool DNA (sDNA) test and the effects of covariates on test performance. The authors conducted a blinded, multicenter, case-control study using archived samples. The study population included 252 participants with CRC, 133 participants with adenomas ≥ 1 cm, and 293 subjects with normal colonoscopy results who served as the control group. Two-thirds of the participants were randomly assigned to a training set and one-third to a test set. The sDNA test was able to detect 85% of the subjects with CRC and 54% of subjects with adenomas ≥ 1 cm with 90% specificity. The sDNA test detection rates increased with adenoma size; identifying 54% ≥ 1 cm, 63% > 1 cm, 77% > 2 cm, 86% > 3 cm, and 92% > 4 cm. Based on receiver operating characteristic analysis, the rate of CRC detection was slightly greater for the training than the test set (p=0.04), whereas the rate of adenoma detection was comparable between sets. There was no difference in the sensitivities for detection of CRC and adenoma based on lesion site. The authors concluded the sDNA test is able to identify early-stage CRC and large adenomas with high levels of accuracy and that the size of a neoplasm but not the anatomical site affects detection rates. The authors acknowledge that larger population studies are needed to validate the findings of this study.

In another study, Ahlquist and colleagues (2012b) compared the sensitivities of a multimarker test for sDNA and a plasma test for methylated septin 9 (SEPT9) in identifying individuals with large adenomas or CRC. Using archived samples from a single institution, the researchers analyzed paired stool and plasma samples from 30 subjects with CRC and 22 subjects with large adenomas. Forty-six (46) stool samples and 49 plasma samples from age- and sex-matched participants with normal colonoscopy results served as controls. The sDNA test identified adenomas (median, 2 cm; range, 1-5 cm) with 82% sensitivity (95% confidence interval [CI], 60%-95%); SEPT9 had 14% sensitivity (95% CI, 3%-35%; p=0.0001). The sDNA test detected individuals with CRC with 87% sensitivity (95% CI, 69%-96%); SEPT9 had a 60% sensitivity rate (95% CI, 41%-77%; p=0.046). The sDNA test detected individuals with stage I-III CRC with 91% sensitivity (95% CI, 71%-99%); SEPT9 had a 50% sensitivity rate (95% CI, 28%-72%; p=0.013). In the stage IV CRC group, the sDNA test had a sensitivity rate of 75% (95% CI, 35%-97%) while the SEPT9 had a sensitivity rate of 88% (95% CI, 47%-100%; p=0.56). False positive rates were 7% for the sDNA test and 27% for SEPT9 test. A post analysis clinical review indicated that non-gastrointestinal malignancies accounted for 4 (31%) of the false positives. According to the authors, "SEPT9 essentially failed to detect large adenomas and detected significantly fewer early stage CRCs than did sDNA." The authors acknowledge that one of the limitations of the study involved the selection of participants from the referral/outpatient setting and that the findings of the study may not be representative of those in asymptomatic individuals undergoing general screening.

In a blinded, multicenter, case-control study, Lidgard and colleagues (2013) investigated the ability of an automated stool DNA assay to detect colorectal neoplasia. The researchers collected stools from 459 asymptomatic individuals before screening or surveillance colonoscopies and from 544 referred subjects. Cases included CRC (n=93), advanced adenoma (n=84), or sessile serrated adenoma (SSA) greater than or equal to 1 cm (n=30). The controls consisted of nonadvanced polyps (n=155) or no colonic lesions (n=641). Samples were analyzed by using an automated multi-target sDNA assay which measured β-actin, mutant KRAS, aberrantly methylated BMP3 and NDRG4, and fecal hemoglobin. The data were analyzed using a logistic algorithm to categorize participants as positive or negative for advanced colorectal neoplasia (CRC, advanced adenoma, and/or SSA ≥ 1 cm). The authors reported that at 90% specificity, the stool DNA analysis identified individuals with CRC with 98% sensitivity. Sensitivity data for other conditions studied were reported as follows: stage I cancer (95%); stage II cancer (100%); stage III cancer (96%); stage IV cancer (100%); stages I - III cancers (97%); advanced adenoma and SSA greater than or equal to 1 cm (57%); advanced adenoma and SSA greater than 2 cm (73%); advanced adenoma and SSA greater than 3 cm (83%). The test identified advanced adenoma with high-grade dysplasia with 83% sensitivity. The authors concluded that the automated test might be used as a non-invasive method for general CRC screening.

