Factors Associated with Advanced Adenoma Detection by Colonoscopy After Negative Multitarget Stool DNA Testing

Multitarget stool DNA (mt-sDNA) testing is a non-invasive colorectal cancer (CRC) screening tool, but false-negative results may delay diagnosis. Understanding which patients are more likely to have advanced lesions after a negative test is essential, particularly given real-world off-label use.

We retrospectively studied patients across a multi-site health system who had negative mt-sDNA results and underwent colonoscopy within 3 years. Negative predictive values (NPVs) for advanced adenoma (AA) and CRC were calculated. Demographics, colonoscopy indications, polyp characteristics, endoscopist training level, prior colonoscopy history, and off-label mt-sDNA use were abstracted. All assays used the original Deep-C version of Cologuard. Because only patients who underwent colonoscopy were included, NPVs represent conditional performance in this subset.

Among 370 patients, 31 (8.4%) had AA and 3 (0.8%) had CRC; 34 (9.2%) had advanced precancerous lesions (APL). AA was associated with a higher number of polyps and larger polyp size. Proximal lesions-particularly in the hepatic flexure and transverse colon-were more common among AAs. Gastrointestinal bleeding was more frequent in patients with AA (32.3% vs 14.2%). GI attendings performed 95.4% of colonoscopies and detected all AAs and CRCs. Off-label mt-sDNA testing occurred in 10.3% of patients, none of whom had AA or CRC. Prior colonoscopy was documented in 8.9% of patients.

Conditional NPVs for AA and CRC after negative mt-sDNA were 91.6% and 99.2%. Proximal lesions were more likely to be missed, highlighting the need for meticulous examination. Negative mt-sDNA results should be interpreted cautiously, particularly in symptomatic patients, and colonoscopy should be pursued when clinically indicated.