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Fecal DNA testing — a new threat to screening colonoscopy?

Thomas Rösch, Hamburg and Michael Bretthauer, Oslo

The New England Journal of Medicine

Multitarget Stool DNA Testing for Colorectal-Cancer Screening
Thomas F. Imperiale, M.D., David F. Ransohoff, M.D., Steven H. Itzkowitz, M.D., Theodore R. Levin, M.D., Philip Lavin, Ph.D., Graham P. Lidgard, Ph.D., David A. Ahlquist, M.D., and Barry M. Berger, M.D.

Background

An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening.

Methods

We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings.

Results

Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT.

Conclusions

In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; ClinicalTrials.gov number, NCT01397747.)

What you need to know

Fecal tests have increasingly moved on from the classic fecal occult blood test (FOBT) to fecal immunologic testing (FIT), particularly in countries with newly introduced screening programs such as the Netherlands (1–5). The search is of course not only for carcinomas (in the early stage if possible), but also for colorectal adenomas. Advanced adenomas (< 1 cm, with villous components, high-grade dysplasias) are the most important and are also used as assessment parameters in many studies. In one study conducted before it was introduced, the level of acceptance for FIT was surprisingly higher than that for FOBT (61.5% vs. 49.5%), on the one hand. On the other, the yield for advanced adenomas was also higher (2.4% vs. 1.1%) (5). However, the performance of various FIT tests is highly varied (6–8). In the Netherlands, what is known as the OC Sensor Test is used (Eiken Chemical, Tokyo); in the study examined here, the OC FIT-CHEK test was used (Polymedco, Cortland Manor, New York). In Germany, the OC Sensor Test was compared with two other FIT tests, without any substantial differences being found between them (sensitivity for advanced adenomas 20–25%, specificity 95–97%) (10).

A fecal DNA test that was presented several years ago (12, 13) has now been tested in a large American study (14) in comparison with FIT, with colonoscopy as the gold standard. Overall, more than 12,000 individuals were included in the study, with 9989 ultimately included in the analysis; 65 had carcinomas on colonoscopy, 757 had advanced adenomas, and 2893 had adenomas that were not advanced and therefore usually small. In 6274 participants, nothing was found. The patients had to provide fecal samples before colonoscopy preparation (without dietary limitations). The gold standard was screening colonoscopy in each case, which in 90% of cases had been carried out within nearly the previous 18 months.

The results (14) show, with a limited number of carcinomas (n = 65), a sensitivity of 92%, and for advanced adenomas 42%; these values were approximately 20% superior to those with the FIT test. The specificity was 87%, and thus slightly poorer than FIT (95%). The detailed figures were as follows:

Sensitivity for n Fecal DNA FIT
Carcinoma 65 92.3% 73.8%
Stage I–III carcinomas 60 93.3% 73.3%
Carcinoma and HGD 104 83.7% 63.5%
Advanced adenomas 757 42.4% 23.8%
Non-advanced adenomas 2893 17.2% 7.6%
Specificity for
Normal colonoscopy 4457 89.8% 96.4%
Normal colonoscopy + non-adv. adenomas 9167 86.6% 94.9%

Limitations of the study include a certain element of patient selection and the unclear practicability of the test and acceptance for it. Uptake studies are certainly needed. Overall, out of an initial 12,766 individuals who provided informed consent, 1760 were excluded because consent was withdrawn or no colonoscopy was actually carried out. A total of 689 were excluded due to technical problems in collecting or analyzing the fecal samples (6.2%); the extent to which this would reflect possible everyday conditions later is unclear. A further 304 patients were excluded due to incomplete colonoscopy or colonoscopy without good preparation (2.8%), and in 34 cases the FIT test did not function. Overall, therefore, there was positive selection in relation to the research aims. Samples for fecal DNA assessment have to be supplied in a relatively large box (about the size of a shoe box), so that screening programs that require postage methods are currently still a challenge. Further studies, particularly in relation to acceptance and uptake, are needed in order to show whether this test could be incorporated into colon screening in everyday conditions. It certainly does not replace colonoscopy, but a good and practicable filter test will eventually reduce colonoscopies to mainly therapeutic procedures, while at the same time potentially increasing the numbers due to greater acceptance of this type of screening test. Blood tests are currently not yet a reality for widespread application (15).

References

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