Heigh and colleagues (2014) assessed and compared the noninvasive detection of sessile serrated polyps (SSP) greater than or equal to 1 cm by sDNA and an occult blood fecal immunochemical test (FIT). In the blinded prospective study, a single stool sample was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy for the purposes of conducting both FOBT and FIT. The 29 individuals found to have SSP greater than or equal to 1 cm were included as cases. The 232 participants with no neoplastic findings served as controls. Exact Sciences performed analyses of stool DNA in batches using a pre-commercial multi-marker sDNA assay which targeted methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. The FIT (Polymedco OC-FIT Check) was performed in a separate laboratory within 2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). In the group of cases, the median SSP size was 1.2 cm (range 1-3), 28/29 (93%) and were located proximal to the splenic flexure. Only one SSP contained dysplasia. Synchronous small or diminutive polyps were present in 64% of cases. In the multi-target sDNA markers group, the sensitivity of the sDNA test for detection of SSP greater than or equal to 1 cm was 55% (95% CI, 36-74) and the specificity was 91% (95% CI, 87-94). Within the narrow size range of SSP cases identified, the detection rate was 55% for the 11 participants with lesions 1-1.4 cm and 53% for those 17 with lesions 1.5-3 cm, p=0.9. Among the multi-target sDNA markers, mBMP3 was most discriminant for SSP detection, with an area under the curve (AUC) of 0.87 (95% CI, 0.80-0.95; p=0.0001). The other informative DNA markers, mNDRG4 (AUC 0.79; 95% CI, 0.70-0.88; p=0.0001) and mutant KRAS (AUC 0.64; 95% CI, 0.53-0.75; p=0.0068), did not provide statistically significant incremental sensitivity above that provided by mBMP3. Fecal hemoglobin alone showed no discrimination (AUC=0.50; 95% CI, 0.40-0.61; p=0.4724). At matched specificities, stool assay of mBMP3 was more sensitive for detection of SSP greater than or equal to 1 cm than FIT. At 95% specificity cutoffs, stool assay of mBMP3 identified 63% of SSP lesions compared to 0% by FIT-100, p=0.0001; at 91% specificity, stool assay of mBMP3 identified 66% compared to 10% by FIT-50, p=0.0003. The authors concluded that in a screening setting, SSP greater than or equal to 1 cm can be detected by a noninvasive stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.

Cologuard, manufactured by Exact Sciences Corp., is a newer multi-targeted test which uses a stool DNA-based assay to detect advanced adenoma and CRC. Cologuard analyzes DNA present in stool for specific genetic changes in the Kirsten rat sarcoma viral oncogene homolog (the KRAS gene), bone morphogenetic protein 3 gene (BMP3) and n-MYC downstream-regulated gene 4 (NDRG4), all of which are associated with the growth and/or development of CRC. The assay also employs FIT to measure the concentration of hemoglobin in the stool sample. Lastly, a complex algorithm is used to differentiate positive and negative results. The manufacturer of Cologuard expects that use of this noninvasive test may both increase patient compliance with current CRC screening recommendations and significantly reduce the number of invasive screening procedures performed.

