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MP 2.04.29 Analysis of Human DNA in Stool Samples as a Technique for Colorectal Cancer Screening

Medical Policy    
Section
Medicine
 
Original Policy Date
10/08/02
Last Review Status/Date
Reviewed with literature search/11:2012
Issue
11:2012
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

Detection of genetic abnormalities associated with colorectal cancer in stool samples has been proposed as a screening test for colorectal cancer. This technology is another potential alternative to currently available screening approaches such as fecal occult blood testing or colonoscopy.

Several genetic alterations have been associated with colorectal cancer. In the proposed multistep model of carcinogenesis, the tumor suppressor gene p53 and the proto-oncogene K-ras are most frequently altered. Mutations in APC (adenomatous polyposis coli) genes and epigenetic markers (e.g., hypermethylation of specific genes) have also been detected. Colorectal cancer is also associated with DNA replication errors in microsatellite sequences (termed microsatellite instability or MSI) in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and in a subgroup of patients with sporadic colon carcinoma. Tumor-associated gene mutations and epigenetic markers can be detected in exfoliated intestinal cells in stool specimens. Since cancer cells are shed into stool, tests have been developed that detect these genetic alterations in the DNA from shed colorectal cancer cells isolated from stool samples. This has been proposed for use in screening two populations of patients for colon cancer:

1. Known or suspected carriers of HNPCC mutations, considered at high risk of developing colorectal cancer.

In this setting, testing of fecal samples could be used to monitor patients over time for development of colorectal cancer. The test could be used either in lieu of routinely scheduled surveillance colonoscopies or during intervals between scheduled colonoscopies. Those patients testing positive for cancer-related genetic alterations could be further evaluated with colonoscopy.

2. In patients at average risk of colorectal cancer

In this setting, testing of fecal samples could be offered in lieu of, or as an adjunct to, other recommended colorectal cancer screening tests, including fecal occult blood testing, flexible sigmoidoscopy, colonoscopy, or double contrast barium enema.

Several types of tests have been evaluated in studies and some have been marketed. One of these, PreGen-Plus™, tests for 21 different mutations in the p53, APC, and K-ras genes; the BAT-26 MSI marker; and incorporates the DNA Integrity Assay (DIA®). PreGen-Plus™ has not been cleared by the U.S. Food and Drug Administration (FDA). Although the scientific studies that are the basis of the PreGen-Plus™ test were conducted or funded by EXACT Sciences, LabCorp is identified as the test developer. LabCorp is regulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 and is certified as qualified to perform high-complexity testing. As a result, LabCorp may develop tests in-house and offer them as laboratory services (i.e., laboratory-developed tests). Historically, the FDA has not regulated laboratory-developed tests. However, on January 13, 2006, the FDA sent correspondence to LabCorp indicating that PreGen-Plus™ may be subject to FDA regulation as a medical device. As a consequence, and as a result of studies showing better performance of other tests, this test is no longer offered.

The currently available test is called ColoSure™, developed by OncoMethylome, which detects aberrant methylation of the vimentin (hV) gene. This test is offered as a laboratory-developed test, not subject to FDA regulation.


Policy

DNA analysis of stool samples is considered investigational as a screening technique for colorectal cancer in both patients with average to moderate risk, and in patients considered at high risk for colorectal cancer.


Policy Guidelines

The CPT coding for DNA analysis of stool samples will consist of a number of CPT codes describing the individual steps in the DNA analysis. These codes may vary according to which and how many DNA markers are tested. Individual codes may be used multiple times if more than one marker is tested for as part of a panel of markers. The following codes may be used:

Molecular diagnostics;

83890: molecular isolation or extraction, each nucleic acid type (i.e., DNA or RNA)

83891: isolation or extraction of highly purified nucleic acid, each nucleic acid type (i.e., DNA or RNA)

83892: enzymatic digestion, each nucleic acid type (i.e., DNA or RNA)

83894: separation by gel electrophoresis, each nucleic acid preparation*

83896: nucleic acid probe, each*

83898: amplification, target, each nucleic acid sequence*

83904: mutation identification by sequencing, single segment, each segment*

83907: lysis of cells prior to nucleic acid extraction (e.g., stool specimens, paraffin embedded tissue), each specimen

83912: interpretation and report

*These CPT codes are reported multiple times as part of a single panel of tests.

