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Clinical Trial Indicates High Sensitivity for Exact Sciences DNA-based Colorectal Cancer Screening Test

NEW YORK (GenomeWeb News) – Researchers reported in the New England Journal of Medicine this week that, in a clinical study, a DNA-based colorectal cancer screening test was better able to detect instances of cancer than a standard immunochemical test.

The test, Exact Sciences' Cologuard, examines DNA methylation markers, mutation markers, and more in combination with hemoglobin levels in patients' stool samples to determine the presence of colorectal cancer.

For the study, the researchers, led by Exact Sciences' Barry Berger, compared this test to one-time use of a fecal immunochemical test (FIT) for hemoglobin in a cohort of nearly 10,000 people who had an average cancer risk.

As they reported in NEJM, the Cologuard test had a 92.3 percent sensitivity for detecting colorectal cancer, while FIT had a 73.8 percent detection sensitivity.

"The most important finding of the study is the high sensitivity of Cologuard for curable stage colorectal cancer, which represents the highest sensitivity of any noninvasive test to date," Thomas Imperiale, a professor of medicine at Indiana University Medical Center and study author, said in a statement.

However, the Cologuard test had a higher false positive rate, and, as an accompanying editorial in NEJM from the Geisel School of Medicine's Douglas Robertson and the University of Washington School of Medicine's Jason Dominitz noted, a higher technical failure rate.

In this study, which was funded by Exact Sciences, Berger and his colleagues evaluated the test as a screening tool to detect colorectal cancer as well as its ability to uncover precancerous lesions in relation to the FIT hemoglobin test.

According to Exact Sciences, the test relies on Quantitative Allele-specific Real-time Target and Signal amplification technology to detect DNA molecular markers in stool samples that contain cells shed from the colon wall. The test searches for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and β-actin, a reference gene used to indicate DNA quantity.

QuARTS uses both DNA amplification and invasive cleavage to give simultaneous target and signal amplification, and is run using a real-time thermocycler. That data is then combined with the hemoglobin assay result to produce a positive or negative result.

The trial, also known as the DeeP-C study, included 9,989 asymptomatic participants between the ages of 50 years and 84 years old who were at average risk for developing colorectal cancer. All participants gave stool samples for Cologuard and FIT testing and underwent colonoscopies.

Based on colonoscopy, 65 study participants were found to have colorectal cancer, 60 of whom had "screening-relevant" — or stage I through stage III — cancers, and 757 participants had advanced precancerous lesions.

The Cologuard test identified 60 of those 65 participants with colorectal cancer, the researchers reported, for a 92.3 percent sensitivity, and could detect 321 of the 757 precancerous lesions, a specificity rate of 42.4 percent.

By comparison, FIT detected 48 of those 65 cancers, for a specificity of 73.8 percent, and 180 of the 757 advanced cancerous lesions, a specificity of 23.8 percent.

The researchers argued that sensitivity is the key characteristic for screening tests as such tests aim to rule out disease, though they noted that specificity is important as it affects the number of false positive reports.

FIT, they reported, had a higher specificity, 94.9 percent, than the DNA test, 86.6 percent, and a corresponding lower rate of false positives, 3.6 percent as compared to 10.2 percent.

"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," the researchers said.

Berger and his colleagues noted that the specificity calculation included people with non-advanced adenomas, which they said could give positive results, in addition to those with a negative colonoscopy result. Also, they said that specificity was inversely correlated with age, suggesting lesions might have been missed by colonoscopy or that it is affected by age-related methylation.

They also calculated that 166 people would need to be screened with Cologuard to detect one colorectal cancer case, as compared to 208 with FIT, and 31 people would need to be screen with Cologuard or 55 with FIT to detect one advanced precancerous polyp. "These calculations show that multitarget DNA testing detected clinically significant lesions more efficiently than FIT," the researchers added.

Robertson and Dominitz, in their accompanying editorial, wrote that this test is better than its predecessors, but added that this study comes with a few caveats that need to be taken into consideration when weighing and developing the test as a screening tool.

For instance, they noted the multitarget DNA test had a higher technical failure rate than FIT, 6.3 percent as compared to 0.3 percent. They estimated that as many as four cancers may have been missed due to the complexity of the test. The false positive rate, they added, would also be an important consideration when determining how often people should undergo screening.

Additionally, DNA testing, Robertson and Dominitz said, likely wouldn't be used in the same way as FIT in the clinic, due to that complexity as well as its expense, and while it has been suggested that stool DNA screening may be preferred over other screening methods, this hasn't been tested in practice.

Before adding it to the roster of screening tools, they argued for comparative effectiveness studies.

"Only through a better understanding of other key factors, such as the screening interval, adherence, cost, and diagnostic evaluation of positive results, can we determine the appropriate place for stool DNA testing on the screening menu," they said.

Exact Sciences is in the process of seeking US Food and Drug Administration approval for the use of Cologuard for colorectal cancer screening. The FDA Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee is scheduled to review the premarket approval application for Cologuard next week.

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