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Background & Aims: Multi-target stool DNA (mt-sDNA) is an established stool-based colorectal cancer screening test, yet long-term performance is not well-described. We evaluated follow-up colonoscopy rates & quality, neoplasia yield, and repeat-testing adherence over 10 years with an integrated screening program. Methods: We assembled a retrospective cohort of mt-sDNA tests (September 2014–July 2025) within a multi-site health system. A validated large-language-model pipeline extracted colonoscopy, pathology, and quality endpoints from free-text reports. Detection outcomes (adenoma detection rate, advanced neoplasia, modified advanced adenoma, sessile serrated lesion (SSL), and negative exams) were calculated among high-quality exams; adenocarcinoma, bowel preparation adequacy, and cecal intubation rate (CIR) used all screening exams. We assessed colonoscopy completion ≤1 year after positive mt-sDNA, follow-up colonoscopy findings, findings by time-to-colonoscopy, and adherence to repeat mt-sDNA after negative result. Results: Among 148,624 tests in 110,410 individuals, positivity was 13.6%. Of 19,506 positives, 65.1% completed colonoscopy within 12 months (median 82 days). Colonoscopy after a positive mt-sDNA had high yield: advanced adenoma diagnosis was 30.7%; adenocarcinoma was 1.3%. Of patients who had colonoscopy within 3 years of a negative mt-sDNA test, 45.2% had adenoma/serrated lesion, 9.3% had advanced adenoma and 0.5% had colon cancer. Adenoma detection rate after positive mt-sDNA (>50%) exceeded specialty society quality benchmarks and increased over time; Longer intervals (>6 months) to colonoscopy after a positive test were associated with higher advanced adenoma (trend P=0.001).After an initial negative mt-sDNA, only 35.3% were screened again by mt-sDNA testing within 3 years. Conclusions: Over a decade,mt-sDNA screening achieved high colonoscopy qualitybut revealed critical gaps in the care cascade. One-third of positive tests lacked timely follow-up and nearly two-thirds of negative tests were not repeated on schedule, suggesting opportunities for system-level interventions.

Introduction: Multitarget stool DNA (mt-sDNA) is a sensitive stool-based test for colorectal cancer (CRC) screening. Limited referral-center data suggest low rates of incident aerodigestive cancers after a positive mt-sDNA 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 post-colonoscopy 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 (SEER) data. Results: Of 1,176 patients completing colonoscopy after positive mt-sDNA, 328 (28%) had negative findings. Median cohort age was 67 (IQR 59-72) years. Colonoscopy was performed at a median of 53 days after mt-sDNA sample collection. Post-colonoscopy 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 CRC was detected. 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 SEER incidence (n=7.62) (p=0.823). Discussion: In this community cohort, when a positive mt-sDNA 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 extra-colonic malignancy in asymptomatic patients after high quality follow-up colonoscopy.

Background: Fecal immunochemical tests (FITs), fecal occult blood tests (FOBTs), and multitarget stool DNA (mt-sDNA) tests are convenient, noninvasive colorectal cancer (CRC) screening strategies. However, delays in or failure to complete follow-up colonoscopy (FU-CY) after a positive noninvasive test are associated with higher CRC incidence, complications, and mortality. We sought to evaluate FU-CY rates, time to colonoscopy, and compliance predictors. Patients and Methods: This retrospective cohort study linked 2 data sources: Komodo Health Data with Exact Sciences Laboratories. Data were collected from January 2016 to June 2023 and analyzed in 2024. Study participants (ages 45–75 years) were individuals with positive stool-based CRC screening tests (FIT, guaiac-based FOBT, or mt-sDNA tests). FU-CY compliance was assessed at 30-day intervals up to 365 days, and logistic regression was used to identify predictors of FU-CY. Results: Among 362,646 participants, colonoscopy compliance was 77.1% for mt-sDNA and 45.1% for FIT/FOBT ( P <.001). Overall FU-CY compliance was lowest among Asian and Black populations, but was significantly higher in these subgroups for mt-sDNA versus FIT (Asian: 74.2% vs 41.1%; Black: 71.3% vs 44.6%). The strongest predictor of compliance was use of mt-sDNA (odds ratio, 3.98; P <.001). More than half of participants across all race groups who completed FU-CY after mt-sDNA did so within the first 120 days, whereas none of the FIT/FOBT racial subgroups reached 50% completion within 365 days. Conclusions: Timely completion of colonoscopy after a noninvasive test is critical, as failure to undergo colonoscopy or delays in completion are associated with increased CRC incidence and more advanced-stage disease. These findings demonstrate that mt-sDNA use may help close CRC screening disparity gaps compared with FIT testing. FU-CY adherence is higher, and time to colonoscopy is shorter following a positive mt-sDNA test versus FIT across all racial and ethnic subgroups.

