Noninvasive Screening Tests Show Promise for Catching Colorectal Cancer

Two noninvasive screening tests appeared to be effective in detecting colorectal cancer in an average-risk population, two trials suggested.

In the BLUE-C trial, a next-generation multi-target stool DNA test was more likely to detect colorectal cancer compared with standard fecal immunochemical testing (FIT), with a sensitivity of 93.9% versus 67.3%, as well as advanced precancerous lesions (43.4% vs 23.3%), reported Thomas F. Imperiale, MD, of Indiana University School of Medicine in Indianapolis, and colleagues in the New England Journal of Medicine (NEJM).

Specificity for advanced neoplasia was 90.6% with the next-generation test, which was an improvement over the current multi-target stool DNA test, but was lower than the 94.8% specificity of the FIT test.

Results from the ECLIPSE trial, also published in NEJM, showed that a cell-free DNA (cfDNA) blood-based test had a sensitivity of 83.1% for colorectal cancer and a specificity of 89.6% for advanced neoplasia, reported William M. Grady, MD, of the Fred Hutchinson Cancer Center in Seattle, and colleagues.

“The lower boundaries of the 95% confidence intervals for sensitivity for colorectal cancer and specificity for advanced neoplasia met the prespecified acceptance criteria as established in other FDA-approved screening tests for colorectal cancer,” Grady and team wrote.

The authors of both studies noted that while asymptomatic screening reduces the incidence of colorectal cancer and related deaths and is recommended by multiple professional societies, colorectal cancer screening adherence is only about 60% — well below the 80% target set by the National Colorectal Cancer Roundtable.

In an editorial accompanying the two studies, John M. Carethers, MD, of the University of California San Diego, suggested that the best screening test “is the one that gets completed by the patient.”

“Most of the recommended tests, including the two newer tests assessed in the studies … improve on the sensitivity and approach the specificity of FIT, such that these tests appear to be at least as effective as FIT,” he added. “Adherence to screening is a key factor, and ease of test use may contribute to increased adherence.”

Thus, the hope is that these newer tests “will increase use and adherence and elevate the percentage of the population undergoing screening in order to reduce deaths from colorectal cancer,” he wrote.

BLUE-C Trial

This prospective study included 20,176 adults ages 40 and older who were scheduled to or planned to undergo screening colonoscopy. Mean age was 63, 53.2% were women, and 60.1% were white.

Colorectal cancer was detected in 98 participants, of whom 82 had stage I, II, or III disease. Of this latter group, the sensitivity of the next-generation multi-target stool DNA test was 92.7%.

Sensitivity for colorectal cancer was 93.3% among participants younger than 65, and 94.3% among those 65 and older, while the sensitivity for advanced precancerous lesions in these subgroups was 39.6% and 47%, respectively.

Imperiale and colleagues noted that one of the goals in developing this next-generation multi-target stool DNA test was to improve its specificity (86.6% with the current version in the DeeP-C study), while maintaining or improving sensitivity.

Accordingly, they found that the specificity of the new version is higher than that of the current version.

Carethers suggested that the higher specificity — while still lower than that observed with FIT — “should increase the detection efficiency for users by reducing the occurrence of false-positive results and thus lowering the number of follow-up colonoscopies.”

However, Imperiale and team acknowledged that a limitation of BLUE-C is that they did not directly compare the performance of the next-generation test with the current version.

“Thus, the results from this study cannot be reliably compared with published findings for the multi-target stool DNA test that is currently available for screening purposes,” they wrote.

ECLIPSE Trial

In the prospective, observational, multicenter ECLIPSE trial, Grady and colleagues evaluated the cfDNA blood-based test in a population that included adults ages 45 to 84 who had an average risk for colorectal cancer and were undergoing routine screening with colonoscopy.

The clinical validation cohort included 10,258 patients, 7,861 of whom met eligibility criteria and were evaluable. Mean age was 60, 53.7% were women, and demographic characteristics mirrored the racial and ethnic distribution in the 2020 U.S. Census (78.5% white, 13.3% Hispanic or Latino, 11.8% Black, 7.1% Asian).

The cfDNA blood-based test had a sensitivity of 87.5% for screening-relevant (stages I, II, or III) colorectal cancers, with a sensitivity of 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 stage IV colorectal cancers.

Among 1,116 participants with advanced precancerous lesions, the cfDNA blood-based test was positive for 147, for a sensitivity of 13.2%.

The false-positive rate of the test was 10.1%.

In a “Science Behind the Study” editorial, Y.M. Dennis Lo, DM, DPhil, of the Li Ka Shing Institute of Health Sciences at the Chinese University of Hong Kong, called the relatively low sensitivity for the detection of advanced precancerous lesions a limitation.

“Moreover, colonoscopy not only detects such lesions with high sensitivity but also permits their immediate removal,” Lo wrote. “The noninvasiveness (relatively speaking) of the plasma cfDNA assay, though, is a feature that seems likely to result in greater uptake than colonoscopy: further work is warranted to determine whether this is true and whether the cost-benefit ratio would justify its implementation.”

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