The LabCorp website currently lists the coding for ColoSure™ as follows:

83891; 83894(x2); 83898(x2); 83907; 83912

There is a HCPCS “S” code specific to this testing:

S3890: DNA analysis, fecal, for colorectal cancer screening.


Benefit Application

BlueCard/National Account Issues

Benefit/contractual restrictions regarding preventive medicine may apply when testing is performed as part of a screening test.


Rationale

As with any diagnostic test, the key outcomes are the diagnostic performance (i.e., sensitivity, specificity, positive and negative predictive value) compared to a gold standard, and consideration of how the results of the test will be used to benefit patient management. Of the various screening options (fecal occult blood testing, flexible sigmoidoscopy, double contrast barium enema, colonoscopy), colonoscopy is considered the gold standard. For example, in patients considered at high risk for colorectal cancer, due either to a family history or hereditary nonpolyposis colorectal cancer (HNPCC) mutation, colonoscopy at varying intervals is recommended by the American Society of Colorectal Surgeons, the American Gastroenterological Society, and the American Cancer Society. (1) Therefore, for patients at high risk of colorectal cancer with suspected or known mutations of the HNPCC gene, the diagnostic performance of DNA analysis of stool samples will be compared with colonoscopy. In addition, the role of DNA analysis in the context of the recommended colonoscopic screening must be explored. Will this test be offered in lieu of colonoscopy, such that patients with a negative test can defer a scheduled colonoscopy, or will this test be offered as an adjunct to colonoscopy screening, for example during the intervals between colonoscopies?

For patients at average to moderate risk for colorectal cancer, these organizations also recommend colonoscopy starting at age 50 years, with an interval of 10 years, as one screening option. In addition, other screening techniques are also considered options, and the choice of screening option may be dictated in part by patient preference. Many authors have noted the low patient acceptance of current colorectal cancer screening options, particularly flexible sigmoidoscopy and colonoscopy; at the present time, only approximately 40% of eligible patients undergo screening for colon cancer. Advocates of genetic testing of stool samples have hypothesized that the relative simplicity of collecting a stool sample might increase the overall compliance with screening recommendations. Therefore, for patients at average to moderate risk of colon cancer, genetic testing of stool samples will be compared to colonoscopy and also to fecal occult blood testing, the other entirely noninvasive technique. Patient acceptance of the different options is also a relevant outcome as a technique to increase screening compliance.

Literature Review

No clinical trials have been published that evaluate use of DNA stool tests in those at high risk for colon cancer.

The largest study of those at average risk for colon cancer is that of Imperiale and colleagues who reported on the results of a prospective trial of 5,486 enrolled subjects. (2) However, this study evaluates a test that is no longer available and that uses completely different DNA markers than the Colosure™ test. Thus, the results do not represent the performance of the Colosure™ test. It is worth reviewing here because it is the central piece of evidence used by some organizations to endorse such screening.

Subjects underwent fecal occult blood testing (FOBT), fecal DNA analysis using a precommercial version of the test, and colonoscopy, considered the gold standard for this trial. Of the 5,486 enrolled, 4,404 completed all aspects of the study and, from this group, 2,507 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% versus 14.1%, respectively. Specificity in subjects with a negative finding on colonoscopy was 94.4% for fecal DNA and 95.3% for FOBT. This study is the first large study of fecal DNA testing in an asymptomatic average-risk population. The following limitations are noted:

  • The Imperiale et al. study is not an intention-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 that “the difference between our results (on Hemoccult sensitivity) and those of other reports is potentially important and deserves further study.”
  • 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.

However, the results of this study suggest that fecal DNA analysis offers an improved sensitivity, and thus the question arises as to whether fecal DNA should be considered an alternative to FOBT for patients who are unwilling to undergo, or do not have access to, colonoscopy. The authors comment on the large percentage of patients who forego recommended screening for colorectal cancer, particularly the gold standard of colonoscopy, and propose that a simple noninvasive screening test with an improved sensitivity compared to FOBT would be a viable alternative.

These issues are addressed in an accompanying editorial by Woolf, who urges caution in interpreting the results of the Imperiale et al. study. (3) 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. Fecal DNA testing does provide some advantages in that, unlike FOBT, the patient does not have to undergo a specialized diet prior to the test. However, the patient must collect, refrigerate, and mail an entire bowel movement, which may be unacceptable to some patients. Woolf suggests that increasing screening rates is an important outcome but one that may be achieved by improving the accessibility and delivery of current screening methods.