Imperiale and colleagues (2014) reported the result of a large, cross-sectional clinical trial supported by Exact Sciences, Inc. (NCT01397747) which evaluated 9989 asymptomatic individuals between 50 and 84 years of age who were scheduled to undergo a screening colonoscopy and considered at average-risk for CRC. Each of the participants provided a stool specimen prior to routine bowel preparation for colonoscopy. The researchers compared the Cologuard test results with FIT results. Colonoscopy identified CRC in 65 participants (prevalence of 0.7%). Of the 65 individuals identified with CRC on colonoscopy, 60 participants had stage I to III cancers. Colonoscopy also revealed advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring greater than or equal to 1 cm) in 757 (7.6%) of the study population. The sensitivity for the Cologuard and FIT tests to detect CRC were 92.3% and 73.8% respectively (p=0.002). The sensitivity of Cologuard was not affected by location of the colonic lesion or stage of the cancer. The sensitivity of the DNA-based test to identify advanced precancerous lesions was 42.4% compared to 23.8% with FIT (p<0.001). The detection rate of high-grade dysplasia was 69.2% with the DNA-based test compared to 46.2% with FIT (p=0.004). The sensitivity of Cologuard to detect serrated sessile polyps greater than or equal to 1 cm was 42.4% compared to 5.1% with FIT (p<0.001). FIT demonstrated higher specificity than Cologuard (94.9% and 86.6% respectively) amongst individuals with nonadvanced or negative findings and amongst individuals with negative colonoscopy results (96.4% and 89.8% respectively). The implications of these "false-positive" results are unclear. It is not known if the false positive test results were clinically important, possibly representing CRC elsewhere in the gastrointestinal tract.

This study demonstrated that Cologuard was significantly more sensitive than FIT alone and better discriminated clinically relevant colorectal lesions; FIT demonstrated higher test specificity. However, there are some limitations of this study. While it has been hypothesized that use of the DNA-based test will result in an increase in CRC screening amongst asymptomatic, average-risk individuals, and subsequently result in improved overall survival rates, to date, no studies were identified which evaluated the impact of this testing on morbidity, mortality or patient uptake. It still remains to be seen how the test results influence clinical practice and if it results in improved clinical outcomes. Also, the DNA-based test resulted in higher false-positive rates which could result in more colonoscopies being done to rule out CRC. Because the study population consisted primarily of white individuals, it is not clear whether the findings of the study are applicable to individuals of other ethnicities. Information in the U.S. Food and Drug Administration (FDA) Summary of Safety and Effectiveness Data (FDA, 2014b) indicates that the sensitivity for detecting CRC was 96.4% (53 of 55) for whites and 62.5% (5 of 8) for blacks although this analysis is limited significantly by the small number of black participants in the analysis. For the detection of advanced adenomas, the sensitivity was similar in both groups (42.3% for whites and 42.4% for blacks). Lastly, since the study was funded by the manufacturer Exact Sciences Inc., there is the potential for conflicts of interest.

In a prospective, cross-sectional study, Redwood and colleagues (2016) compared the accuracy of Cologuard and FIT for the detection of screening-relevant colorectal neoplasia in asymptomatic Alaska Native individuals. A total of 868 individuals between the ages of 40-85 years who were undergoing screening or surveillance colonoscopy were enrolled in the study. Individuals excluded from the study included those with a history of: (1) invasive screening tests in the previous 4 years; (2) surveillance for CRC or polyp follow-up in the previous 2 years; (3) a history of upper gastrointestinal cancer; (4) overt hematochezia during the previous month; (5) inflammatory bowel disease or known hereditary CRC syndromes (for example, familial adenomatous polyposis, Lynch syndrome). A total of 661 participants completed the study. The major outcome measure was test accuracy for screening-relevant neoplasia, defined as CRC or advanced adenoma (adenomatous polyp larger than 1 cm or containing >25% villous component or high-grade dysplasia, or sessile serrated adenoma/polyp larger than 1 cm) found on screening or surveillance colonoscopy. The test results confirmed that Cologuard testing demonstrated higher sensitivity but lower specificity than FITs to detect colorectal neoplasia with one-time use. While the authors concluded that Cologuard represents "an attractive CRC screening strategy", they also acknowledged that "further consideration and evaluation of the optimal test frequency" are warranted.

Based on the results of the 2014  study by Imperiale and colleagues (discussed earlier), the Cologuard test kit was granted premarket approval by the U.S. Food and Drug Administration (FDA, 2014a) as a screening test for colorectal carcinoma in individuals who are at least 50 years of age and at average-risk for CRC. When results are abnormal, Cologuard should be followed by diagnostic colonoscopy. The FDA approval does not include the use of Cologuard as a CRC surveillance technique.

