Next-Gen Cologuard Test Shows Promise for Early Detection of Colorectal Cancer

Thomas Imperiale, MD
Credit: Regenstrief Institute

A next-generation multitarget stool DNA test from the same company that brought the world Cologuard could be the next great advancement in colorectal cancer screening, according to the results of a new study.

Published in the New England Journal of Medicine on March 13, 2024, results of the 20,000-patient BLUE-C trial, which was presented as a late-breaking abstract at the ACG 2023 Annual Scientific Meeting, suggest the next-generation multitarget stool DNA test offered improved sensitivity for colorectal cancer and advanced precancerous lesions but reduced specificity relative to a commercially available fecal immunochemical test (FIT).¹

“We found that the next generation stool DNA test had a good balance of sensitivity -- detecting disease -- and specificity – low false positive results. Compared to the fecal immunochemical test (FIT), the next gen test had superior sensitivity for both colorectal cancer and advanced pre-cancerous polys, especially the subgroup of advanced polyps containing high grade dysplasia,” said lead investigator Thomas Imperiale, MD, the Lawrence Lumeng Professor of Gastroenterology and Hepatology at Indiana University School of Medicine.² “And even though a direct comparison between the current version of the test and this newer version wasn't made, the numerical values for sensitivity were the same or actually a little better for the next gen test and the specificity was about 30 percent better with this new version of the test, with significantly fewer false positives compared (indirectly) with the current version.”

Since the turn of the century, few, if any, rallying cries in medicine have reverberated with the general public in the same fashion as calls for greater attention around screenings for colorectal cancer, particularly among younger populations. According to the American Cancer Society, colorectal cancer has climbed from being the fourth leading cause of cancer death in both men and women under 50 years of age in the late 1990s to first in men and second in women in 2021.³

With this in mind, oncologists, gastroenterologists, and providers across the spectrum of care have placed a renewed emphasis on the need for cost-effective, non-invasive screening measures. Among the various companies driving change in this space is Exact Sciences, who market the Cologuard test and sponsored the BLUE-C trial.

A prospective trial launched in 2019, the BLUE-C trial enrolled 26,758 asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy from 186 study centers in the US. The primary outcomes of interest for the study were the sensitivity for colorectal cancer and specificity for advanced neoplasia of the next-generation multitarget stool DNA test, with sensitivity defined as the proportion of participants with colorectal cancer who have positive test results and specificity defined as the proportion of negative test results among participants without advanced neoplasia.

Per trial protocol, stool specimens for the next-generation multitarget stool DNA test and FIT were obtained before the colonoscopy preparation, mailed for processing, and inspected for acceptability on receipt. Study investigators described the next-generation test as leveraging a new molecular panel comprised of LASS4, LRRC4, PPP2R5C, and the reference marker ZDHHC1. The commercially available FIT used was the OC-AUTO FIT from Polymedco. Of note, technicians were unaware of the findings of colonoscopy and alternate test, with the sponsor unaware of results until after the algorithm and clinical database lock.

Of the 26,758 enrolled in the trial, 75.4% (n=20,176) had valid results for full evaluation. The mean age of those included in the final analytical sample was 63.0 years, 53.2% were women, and 60.1% were White. Investigators pointed out the cohort was generally representative of the racial and ethnic group distribution of the US.

Upon analysis, results indicated colorectal cancer was present among 0.5% (n=98) of participants. Of these, 84% (n=82) had stage I, II, or III disease. Further analysis indicated 10.6% (n=2144) had advanced precancerous lesions, 6973 (n=34.6%) had nonadvanced adenomas, and 10,961 (n=37.2%) had nonneoplastic findings or negative colonoscopy.

When assessing the screening tools used in the trial, results suggested the next-generation multitarget stool DNA test identified 92 of 98 participants with colorectal cancer and 76 of 82 participants with screening-relevant cancers, which yielded test sensitivities of 93.9% (95% confidence interval [CI], 87.1 to 97.7) and 92.7% (95% CI, 84.8 to 97.3), respectively. According to results, sensitivity did not vary substantially according to disease stage or location. Investigators highlighted additional analyses of the next-generation multitarget stool DNA test revealed a sensitivity of 43.4% (95% CI, 41.3 to 45.6) for advanced precancerous lesions and specificity of 92.7% (95% CI, 92.2 to 93.1) for nonneoplastic findings or negative colonoscopy.

In comparison, the commercially available FIT had a recorded sensitivity of 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions, but a specificity of 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy.

Based on results of the analysis, investigators determined the next-generation test had superior sensitivity for colorectal cancer (P < .001) and for advanced precancerous lesions (P <.001) but had lower specificity for advanced neoplasia (P < .001).

Investigators called attention to specific limitations within their study to consider. These included a relatively high proportion of persons who provided informed consent and were enrolled but whose samples could not be evaluated as well as the inability to perform a direct comparison of test performance.

“While our study establishes superior sensitivity of the next gen DNA stool test to FIT, it does not indicate which screening modality is “best” for a particular patient,” Imperiale added. “That should be discussed in a conversation between the clinician and the patient that explores various factors including disease risk and likelihood that the patient will complete the chosen test, among other factors.”

References:

1. _{^{Imperiale TF, Porter K, Zella J, et al. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening. N Engl J Med. 2024;390(11):984-993. doi:10.1056/NEJMoa2310336}}
2. _{^{Regenstrief. Next generation stool DNA test has best detection rate of noninvasive colorectal cancer screening tools. EurekAlert! March 13, 2024. Accessed March 13, 2024. https://www.eurekalert.org/news-releases/1037034.}}
3. _{^{Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024 [published correction appears in CA Cancer J Clin. 2024 Feb 16;:]. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820}}