e15647 Background: Colorectal cancer (CRC) screening offers an opportunity to prevent invasive disease by detecting and removing precancerous lesions. Colonoscopy-based detection of adenomas and serrated polyps is strongly associated with reduced risk of interval CRC. While the performance of noninvasive CRC screening tests is well described, comparative evidence on adenoma detection across screening colonoscopy and stool-based strategies with follow-up colonoscopy remains limited. We conducted a systematic review to compare adenoma detection across CRC screening modalities. Methods: MEDLINE (PubMed) and Embase were searched from January 1, 2000, through July 10, 2025, for peer-reviewed, U.S.-based studies reporting colonoscopy among average-risk adults aged ≥45 years, who underwent screening colonoscopy or follow-up colonoscopy after a positive stool-based screening test [fecal immunochemical test (FIT) or multi-target stool DNA (mt-sDNA) test]. The primary outcome was the detection of one or more adenomas at colonoscopy. High-risk or surveillance cohorts, AI-assisted colonoscopy, diagnostic accuracy trials, and non-U.S. studies were excluded. Results: Among 7,710 de-duplicated records, 147 studies underwent full-text review, and 47 studies were included in quantitative synthesis, with reported adenoma detection for screening colonoscopy alone (n = 31), follow-up colonoscopy after a positive FIT alone (n = 4), follow-up colonoscopy after a positive mt-sDNA test alone (n = 4), and for more than one of the screening strategies of interest (n = 8). Across included studies, overall adenoma detection differed by screening pathway. Follow-up colonoscopy after a positive mt-sDNA test demonstrated the highest adenoma detection (66.3%; 95% CI, 61.2-71.1), with lower adenoma detection observed for colonoscopy after a positive FIT (50.6%; 95% CI, 43.4-57.8) and screening colonoscopy alone (33.8%; 95% CI, 30.9-36.8) (Table 1). Conclusions: Detection of adenomas was highest following colonoscopy performed after a positive mt-sDNA test compared with FIT-positive follow-up or screening colonoscopy alone. These findings highlight differences in downstream detection across CRC screening tests and suggest that, in settings where colonoscopy resources are constrained, initial mt-sDNA screening with timely follow-up colonoscopy may help prioritize patients most likely to benefit. CRC screening modality No. of Studies Adenoma detected Study population Proportion, % (95% CI) Heterogeneity, I² (%) Between-study variance (τ 2 ) P-value* mt-sDNA 8 17,436 29,098 66.3 (61.2-71.1) 94.6 0.0924 <0.0001 FIT 11 17,588 32,630 50.6 (43.4-57.8) 94.0 0.2187 <0.0001 Screening colonoscopy 38 2,351,801 6,378,891 33.8 (30.9-36.8) 99.8 0.1710 NA *P-value represents adenoma detection vs. screening colonoscopy adenoma detection.

ABSTRACT Background Several colorectal cancer (CRC) screening modalities are guideline-recommended in the United States, yet they vary considerably in screening interval and real-world adherence. As a result, single-round test performance may not reflect cumulative effectiveness over time. This study compared the 10-year longitudinal outcomes of two CRC screening strategies— triennial next-generation multitarget stool DNA testing (ng mt-sDNA) and decennial screening colonoscopy. Methods This study used the validated, microsimulation-based Colorectal Cancer and Adenoma Incidence and Mortality (CRC-AIM) model to estimate 10-year cumulative outcomes for two guideline-recommended screening strategies: triennial ng mt-sDNA and decennial colonoscopy. Model inputs included test-specific performance and real-world adherence. Outcomes included CRC and precancerous lesions detected, CRC mortality reductions, and life-years gained (LYG). Sensitivity analyses examined the effects of varying both screening adherence and follow-up colonoscopy adherence. Results Over 10 years per 1,000 individuals offered screening, the ng mt-sDNA screening test detected 13% more precancerous lesions and 11% more CRC cases than colonoscopy, with a greater proportion of CRCs identified through screening rather than symptomatic detection. ng mt-sDNA resulted in greater CRC mortality reduction (33% vs 20%) and 62% more life-years gained, with consistent findings across sensitivity analyses. Conclusions With real-world adherence, screening with triennial ng mt-sDNA demonstrates superior cumulative effectiveness compared with decennial colonoscopy, driven by higher adherence and favorable longitudinal performance. These findings support the expanded use of noninvasive stool-based screening to reduce CRC mortality and alleviate capacity constraints associated with colonoscopy-based screening. Broader adoption of ng mt-sDNA may enhance population-level CRC prevention by increasing participation and improving early detection across the screening eligible population. Plain language summary Colorectal cancer screening tests are recommended at different time intervals and completed at different adherence rates in clinical practice. The analysis used a validated simulation model to compare 10-year outcomes of triennial next-generation multi-target stool DNA test (ng mt-sDNA) with a single colonoscopy, accounting for real-world screening and follow-up colonoscopy adherence. Our findings indicate that repeated ng mt-sDNA provides greater cumulative screening effectiveness than colonoscopy over a 10-year period.