Several organizations have issued position statements or published guidelines related to screening for CRC, including fecal DNA analysis. In the 2008 American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults, the panel concluded that the data are sufficient to consider analysis of fecal DNA an acceptable option for CRC screening. The guideline also provides extensive discussion of the pros and cons of this test. The benefits of fecal analysis of DNA for CRC screening include, but are not limited to 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 CRCs; (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 (Levin, 2008).

The American College of Gastroenterology (ACG) Guidelines for Colorectal Cancer Screening (2009) states that there is no rationale for the primary use of fecal DNA testing as a CRC 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 3 years to be cost prohibitive (Rex, 2009).

The Agency for Healthcare Research and Quality's (AHRQ) review of the evidence on fecal DNA testing to screen for CRC in adults at average-risk for CRC found that there is insufficient evidence about the diagnostic accuracy of fecal DNA testing to screen for CRC in asymptomatic, average-risk individuals. The authors also state "there is also insufficient evidence for the harms, analytic validity, and acceptability of testing in comparison to other screening modalities. Existing evidence has little or no applicability to currently available fecal DNA testing" (Lin, 2012).

The Blue Cross Blue Shield Association (BCBSA) concluded in its 2014 TEC Assessment Special Report entitled "Fecal DNA Analysis for Colon Cancer Screening" that:

The recent study evaluating a fecal DNA test showed higher sensitivity but lower specificity than FIT. The diagnostic characteristics of the test are consistent with reduced colorectal cancer mortality if used in a longitudinal screening program. However, it remains to be determined how effective the test would be when used at a particular frequency within a screening program, and thus its efficacy and impact on resource use compared with established methods are unknown.

The National Cancer Institute (2014) acknowledges that genetic testing of stool samples is being studied as an alternative modality for CRC screening and states that "There are no data on the effect of other screening interventions (i.e., fecal occult blood test combined with sigmoidoscopy, barium enema, colonoscopy, computed tomographic colonography, and stool DNA mutation tests) on mortality from colorectal cancer." The document also states that current unknowns with regard to stool DNA mutation testing include internal validity, consistency, magnitude of effects on surrogate endpoint (e.g., state at diagnosis and adenoma detection) and external validity.

The August 11, 2014, Centers for Medicare & Medicaid Services (CMS) Decision Memo for Screening for Colorectal Cancer - Stool DNA Testing (CAG-00440N) indicates that CMS covers Cologuard once every 3 years for asymptomatic Medicare beneficiaries between 50-84 years of age who are at average-risk for CRC (CMS, 2014).

The National Comprehensive Cancer Network (NCCN) guideline on Colorectal Cancer Screening (V2. 2016) state that:

For screening of individuals at average risk for CRC:

It is recommended that screening for persons at average risk begin at age 50 after discussions of the available options. Currently recommended options include colonoscopy every 10 years; annual fecal-based tests (every 3 years with DNA-based testing); flexible sigmoidoscopy every 5 to 10 years with or without interval guaiac-based or immunochemical-based testing at year 3; or CT colonography every 5 years. If a colonoscopy is incomplete or preparation is suboptimal, other screening methods or repeat colonoscopy in 1 year should be considered. Following a negative test, rescreening at the appropriate interval can be done with any accepted modality (NCCN, 2016)

For screening of individuals at average risk for CRC using the combined stool DNA/FIT test:

The NCCN panel recommends the use of stool-based DNA/occult blood testing as a screening modality in average-risk individuals but data to help determine an appropriate interval between screening, adherence to/participation rates of screening, and how stool DNA testing may fit into an overall screening program are limited. A rescreening interval of every 3 years has been suggested and is approved by the FDA... In addition, there are no or limited data in high-risk individuals, therefore, the use of stool-based DNA/occult blood testing should be individualized. If a result is determined to be a false positive, clinical judgment and shared-decision making should be used (NCCN, 2016). 