Subsequently, Schroy and Heeren conducted a study of patient perceptions of stool-based DNA testing of those participating in the Imperiale et al. study. (4) A total of 4,042 subjects completed the survey, an 84% response rate. The survey consisted of 25 questions using a 5-point ordinal scale or a yes/no format. Stool-based testing received the same or higher mean ratings as fecal occult blood, and higher ratings than colonoscopy, except for perceived accuracy.

Published evidence on the currently available Colosure™ test is relatively slim. Two studies allow calculation of the performance characteristics of the hypermethylated vimentin (hV) gene alone. In a study by Itzkowitz et al., separately assembled groups of patients with colorectal cancer (n=40) and patients with normal colonoscopy (n=122) were tested with hV. (5) Sensitivity was 72% and specificity was 87%. In a second study by Itzkowitz et al., separately assembled groups of patients with colorectal cancer (n=82) and patients with normal colonoscopy (n=363) were tested with hV and a two-site DNA integrity assay. (6) The purpose of the study was to calculate diagnostic performance characteristics of this combined test, but the results are also presented for hV alone. Using data-derived cut off values, the sensitivity for cancer was 77% and the specificity was 83%. Other studies of hypermethylated vimentin using different assays have shown sensitivities of 38% and 41% for detecting colorectal cancer (Baek et al., 2009, Li et al., 2009). (7,8)

None of these studies is adequate to evaluate a test that is to be used in the screening setting. The study samples are enriched with cancer cases that may not represent the prevalence or spectrum of disease present in a screening situation. The sensitivity and specificity values calculated from these studies should not be generalized to actual clinical populations. Patients with any other clinically relevant abnormalities such as polyps have been excluded from many of the studies. The cut off values have been determined post hoc by examining the data.

Another study by Ahlquist et al., evaluated a screening test in which one component of the test was hV. (9) However, hV was only 1 of 3 different types of markers used in this multicomponent test. Data were not analyzed separately for hV, thus the results of this study do not represent the performance of hV alone. In addition, normal patients were not tested, meaning that specificity could not be calculated. Without knowing what the corresponding specificity is, the sensitivity of a test is uninformative because it can be manipulated by simply changing the cut off value for a positive test.

A next-generation stool test has been developed by EXACT Sciences and has been evaluated in a study by Ahlquist et al. (10) This test detects 4 methylated genes, a mutant form of KRAS, and the alpha-actin gene. In a study of 252 patients with colorectal cancer, 133 patients with adenomas >= 1 cm, and 293 subjects with normal colonoscopy, the test detected 85% of colon cancer cases and 54% of subjects with adenomas, with 90% specificity. Another smaller study of this same test showed a sensitivity of 87% for detecting colorectal cancer and 82% sensitivity for detecting adenomas. (11) This test is not yet commercially available. The test characteristics need to be evaluated in a prospective manner in general population samples, rather than predefined cancer cases and normal controls.

Summary

The evidence on the accuracy of stool DNA as a screening test for colorectal cancer consists of a number of studies that have compared stool DNA analysis to colonoscopy. The largest study was done with a test that is no longer commercially available, and the evidence on the commercially available test is limited to smaller studies. These studies report a low to moderate sensitivity and a high specificity for the test. The sensitivity varies widely in the available studies and the evidence is not sufficient to determine the true sensitivity of the test. A new test that uses next generation sequencing technology has reported a higher sensitivity, but prospective studies are lacking and this test is not yet commercially available. In addition to uncertainty about the diagnostic accuracy of the test, clinical utility of this test has not yet been demonstrated since there is no evidence that this test improves outcomes. As a result, analysis of DNA in stool samples is considered investigational as a screening technique for colorectal cancer.

Clinical Practice Guidelines and Consensus Recommendations

Recommendations of specialty organizations regarding fecal DNA testing largely base their statements on the study by Imperiale et al. summarized previously, which used a different test than the currently offered Colosure™ test.

The U.S. Preventive Services Task Force updated their guidelines for colon cancer screening in 2008. (8) Fecal DNA testing was judged to have insufficient evidence to assess the benefits and harms of testing for all populations. They limited their evidence review to only 1 study, (9) the previously summarized study by Imperiale et al. (2)

Updated guidelines for colon cancer screening were also issued in 2008 by a group consisting of the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. (10) This guideline endorses the use of fecal DNA testing as an acceptable means of colon cancer screening. However, unlike all the other recommendations in this guideline that recommended specific time intervals between tests, the recommended interval for fecal DNA testing is “uncertain.” The document notes that the manufacturer of the 1 commercially available test recommends a 5-year interval after an examination with normal results. Such an interval was judged by the committee to be only suitable for a test that has high sensitivity for both cancer and adenomatous polyps—a standard that has not been documented for fecal DNA to date. The evidence supporting the joint guideline consisted of the previously summarized study by Imperiale et al., (2) and additional older studies of diagnostic performance that did not use screening populations but used previously diagnosed or advanced cancer patients.

