Doré, Michaël

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.

89 Background: With estimates of over 150,000 incident and 50,000 fatal colorectal cancer (CRC) cases in 2024, efforts are ongoing to improve the national screening performance and engagement in the US. The Centers for Medicare & Medicaid Services (CMS) have established criteria for covering new blood-based CRC screening tests if minimum CRC sensitivity and specificity thresholds are met. However, the current blood-based tests are challenged by their relative inability to detect advanced precancerous lesions (APLs). At present, the importance of APL versus CRC sensitivity on screening outcomes remains undetermined. To address this knowledge gap, we conducted a simulation study to compare the screening effectiveness and outcomes of a hypothetical blood-based test across a range of sensitivities for CRC and APL detection. Methods: Outcomes were simulated using the CRC-AIM microsimulation model, which has been previously calibrated and validated. Predicted outcomes were calculated for average-risk individuals screened triennially with a blood-based test between ages 45-75 years, assuming perfect adherence. Base-case screening sensitivity and specificity inputs were based on CMS minimum thresholds (74% CRC sensitivity, 90% specificity) with assumed 10% APL sensitivity. Additional scenarios considered an increase in either APL or CRC sensitivity. Outcomes of interest included life years-gained (LYG), CRC incidence, and mortality reductions. Results: Compared to the CMS minimum performance (Table), increasing APL sensitivity by 1% (from 10% to 11%) resulted in a similar increase in LYG as compared to increasing CRC sensitivity by 11% (from 74% to 85%). Additionally, increasing APL sensitivity by 1% resulted in greater reductions in CRC cases and deaths (3% decrease) as compared to increasing CRC sensitivity by 11% (0% and 1% reductions, respectively). Conclusions: Data from this study show that increased APL sensitivity is a key determinant of screening-related outcomes, such as LYG, derived from a blood-based strategy, and that similar results would require much larger increases in CRC sensitivity. With the current CMS minimum performance threshold, blood-based tests that are designed to have high APL sensitivity can outperform tests with higher CRC sensitivity and little to no APL sensitivity. Comparison of CRC screening health outcomes with CMS proposed minimum threshold blood-test versus hypothetical tests with either increased APL and CRC sensitivity. APL Sensitivity CRC Sensitivity CRC Specificity Follow-up Colonoscopies CRC Cases (% reduction) CRC Deaths (% reduction) Life-Years Gained (LYG) (% increase) 10% 74% 90% 809 50 (ref) 18 (ref) 220 (ref) 11% 74% 90% 813 48 (-3%) 17 (-3%) 226 (3%) 10% 85% 90% 809 50 (0%) 18 (-1%) 227 (3%) APL: Advanced precancerous lesions; CRC: Colorectal cancer.

88 Background: There are an estimated 60 million individuals in the US who are not up-to-date with average-risk colorectal cancer (CRC) screening, as screening rates and adherence have remained stubbornly below the national target of 80%. Efforts are ongoing to improve CRC screening performance and participation, including the development of new blood-based tests. Despite high expectations for these tests, performance remains lower than other guideline-recommended strategies, particularly with respect to advanced precancerous lesion (APL) sensitivity. We conducted a simulation study of estimated clinical and economical outcomes for CRC screening with a blood-based test (at perfect adherence) compared to the multi-target stool-DNA (mt-sDNA) test (at published adherence rates). Methods: Utilizing CRC-AIM, a calibrated and validated microsimulation model, CRC screening outcomes were calculated for 1 million average-risk individuals screened between ages 45-75 years with triennial blood-based versus mt-sDNA testing. CRC and APL sensitivity and specificity inputs were derived from two large clinical validation studies for these screening modalities: ECLIPSE (NCT04136002) and DeeP-C (NCT01397747), respectively. To demonstrate the maximum benefits and burdens of blood-based screening, adherence to initial screening and follow-up colonoscopy after a positive blood test was modeled at 100%, while real-world adherence estimates of 65.6% were used for the mt-sDNA test. Outcomes of interest included life years-gained (LYG) and CRC cases missed by the blood-based test compared to the stool-based test, additional treatment costs imposed by theblood-based test, and additional CRC-related deaths per 1 million screened. Results: Compared to triennial screening with mt-sDNA at real-world adherence, blood-based screening at perfect adherence resulted in a higher number of incident (n=18,464) and fatal (n=6,483) CRC cases that would been avoided with the mt-sDNA test. Over a lifetime, screening with blood-based tests required 1,276,310 more tests (21% more) and 52,942 additional follow-up colonoscopies (7% more) compared to mt-sDNA screening. This increased testing burden did not generate additional benefits and instead reduced life-years gained by 67,645 per 1 million screened, resulting in an additional $1.6 billion in treatment costs compared to the mt-sDNA strategy. Conclusions: Data from this CRC-AIM modeling study show that even with perfect adherence, blood-based screening yields inferior clinical and economic benefits compared to mt-sDNA screening, due to suboptimal APL detection with the former test.

