New and emerging next-generation CRC screening tests
Key Takeaways
The mSEPT9 test is the only FDA-approved blood-based test for colorectal cancer (CRC); however, it has limited adoption, necessitating further research on non-invasive screening options.
Next-generation tests for CRC are less invasive than the gold standard colonoscopy, and have the potential to increase screening rates, leading to earlier diagnosis and improved outcomes.
Though these next-generation tests, including improvements to multi-target stool DNA tests and virtual colonoscopy, may encourage more people to participate in screening, they still require a follow-up colonoscopy to validate a positive result.
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide, according to the World Health Organization.[] The year 2020 witnessed over 1.9 million new cases and 930,000 deaths. These numbers are expected to rise by 63% and 73%, respectively, by 2040.
Though it is rare in people under 50, affecting only 1%,[] cases in younger people have skyrocketed in recent decades, and are now twice as high as in the 1990s.[]
Fortunately, advancements in CRC screening have addressed the rising rates among young people, with new, noninvasive options resulting in higher screening rates and lower CRC prevalence.[]
Next-generation mt-sDNA
In 2014, the multi-target stool DNA (mt-sDNA) test, also called FIT-DNA and multitarget fecal DNA, was FDA-approved for screening in people with an average risk of CRC.[] The test assesses DNA for mutation or methylation and hemoglobin levels in the stool, and showed higher sensitivity for detecting CRC than fecal immunochemical test (FIT) (92.3% vs 73.8%) but lower specificity (86.6% vs 94.9%), increasing the likelihood of false-positive results.
Due to the lower specificity of the mt-sDNA, a next-generation version was developed and analyzed in a 2024 study,[] with results indicating it still showed lower specificity (though improved from the prior version: 90.6% vs 94.8%), as well as higher sensitivity (93.9% vs 67.3%) compared to FIT.
Though the manufacturers recommend undergoing an mt-sDNA test every 1 to 3 years, it is typically done every 3 years. There is some evidence that it may help increase screening adherence and quality, and also clinical outcomes.[]
Capsule endoscopy
Capsule endoscopy, also called capsule colonoscopy, is used to screen the colon for abnormalities, with research underway for potential benefits in CRC screening, specifically.
This method requires the person to swallow a pill-shaped capsule equipped with a camera that takes pictures of the colon to be examined for any abnormalities.
Capsule endoscopy is only recommended for patients who were not able to complete a colonoscopy and those with GI bleeding. However, the USPSTF does not recommend it for CRC screening, and therefore shouldn't be relied on as the only screening test.
Its minimal invasiveness, avoidance of radiation exposure and associated risks, and the ability for a gastroenterologist to perform it, leading to potentially faster diagnosis, make it a promising method for increasing patient screening rates. However, its cost, bowel preparation requirement, and need for a follow-up colonoscopy are factors that may limit its adoption in clinical settings.[]
Virtual colonoscopy
Colonoscopy is the gold standard for CRC screening and diagnosis. The CDC recommends having this test every 10 years for people with average risk.[]
Colonoscopies are invasive—they involve thorough bowel preparation, sometimes require sedation, and are associated with complications like colon perforation and bleeding, all of which may discourage patients from participating in screening.[]
Virtual colonoscopy, also called computed tomographic (CT) colonography, is a painless and noninvasive screening method.[] As explained by the National Cancer Institute, it uses a CT scanner and a computer to display images of the colon that can be investigated for polyps and any abnormalities. It may also show pictures of areas surrounding the colon and thus unintentionally reveal other medical findings and diagnoses. The CDC recommends that virtual colonoscopy be done every 5 years.
Its noninvasive nature and nonexistent risk of complications make it a more appealing screening method for patients; however, it still requires extensive colon cleansing. Unlike colonoscopy, virtual colonoscopy cannot remove polyps and other abnormal growths. A positive result requires a follow-up colonoscopy test.
mSEPT9 test
Authors writing in Nature Reviews Gastroenterology & Hepatology point out that the mSEPT9 test is the only blood-based CRC test that checks the blood for methylated septin 9, a CRC marker.[]
The test showed a specificity of 80% for all stages of cancer, 68% sensitivity for detecting CRC overall, and only 64% sensitivity for detecting advanced disease, thus raising the potential for false negatives. The study that determined the performance of mSEPT9 in detecting CRC included only patients with known colon pathology rather than the general population.
mSEPT9 test is also not associated with a decreased risk of CRC and mortality as it performs poorly in detecting precancerous lesions. This test isn’t approved for CMS reimbursement, and due to its insufficient sensitivity, it is not included in the latest USPSTF guidelines.
According to the National Cancer Institute, it is only recommended for people 50 years or older who don’t want to or can’t completely take standard CRC screening tests like FIT or colonoscopy. A positive test needs to be confirmed with a colonoscopy.
With the need for more convenient and less invasive screening methods, many blood-based tests are currently under research.
These tests include CancerSEEK, Freenome, Guardant, and Grail. However, adopting novel diagnostic tools for clinical practice is often hindered by regulatory authorization and approval, affordability and availability, patient acceptance, ethical and legal factors, and more.[]
Collaboration among researchers, healthcare providers, government regulators, and industry players can help address these challenges.
What this means for you
For CRC, colonoscopy is the gold standard for screening and diagnosis. However, it involves sedation and colon cleansing, is invasive, and is associated with complications which may discourage people from seeking preventative screenings. The growing focus on blood-based tests as alternatives to more invasive and preparation-intensive CRC screening tests has led to promising research in the field of CRC screening.