 References:

  1. National Guideline Clearinghouse. Available online at: www.guidelines.gov . Last accessed December 2010.
  2. Imperiale TF, Ransohoff DF, Itzkowitz SH et al. Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average risk population. N Engl J Med 2004; 351(26):2704-14.
  3. Woolf SH. A smarter strategy? Reflections on fecal DNA screening for colorectal cancer. N Engl J Med 2004; 351(26):2755-8.
  4. Schroy PC, Heeren TC. Patient perceptions of stool-based DNA testing for colorectal cancer screening. Am J Prev Med 2005; 28(2):208-14.
  5. Itzkowitz SH, Jandorf L, Brand R et al. Improved fecal DNA test for colorectal cancer screening. Clin Gastroenterol Hepatol 2007; 5 (1):111-7.
  6. Itzkowitz S, Brand R, Jandorf L et al. A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol 2008; 103(11):2862-70.
  7. Baek YH, Chang E, Kim YJ et al. Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients. Dis Colon Rectum 2009; 52(8):1452-9.
  8. Li M, Chen WD, Papadopoulos N et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 2009; 27(9): 858-63.
  9. 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):441-50
  10. Ahlquist DA, Zou H, Domanico M et al. Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 2012; 142(2):248-56.
  11. 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 2012; 10(3):272-7.
  12. U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 149(9):627-37.
  13. Whitlock EP, Lin JS, Liles E et al. Screening for colorectal cancer: a targeted, updated systematic review for the US Preventive Services Task Force. Ann Intern Med 2008; 149(9):638-58.
  14. 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):130-60. Available online at: http://caonline.amcancersoc.org/cgi/reprint/58/3/130. Last accessed November 2008.

 

Codes

Number

Description

CPT    See Policy Guidelines section 
HCPCS S3890 DNA analysis, fecal, for colorectal cancer screening 
ICD-9 Diagnosis    Investigational for all codes
ICD-10-CM (effective 10/1/14)     Investigational for all diagnoses  
   C18.0-C18.9 Malignant neoplasm of colon code range  
   C19 Malignant neoplasm of rectosigmoid junction  
   Z12.10-Z12.13 Encounter for screening for malignant neoplasm of intestinal tract code range  
   Z15.09 Genetic susceptibility to other malignant neoplasm  
  Z80.0 Family history of malignant neoplasm of digestive organs  
ICD-10-PCS (effective 10/1/14)     Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. 
Type of Service  Oncology 
Place of Service  Outpatient 


Index

Analysis of Human DNA in Stool Samples
DNA Analysis, Stool Sample
Pre-Gen


Policy History

Date Action Reason
10/08/02 Add to Medicine section New policy
10/9/03 Replace policy Literature review update; added findings from the ACS and the AGA; policy statement unchanged
04/1/05 Replace policy Policy updated with literature search; policy statement unchanged, reference numbers 6 and 7 added
04/25/06 Replace policy Policy updated with literature search; policy statement unchanged. Rationale revised to focus on larger Imperiale study. Reference numbers 2–5 deleted, reference number 4 added
10/10/06 Replace policy Policy updated with TEC Special Report and literature search; no change in policy statement. Information about regulatory review added to description. Reference number 7 added. S code added.
09/18/07 Replace policy Policy updated with literature search, policy statement unchanged. Reference numbers 8 and 9 added.
12/11/08 Replace policy  Policy updated with literature search; no change in policy statement. Reference numbers 10-13 added
12/10/09 Replace policy Policy updated with literature search; no change to policy statement. Reference number 5 added
12/09/10 Replace policy Policy updated with literature search; no change to policy statement. Reference number 5 added
11/10/11 Replace policy Policy updated with literature search; Rationale extensively revised and focused on the commercially available test (Colosure™). References 5-7 added. No change to policy statement
11/08/12 Replace Policy Policy updated with literature review; references 7, 8, 10, 11 added. No change to policy statement