In the updated 2016 Screening for Colorectal Cancer guidelines, the United States Preventive Services Task Force (USPSTF) concluded that there is "convincing evidence that screening for colorectal cancer in adults aged 50 to 75 years reduces colorectal cancer mortality." The guidelines authors also noted that "the USPSTF found no head-to-head studies demonstrating that any of these screening strategies are more effective than others, although they have varying levels of evidence supporting their effectiveness, as well as different strengths and limitations". The USPSTF endorses the following options for screening strategies:

Stool based tests:

Endoscopic or radiologic imaging:

Because fecal DNA testing is only one of several average-risk CRC screening options, it is possible that prior to undergoing fecal DNA screening, an individual may have undergone CRC screening using another testing method (for example: colonoscopy, flexible sigmoidoscopy, immunochemical-based testing or CT colonography). When previous screening has been undertaken using an alternative method, then the initial use of the fecal DNA test should be used as a screening technique for individuals at average risk for CRC based on the preceding test's designated next appropriate screening interval. The NCCN guidelines indicate that for average risk individuals who have undergone CRC screening using colonoscopy with negative results (no polyps), the next rescreening using any modality may take place in 10 years (NCCN, 2016).

Re-screening Interval Using Fecal DNA Test for Individuals at Average-risk for Colorectal Cancer

Several organizations have provided guidance with regards to the interval for repeating a negative fecal DNA test in average-risk individuals. The ACS, FDA, NCCN and USPSTF all recommend a rescreening interval of every 3 years for individuals at average risk for CRC who have had a negative fecal DNA test. In the event the fecal DNA test is positive, the individual should undergo a colonoscopy. Fecal DNA testing is not recommended for individuals who are not considered at average-risk for CRC (ACS, 2016a; FDA, 2014a; NCCN, 2016; USPSTF, 2016).

Background/Overview

Description of Colorectal Cancer

According to the American Cancer Society, with the exception of skin cancer, CRC is the third most commonly diagnosed cancer in the United States. CRC is also the third leading cause of cancer deaths in women and the second leading cause of cancer deaths in men in the United States. It has been estimated that approximately 95,000 new cases of colon cancer and 40,000 new cases of rectal cancer will be diagnosed and more than 50,000 Americans will die from CRC in 2017. CRC survival is closely related to the clinical and pathological stage of the disease at diagnosis (ACS, 2016b).

Evidence exists indicating that reductions in CRC morbidity and mortality can be achieved through detection and treatment of early-stage CRCs and the identification and removal of adenomatous colon polyps, the precursors of CRC. CRC 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 CRC. FOBT is a simple exam used to look for blood from bleeding polyps in the stool. FIT uses antibodies directed against human hemoglobin to expose blood in the stool. Sigmoidoscopy looks for polyps and cancer in the lower portion of the colon, known as the sigmoid colon. Colonoscopy is a similar procedure to inspect the entire colon for polyps and cancer. During both of these scope procedures, any polyps found can be removed and tumors biopsied. Colonoscopy is considered the gold standard for CRC screening.

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 CRC. The premise for this type of testing is based upon the knowledge that CRC 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, CRC cells slough off from the main tumor body and are expelled from the body in feces.

PreGen-26 and PreGen Plus

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 CRC cells. One test, PreGen-26, detected a mutation in a gene called BAT-26. Mutations in BAT-26 have been associated with CRCs arising in individuals with Lynch Syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), which is a common cause of CRC 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 CRC, including mutations in BAT-26. Additionally, 21 other point mutations in other genes associated with CRC 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 CRC. 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.

ColoSure

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. ColoSure was available thru DNA Direct and LabCorp as a laboratory-developed test; however, this product is no longer offered on the DNA Direct or LabCorp web sites.

Cologuard

The Cologuard test combines stool DNA testing employing a gene amplification technique (to identify low frequency mutations with increased sensitivity for advanced adenomas) with testing of hemoglobin and patterns of DNA methylation. In August 2014, Exact Sciences Inc. received premarket approval from the FDA to begin marketing the Cologuard test kit. According to the FDA premarket approval letter, Cologuard may be used as a screening test for colorectal carcinoma in adults age 50 years or older who are at average-risk for CRC. According to information on the Exact Sciences website, "both false positives and false negatives do occur. In the clinical study of Cologuard, 13% of people without cancer or precancer tested positive." Positive test results based on Cologuard screening should be followed by diagnostic colonoscopy. Cologuard is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in individuals at increased risk for CRC (FDA, 2014a).

