Negative Colonoscopy After Positive Multitarget Stool DNA: Subsequent Aerodigestive Cancer Diagnosis and Recommendations in the Community Setting

INTRODUCTION: Multitarget stool DNA (mt-sDNA) is a sensitive stool-based test for colorectal cancer screening. Limited referral-center data suggest low rates of incident aerodigestive cancers after a positive mt-sDNA test and negative colonoscopy; community-based outcomes are unknown. METHODS: Retrospective cohort study of adults referred for colonoscopy after positive mt-sDNA in a large community practice (2017–2021). Among patients with negative colonoscopy, we manually recorded postcolonoscopy recommendations, findings if additional colonoscopies had been performed, aerodigestive cancer diagnosis, and last clinical follow-up. Observed cancer incidence was compared with Surveillance, Epidemiology, and End Results data. RESULTS: Of 1,176 patients completing colonoscopy after positive mt-sDNA, 328 (28%) had negative findings. The median cohort age was 67 (interquartile range 59–72) years. Colonoscopy was performed at a median of 53 days after mt-sDNA sample collection. Postcolonoscopy recommendations aligned with Multi-Society Task Force (MSTF) guidelines in 59% of patients. Thirty-two patients underwent repeat colonoscopy with a median of 3.5 (1.9–4.4) years later; 2 (6.3%) had advanced serrated lesions, and no colorectal cancer was detected. The median clinical follow-up was 4.4 (3.4–5.6) years. Seven patients developed aerodigestive cancers (2 pancreatic, 5 lung), consistent with expected age- and sex-adjusted Surveillance, Epidemiology, and End Results incidence (n = 7.62) ( P = 0.823). DISCUSSION: In this community cohort, when a positive mt-sDNA test was followed by negative colonoscopy, rates of subsequent advanced colorectal neoplasia and aerodigestive cancer were low. Most patients received recommendations for subsequent colonoscopy that were consistent with MSTF guidelines. Findings further support the current MSTF recommendation of no additional evaluation for extracolonic malignancy in asymptomatic patients after high-quality follow-up colonoscopy.