TEC Assessment Index

Special Report: Fecal DNA Analysis for Colon Cancer Screening*

Assessment Program
Volume 21, No. 6
August 2006

Executive Summary

Background
Various methods for screening for colorectal cancer in persons at average risk are available. Highly effective methods (e.g., colonoscopy) are invasive and costly, and would require greater capacity within the healthcare system than currently exists to screen all adults over 50 years of age. Low-cost, noninvasive methods (e.g., fecal occult blood testing or FOBT) have been shown to be effective at reducing mortality from colorectal cancer, but have much poorer sensitivity for neoplasia than colonoscopy, and required sample collection procedures may reduce compliance. New methods of screening that are noninvasive, highly sensitive, and patient friendly would be ideal. Fecal DNA testing has been proposed as an alternative screening method.

Objective
This Special Report will provide information relevant to the evaluation of fecal DNA screening for colon cancer in asymptomatic patients at average risk. This report will summarize:

• the current context of existing and emerging screening tests for colorectal cancer, including current published recommendations;
• the molecular basis for fecal DNA screening and the commercially available fecal DNA screening test, PreGen-Plus™;
• direct and indirect evidence comparing the performance of PreGen-Plus™ testing to other methods of colon cancer screening;
• evidence regarding the likelihood of compliance with fecal DNA screening; and
• available cost-effectiveness analyses of fecal DNA screening.

Methods
MEDLINE® (via PubMed) was searched through June 2006, using the following search terms: "(neoplas* OR cancer) AND (fecal DNA OR stool DNA OR (stool AND DNA))." Selected studies were fully published in a peer-reviewed journal; publicly available, FDA-reviewed information was also acceptable. Studies were selected as evidence if they reported:

• analytical performance characteristics of fecal DNA assays;
• clinical performance, specifically the results of prospective studies that targeted an average-risk screening population, compared fecal DNA to a currently accepted screening method (per USPSTF guidelines), and administered colonoscopy to all patients;
• patient preferences or compliance for fecal DNA tests compared to conventional
  screening tests; or
• cost-effectiveness of fecal DNA testing versus conventional methods.

Results
In a prospective, multicenter screening study of 5,486 asymptomatic, average-risk individuals, all of whom received colonoscopy, 80% of participants completed all tests adequately. For these evaluable participants, fecal DNA sensitivity for cancer was 52% versus 13% for conventional FOBT. Sensitivities for large adenomas for both tests were similar at 11–15%; specificities of the two tests were also similar.

Although this study was well designed, it also has several limitations including an older test methodology no longer used in the PreGen-Plus™ commercial version, a loss of 20% of enrolled participants from evaluation, unusually low FOBT sensitivity (evidence from other large screening trials suggest sensitivity in the range of 30–40%), and no improvement in detection of large adenomas. Sources of false-positive results are also not yet well understood and the optimal screening interval is unknown. A newer version of this assay, using different markers, was recently presented at Digestive Disease Week 2006 and suggests improved sensitivity for cancer in highly selected patients; sensitivity for large adenomas was not reported in the abstract.  Information on the performance of this new assay in a screening population will be needed.

In the multicenter screening study, the percentage of noncompliant participants was 12% for fecal DNA analysis versus 8% for FOBT (p<0.001). These results suggest that participants preferred FOBT testing, but it is unclear whether these numbers reflect only compliance or also include problems with obtaining sufficient DNA from supplied samples. In contrast, a questionnaire returned by 84% of all evaluable participants indicated that the preferred screening test was fecal DNA for 45% of respondents, FOBT for 32%, and colonoscopy for 15%. Additional evidence is needed to determine patient compliance with various tests in clinical practice.

Two studies using the same cost-effectiveness model and testing various assumptions found that fecal DNA testing is nearly always dominated by conventional testing strategies. Assuming sensitivities for cancer and large adenoma of 65% and 40%, respectively, and specificity of 95%, the screening interval would have to be 2 years (current recommendation 5 years) and the cost of fecal DNA testing $195 (currently $400–500) to make fecal DNA comparable with colonoscopy.

Conclusions
Fecal DNA testing is a noninvasive colorectal cancer screening technology that may eventually offer sensitivity for cancer closer to that of colonoscopy than that of conventional, guaiac-based FOBTs. Although the impact of fecal DNA screening on cancer morbidity and mortality has not yet been studied, it seems reasonable to assume that attaining sensitivities equal to or better than that of FOBT would result in similar or improved outcomes. However, several questions remain before fecal DNA screening can be widely recommended:

• Can sensitivity for large adenoma be significantly increased compared to FOBT?
• Can false-positive rates be maintained appropriately low for a screening program?
• What is the final configuration of the PreGen-Plus™ test and what are its published
• performance characteristics in an average-risk screening population?
• What is the optimal screening interval?
• Which patients should not be screened with fecal DNA testing?
• Does the test improve compliance with colorectal cancer screening?
• Is the test cost-effective?

* This Special Report evaluates the available evidence on fecal DNA testing. It does not address whether the TEC criteria are met so that the evidence can be examined in the broader context of conventional and other emerging screening tests, published recommendations, patient compliance, and cost-effectiveness. 

TEC Assessment Index

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