Proposed Benefits

It has been proposed that fecal DNA testing may be an alternative to FOBT as a screening test for CRC. While colonoscopy is considered the gold standard screening technique, many individuals are unwilling to undergo this procedure. The data suggest that fecal DNA testing may have 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

There is the possibility that a false positive or a false negative result will occur. False positive results may expose individuals to unnecessary testing and distress. According to the FDA premarket approval letter for Cologuard, any positive results should be followed by diagnostic colonoscopy. A false negative occurs when the sDNA test does not identify colon cancer or precancer even when a colonoscopy identifies the positive result. Following a negative result, the individual should continue participating in a screening program at an interval and with a method appropriate for him or her.

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.

Definitions

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

False negative: A result that indicates a given condition (for example, cancer) is not present when in fact it is.

False positive: A result that indicates a given condition (for example, cancer) is present when in fact it is not.

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.

Screening: Testing in asymptomatic individuals without a history of colorectal polyps or cancer, or inflammatory bowel disease.

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

Surveillance: Follow-up testing for CRC in individuals who have a history of colorectal polyps or cancer, or inflammatory bowel disease.

Coding

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 may be Medically Necessary when criteria are met:

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
Cologuard, Exact Sciences, Inc.
   
ICD-10 Diagnosis  
  All diagnoses

When services are Investigational and Not Medically Necessary:
For the procedure code listed above when criteria are not met.

When services are also Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT  
81479 Unlisted molecular pathology procedure [when specified as stool DNA analysis for colorectal cancer screening other than Cologuard]
   
ICD-10 Diagnosis  
  All diagnoses
   
References

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, W81.
  2. Ahlquist DA, Taylor WR, Mahoney DW, et al. The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol. 2012b; 10(3):272-277.
  3. Ahlquist DA, Zou H, Domanico M, et al. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology. 2012a; 142(2):248-256.
  4. 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.
  5. Heigh RI, Yab TC, Taylor WR, et al. Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT). PLoS One. 2014; 9(1):e85659.
  6. 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.
  7. Imperiale TF, Ransohoff DF, Itkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014; 370(14):1287-1297.
  8. 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.
  9. Itzkowitz SH, Jandorf L, Brand R, et al. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol. 2007; 5(1):111-117.
  10. Lidgard GP, Domanico MJ, Bruinsma JJ, et al. Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia. Clin Gastroenterol Hepatol. 2013; 11(10):1313-1318.
  11. Lin JS, Piper MA, Perdue LA, et al. Screening for colorectal cancer: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016; 315(23):2576-2594.
  12. Redwood DG, Asay ED, Blake ID, et al. Stool DNA testing for screening detection of colorectal neoplasia in Alaska Native people. Mayo Clin Proc. 2016; 91(1):61-70.
  13. 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.
  14. 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 Cancer Society. Colorectal cancer prevention and early detection. American Cancer Society recommendations for colorectal cancer early detection (2016a). Last revised 06/24/2016. Available at: http://www.cancer.org/cancer/colonandrectumcancer/moreinformation/colonandrectumcancerearlydetection/colorectal-cancer-early-detection-acs-recommendations. Accessed on January 10, 2017.
  2. American Cancer Society. Colorectal cancer. What is colorectal cancer? Key statistics for colorectal cancer (2016b). Last revised 01/20/2016. Available at: http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-key-statistics. Accessed on January 10, 2017.
  3. Blue Cross Blue Shield Association. Special report. Fecal DNA analysis for colon cancer screening. TEC Assessment, 2014; 29(8).
  4. Centers for Medicare and Medicaid Services. Decision memo for screening for colorectal cancer - Stool DNA testing (CAG-00440N) 2014. Available at: http://www.cms.gov/. Accessed on January 10, 2017.
  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.
  6. Lin JS, Webber EM, et al. Fecal DNA Testing in screening for colorectal cancer in average-risk adults. [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012. Available at: https://www.ncbi.nlm.nih.gov/books/NBK91369/ . Accessed on January 10, 2017.
  7. National Cancer Institute (NCI). Colorectal Cancer (PDQ® ): Screening (health professional version). Summary of evidence. Updated September 19, 2014. Available at: http://www.cancer.gov/. Accessed on January 10, 2017.
  8. NCCN Clinical Practice Guidelines in Oncology™. © 2016 National Comprehensive Cancer Network, Inc. Colorectal cancer screening. V2.2016. Revised October 20, 2016. For additional information visit the NCCN website: http://www.nccn.org.index.asp. Accessed on January 10, 2017.
  9. 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.
  10. U.S. Food and Drug Administration (FDA). Center for Devices and Radiological Health (CDRH). Premarket approval letter. Cologuard. 2014a. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130017a.pdf. Accessed on January 10, 2017.
  11. U.S. Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH). Stool DNA-based colorectal cancer screening test. Cologuard (Exact Sciences Corp., Madison, WI). Summary of Safety and Effectiveness. No. P130017. 2014b. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130017b.pdf. Accessed on January 10, 2017.
  12. U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. JAMA 2016; 315(23):2564-2575.
  13. Whitlock EP, Lin J, 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(9):638-658.
  14. Winawer S, Fletcher R, Rex D, et al. Gastrointestinal Consortium Panel. Colorectal cancer screening and surveillance: clinical guidelines and rationale – Update based on new evidence. Gastroenterology 2003; 124(2):544-560.
Websites for Additional Information
  1. National Cancer Institute. Colorectal Cancer Screening (PDQ® ) (Patient). Updated November 18, 2016. Available at: http://www.cancer.gov. Accessed on January 10, 2017.
Index

