S475 False Positives and Follow-Up in Cologuard: Who’s at Risk?

Introduction: Cologuard is an increasingly used, non-invasive stool DNA test that combines molecular and hemoglobin markers to detect colorectal cancer (CRC) and advanced precancerous lesions (APLs) in average-risk individuals. Although replacing conventional screening modalities like colonoscopy with stool-based tests may reduce clinical benefit, implementation in populations unable or unlikely to undergo colonoscopy could enhance screening adherence and early detection. This study evaluates false positive Cologuard results to identify patient-level factors that may increase false positive risk to inform clinical decision making. Methods: This is a retrospective chart review of patients who underwent Cologuard testing at a single academic medical center from February 21, 2022, to February 21, 2025. A random sample of 123 charts was manually reviewed to compare characteristics of true positives (n = 15) versus false positives (n = 6), based on follow-up colonoscopy findings. Patients with prior CRC or hereditary cancer syndromes were excluded. Data collected included age, gastrointestinal symptoms, colonoscopy history, medication use, and colonoscopy findings. Results: Twenty-five percent of the patients with a positive Cologuard did not follow-up with colonoscopy at time of this review. Among patients with positive Cologuard results, those who did not complete colonoscopy had similar age (74.6 vs 74.9 years) but more frequently reported constipation (85.7% vs 68.2%), diarrhea (42.9% vs 9.1%), and were more likely to be on anticoagulants, antiplatelets, or nonsteroidal anti-inflammatory drugs (NSAIDs; 85.71% vs 72.73%) suggesting symptoms or other comorbidities may contribute to deferred follow-up. False positives were more frequently observed in older individuals (mean age 80.33 vs 73.67 years) and correlated with higher rates of hemorrhoids (83.3% vs 53.3%), constipation (83.3% vs 60.0%), prior colonoscopy (83.3% vs 53.3%), and antiplatelet therapy (66.7% vs 46.7%), suggesting potential confounding from benign pathology that may reduce test specificity. Conclusion: Patient factors such as advanced age, benign gastrointestinal conditions such as diverticulosis or hemorrhoids, and antiplatelet, anticoagulation, or NSAID use may impact both Cologuard specificity and follow-up adherence. While limited by small sample size, these descriptive findings highlight the need for refined risk stratification. Future directions include expanding the sample size to enable statistical analysis and improve generalizability of results, ultimately guiding more personalized screening strategies.