RNA Stool Test Shows High Sensitivity for CRC Detection

David Lieberman, MD

Oregon Health & Science University

A multi-target stool RNA test (mt-sRNA), also known as ColoSense, showed a high level of sensitivity for detecting colorectal cancer (CRC) in individuals aged 45 and older, with significant improvements shown over fecal immunochemical testing (FIT), according to findings from the CRC-PREVENT study presented at the American College of Gastroenterology (ACG) 2023 Annual Scientific Meeting in Vancouver, Canada, and simultaneously published in JAMA.^1,2

According to the findings, the positive detection sensitivity for colorectal cancer was 94% (95% CI, 81%-99%), this included stages I to III cancers, with no stage IV seen in the study. The positive sensitivity for advanced adenomas was 46% (95% CI, 42%-50%). The overall specificity for the test was 88% (95% CI, 87%-89%). Based on these findings, the FDA is currently considering the test for approval, said lead investigator David Lieberman, MD.

"The mt-sRNA test can be an effective non-invasive colorectal cancer screening test across the intended-use population, based on age 45 to 75 years," said Lieberman, from the Oregon Health & Science University, during a presentation of the results. “The navigation to colonoscopy in this study was incredibly successful, and this confirms what we’ve seen in other studies. We reached 85.3% in this case.”

Currently available mt-sDNA tests for CRC detection have a 92% sensitivity to for CRC and a 42% sensitivity for advanced adenomas, Lieberman said; however, there are no currently approved stool-derived eukaryotic RNA (seRNA)-based tests available. Given available DNA tests, the study was powered for a 90% or greater sensitivity for CRC detection and a greater than 45% sensitivity for advanced adenoma detection. The specificity of the test was targeted to 85% or greater.

Enrollment into the study was completed using social media and an online enrollment form. From these efforts, 14,263 individuals were consented for the trial within a 12-month period. Overall, 85% of those enrolled successfully completed the testing process. Of the tests returned, 852 had insufficient RNA, 118 had reception issues, 42 withdrew consent, and 38 had scope before collection, leaving 11,034 for analysis; however, since colonoscopies were not already planned, additional patients were excluded from the study due to not having completed a colonoscopy (n = 1308) and for other exam related issues. A total of 9,266 patients were included in the primary analysis.

"The methods here were interesting because the patients were enrolled via social media online, and provided consent, and then were navigated to completing the stool testing followed by navigated to colonoscopy in their local community," said Lieberman. "The results on this are pretty good, because 85% of the enrolled patients actually completed the sample for detection."

The online enrollment methodology of the trial resulted in a broad sample of patients across a variety of demographics and socioeconomic settings, Lieberman said. Overall, 49 states were represented by the final patient population, with incomes ranging from less than $29,999 per year to over $200,000. The patient population was also well balanced for ethnicity, race, and insurance coverage, and included a wide diversity of ages.

For the study, patients were sent the mt-sRNA ColoSense test along with FIT, to allow for comparison. The sensitivity of 94% was superior to the 78% seen with FIT alone for CRC (P = .02). Additionally, for advanced adenomas, the 46% seen with mt-sRNA was superior to the 29% seen with FIT (P <.001). For specificity, however, FIT was 95% for all findings vs the 85% seen with mt-sRNA and was 96% for no findings compared with 88% for mt-sRNA.

By stage for CRC detection, the mt-sRNA test had a positive sensitivity for stage III CRC of 100% compared with 89% for FIT (P = .15). For stage I and II CRC detection, the mt-sRNA sensitivity was 92% vs 73% for FIT (P = .03). For all CRC detection, the sensitivity was 94% vs 78% for FIT (P = .02).

The sensitivity for adenomas varied by the type, size, and location. For tubular adenoma or traditional serrated adenoma, the test had a sensitivity of 43% vs 25% for FIT (P <.001). For tubulovillous adenoma, the mt-sRNA test was 48% sensitive vs 32% for FIT (P <.001) and for high-grade dysplasia or 10 or more adenomas of any size the mt-sRNA test was 65% sensitive vs 48% for FIT (P <.001).

"Ideally, we would love to have a non-invasive test that detects everyone with advanced adenomas, and we don't have that. There are probably many biological reasons for that," said Lieberman. "Detecting 46% of patients with advanced adenomas will identify key patients who should get further evaluation and if this test is performed on some sort of regular interval presumably other patients will be detected as a result of that. I will note, the patients we really want to detect, with high-grade dysplasia, the sensitivity was 65%."

A similar ascending increase in sensitivity was seen as the size of the adenoma increased, with sensitivities of 35%, 46%, and 50% for <10 mm, 10-19 mm, and 20 or greater mm, respectively. These were all superior to FIT (P = .03). The mt-sRNA test was more sensitive to advanced adenomas in the distal colon (53%) compared with the proximal (37%).

"Not surprisingly, sensitivity increased with advanced adenoma size. At the point where the size was the greatest, the sensitivity was 50%," said Lieberman.

For CRC, the test was 100% sensitive for CRC detection in patients aged 45 to 59. For those 60 or older, the test was 89% sensitive. For advanced adenomas, the test was 45% sensitive in the 45-to-59-year age group compared with 47% sensitive in the 60 or older group. "There's fidelity across all the age groups, including the 45-49 age group," said Lieberman.

The test is being developed by Geneoscopy, which noted it had submitted a Premarket Approval Application (PMA) to the FDA for the mt-sRNA colorectal cancer screening test.³ For this process, the FDA will notify the company within 45 days of whether the application is filed, after this point the FDA takes up to 180 days to review the application. This places a decision in the middle of 2024.

References

1. ^{Lieberman D, Barnell EK, Wurtzler EM, et al. CRC-PREVENT: Multi-Target Stool RNA Test for Detection of Colorectal Cancer and Advanced Adenomas in Average-Risk Individuals 45 and Older. Presented at: ACG 2023 Annual Meeting; October 20-25, 2023. Abstract 9.}
2. ^{Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. Published online October 23, 2023. doi:10.1001/jama.2023.22231}
3. ^{JAMA Publishes Geneoscopy’s Pivotal CRC-PREVENT Trial Results, Reporting Highest Sensitivity for Detecting Colorectal Cancer and Advanced Adenomas Among Available Noninvasive Screening Tests. News release. Geneoscopy. October 23, 2023. Accessed October 23, 2023. https://www.geneoscopy.com/jama-publishes-geneoscopys-pivotal-crc-prevent-trial-results-reporting-highest-sensitivity-for-detecting-colorectal-cancer-and-advanced-adenomas-among-available-noninvasive-screening-tests/}