Background/Objectives: Modeling analyses for colorectal cancer (CRC) screening focusing solely on the costs of screening do not fully capture the value of screening programs. We evaluated the clinical and economic effects of CRC stool-based screening tests, including impacts on cancer-related outcomes. Methods: A cohort-based decision-analytic cost-estimator model estimated outcomes for a single round of screening with next-generation multi-target stool DNA (ng mt-sDNA) test or fecal immunochemical test (FIT) from a US payer perspective. Undiagnosed cancers were assumed to become symptomatic (and detected) within 10 years. Clinical assumptions, advanced precancerous lesion and CRC prevalence, and test performance inputs were from clinical trial data. Adherence rates for initial screening and follow-up colonoscopy after a positive result were from real-world data. Input costs included the screening tests, follow-up colonoscopy (with and without polypectomy), and CRC treatment. Results: Compared with FIT, more individuals completed ng mt-sDNA (321,000 vs. 713,000, respectively), leading to the detection of more CRC cases (436 with FIT vs. 2235 with ng mt-sDNA), more advanced precancerous lesions, and more CRC at earlier stages. The cost of screening per patient screened was USD 801 for ng mt-sDNA and USD 124 for FIT. Follow-up colonoscopy cost was USD 149 million with ng mt-sDNA versus USD 22 million with FIT, whereas CRC treatment costs were lower for ng mt-sDNA (USD 1423 million versus USD 1474 million, respectively). When accounting for both direct and CRC averted costs, the total cost of screening and treatment was USD 1383 million with ng mt-sDNA versus USD 1427 million with FIT. Conclusions: Higher screening costs with ng mt-sDNA versus FIT are counterbalanced by savings realized from enhanced CRC prevention and earlier detection due to the superior test performance and better adherence with ng mt-sDNA.

INTRODUCTION: Colorectal cancer remains a leading cause of cancer associated death in the United States and colonoscopy the primary screening strategy for prevention. Rates of adenomatous and serrated neoplasia detection are inversely associated with postcolonoscopy colorectal cancer. This crucial quality metric depends on accurate ascertainment of colorectal neoplasia findings from both endoscopy and histopathology records. We aimed to assess the feasibility of a random forest machine learning model to rapidly and accurately categorize colorectal neoplasia from electronic health record data. METHODS: A retrospective cohort study compared neoplasia detection rates among individuals undergoing colonoscopy at a large academic institution to develop a rule-based algorithm to categorize colorectal neoplasia from endoscopy reports and pathology systematized nomenclature of medicine – clinical terms. This cohort provided a large training set to develop a natural language processing system using a random forest approach to automatically classify unstructured pathology findings into adenoma, serrated, or advanced neoplasms. This system was manually validated through an independent holdout set. RESULTS: The training set comprised 35,953 unstructured pathology reports with matched systematized nomenclature of medicine – clinical terms from 95,188 unstructured colonoscopy reports. The final model was assessed on an independent holdout set of 337 manually annotated procedures obtaining an area under the receiver operating characteristic curve of 0.997 (confidence interval [CI] 0.994–1), 0.99 (CI 0.98–1), and 0.99 (CI 0.98–0.99) for prediction of adenoma, serrated, and advanced lesions, respectively. DISCUSSION: The random forest-based hybrid natural language processing system for classification of colonoscopy results was both accurate and explainable. NLP combined with effective machine learning algorithms can provide a scalable strategy for colonoscopy quality monitoring.