Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity.
METHODS
In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT).
RESULTS
Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 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; specificity was 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. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred.
CONCLUSIONS
The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).
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Additional Info
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Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening
N. Engl. J. Med 2024 Mar 14;390(11)984-993, TF Imperiale, K Porter, J Zella, ZD Gagrat, MC Olson, S Statz, J Garces, PT Lavin, H Aguilar, D Brinberg, C Berkelhammer, JB Kisiel, PJ LimburgFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Participation in colorectal cancer (CRC) screening is suboptimal, at 60% nationally.1 Growing urgency to increase screening because of increases in younger-onset and advanced-stage CRC may be addressed by offering noninvasive options for screening.2
One option is the currently available multitarget stool DNA test (mt-sDNA 1.0) that evaluates for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and hemoglobin concentration. The mt-sDNA 1.0 was previously shown to have improved sensitivity for CRC (92.3% vs 73.8%) and advanced precancerous lesions (APLs; 42.4% vs 23.8%), albeit with substantially lower specificity for non-precancerous or negative results on colonoscopy (86.6% vs 94.9%).3 Notably, mt-sDNA 1.0 specificity appeared to be lower with increasing age: 92.2% for the <60-year age group, 85.7% for the 65- to 69-year age group, and 82.5% for the 70- to 74-year age group.4
To improve test performance, a next-generation mt-sDNA 2.0 using a new assay with three DNA methylation markers — the CERS4 gene, LLRC4 gene, and PPP2R5C gene — plus fecal hemoglobin concentration was developed. In a prospective study involving 20,176 individuals aged 40 years and older at average risk for CRC who underwent reference colonoscopy, mt-sDNA 2.0, compared with fecal immunochemical test, had superior sensitivity for CRC (93.9% vs 67.3%), APLs (43.4% vs 23.3%), and advanced serrated lesions (45.8% vs 5.2%), with lower specificity for normal colonoscopy/non-neoplastic lesions (92.7% vs 95.7%).
Although not directly compared in the same study, the new results suggest that mt-sDNA 2.0 versus 1.0 achieves comparable CRC and APL sensitivity, but with better specificity. In particular, mt-sDNA 2.0 specificity at older ages was improved: 95.9% for the 50- to 54-year age group, 92% for the 65- to 69-year age group, and 87.0% for the 70- to 75-year age group.
Specificity improvements with mt-sDNA 2.0 are likely to result in a reduction in false positives that drive unnecessary colonoscopies and associated burdens and costs of screening, and support use of the new test as an improved option for noninvasive screening over mt-sDNA 1.0.
References
Advancements in the performance of noninvasive screening methodologies for colorectal cancer (CRC) are needed to improve compliance with CRC screening. The goal for adherence to screening is 80%; however, as a nation we are not reaching this, with recent rates of 60% to 69%. The most accurate test is colonoscopy, which is both diagnostic and preventive for CRC through the removal of adenomas and serrated lesions. The noninvasive alternative most commonly utilized is fecal immunochemical testing (FIT). Although FIT is superior to fecal occult blood testing, it has modest sensitivity for advanced polyps and is 70% to 80% sensitive for CRC. This led to the development of a multitarget stool DNA test (MT-sDNA test; Cologuard), approved in 2014 by the FDA. This test detects approximately 90% of CRCs and 42% of advanced polyps with a specificity of 86%.
In the paper titled “Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening,” the authors present an updated alternative with next-generation stool DNA testing. They demonstrated improved sensitivity of the stool DNA test versus FIT (93.9% vs 67.3% for CRC), but lower specificity for advanced neoplasia (90.6% vs 94.8%). The sensitivity for advanced polyps was 43.4%. This update to the current MT-sDNA test is a laudable advance and does not materially change the considerations when selecting a CRC screening test.
Relevant to the recent study from Imperiale et al, a multitarget stool mRNA test has been developed and showed a sensitivity of 94% for CRC and 46% for advanced polyps with 88% specificity in a large clinical trial.1 This test may be another stool-based CRC screening option in the future. An important consideration is that none of these stool tests is likely to materially improve compliance. However, one may wonder if there is more ground to be gained through investigation into non–stool-related testing, such as a recently published cfDNA blood test.2 A blood-based test would very likely improve compliance and could lead to overall increased participation in CRC screening. Going forward, additional direct comparisons among the various testing methods is needed to guide development of accurate and accessible screening options and inform the screening test selection process by patients and providers.
References