Colorectal Cancer Screening
Cologuard
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.

Document History
Status Date Action
Revised 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Revised Medically Necessary Position Statement to clarify that Cologuard is a screening test for individuals at average risk for colorectal cancer. Added Medically Necessary Position Statement to address the appropriate screening interval in instances where an alternative colorectal cancer screening method had been used prior to switching to the Cologuard test. Updated review date, Rationale, Background/Overview, References and History sections.
Revised 02/04/2016 MPTAC review. In the position statements, changed the word "colon" to "colorectal". Updated review date, Rationale, References and History sections.
  01/01/2016 Updated Coding section with 01/01/2016 CPT and HCPCS changes, removed G0464 and S3890 deleted 12/31/2015; also removed ICD-9 codes.
Revised 02/05/2015 MPTAC review. The word "surveillance" was removed from the title of the document. Added medically necessary indication for the Cologuard test. Revised investigational and not medically necessary statement. Revised position statements were finalized in a follow-up vote on 03/04/2015. Additional position statement added to indicate all other methods for the analysis of DNA in stool samples are considered investigational and not medically necessary. Updated review date, Rationale, Background/Overview, Coding and References sections.
  01/01/2015 Updated Coding section with 01/01/2015 HCPCS changes.
Reviewed 05/15/2014 MPTAC review. Updated review date, Rationale and References sections.
Reviewed 05/09/2013 MPTAC review. Updated review date, Rationale and References sections.
Reviewed 05/10/2012 MPTAC review. Updated review date, Rationale, References and History sections.
Reviewed 05/19/2011 MPTAC review. Updated review date, References and History sections.
Reviewed 05/13/2010 MPTAC review. Updated review date, References and History sections. Updated the Rationale section to specifically address the ColoSure test. In Description section, added note cross-referencing other documents related to colon cancer.
Reviewed 05/21/2009 MPTAC review. Updated review date, Rationale, References and History sections.
Reviewed 05/15/2008 MPTAC review. Updated review date, Rationale, References and History sections.
Reviewed 02/21/2008 MPTAC review. Updated review date, References and History sections. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Revised 03/08/2007 MPTAC review. Revised Position Statement to remove brand names and language regarding colon cancer risk stratification. Rationale and References sections updated. Document re-categorized (changed from LAB.00008 to GENE.00008).
Reviewed 03/23/2006 MPTAC review.
Revised 04/28/2005 MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations Last Review Date Document Number Title

Anthem, Inc.

 

10/27/2004 LAB.00008 Analysis of Fecal DNA for Colorectal Cancer
WellPoint Health Networks, Inc. 03/01/2004 2.11.16 Analysis of Human DNA in Stool as a Technique for Colorectal Cancer Screening