Objectives: To describe member adherence to a mail-based, health insurer-sponsored gap closure program for colorectal cancer (CRC) screening using multi-target stool DNA (mt-sDNA; Cologuard ® ) tests. Methods: Combined patient data from Exact Sciences Laboratories LLC and data from mass-mailed mt-sDNA orders placed by a large Medicare Advantage Insurance Plan were analyzed (03/01/2023-06/30/2023). Adherence and time to test return were the primary and secondary outcomes, respectively. Their association with patient characteristics was evaluated using multivariable regression. Results: Among the 3201 member-patients included (86.6% aged 65-75 years; 58.7% female), adherence rate was 49.4%, and mean time to test return was 25.5 days. After multivariable adjustment, the odds of test return were significantly higher among 65- to 75-year-olds (odds ratio [OR] = 1.59 relative to 45- to 64-year-olds), those living in small towns (OR = 1.43 relative to metropolitan-located individuals), and with digital outreach via both SMS and email (OR = 4.31 relative to no digital outreach). Time to test return was shorter in 65- to 75-year-olds than in 45- to 64-year-olds and was not associated with other patient characteristics. Conclusions: Mass-mailed mt-sDNA tests for CRC screening were associated with an overall adherence rate of about 50% in this Medicare Advantage population, with higher likelihood of test return among patients receiving digital outreach.

e15633 Background: Colorectal cancer (CRC) is the fourth most diagnosed cancer, as well as the second leading cause of cancer death in the United States – with an estimated 152,810 diagnoses and 53,010 fatal cases in 2024. Regular screening and early detection can reduce CRC incidence and improve overall survival; however, recent national survey data (2021) demonstrate that only 59% of the US screen-eligible population (≥ age 45) is up to date. Home-based, non-invasive CRC screening test options, such as the multi-target stool DNA (mt-sDNA) test, have the potential to improve patient outcomes and overcome CRC screening adherence barriers at multiple levels. Given that the recommended interval for mt-sDNA is three years, a better understanding of use in repeat users is warranted. We evaluated the effective rescreen rate of previous mt-sDNA test users. Methods: In this retrospective cohort study, we included patients between the ages of 45 and 75 years who were shipped an mt-sDNA test kit between January 1st – December 31st, 2023, and had previously completed mt-sDNA screening with a negative result > 2.5 years prior. Our primary variable of interest was mt-sDNA completion rate on repeat testing, defined as kit receipt with a valid result within 120 days of the shipment date. Regression analysis was performed to determine baseline characteristics associated with repeat test completion rate. Results: During the analysis period, a total of 481,748 patients who met the inclusion criteria received an mt-sDNA kit. The majority of the cohort was female (61.4%) and between the ages of 65-75 years (50.9%). Overall repeat test completion rate was 83.6%, with the average time to kit return being 18.9 days. Completion rates were similar between males (83.8%) and females (83.6%), and patients receiving included navigation support via mobile phones demonstrated the shortest average time to kit return (18.7 days). Completion rates increased concordantly with patient age: 81.6%, (45-49 years), 82.2% (50-64 years), and 85% (65-75 years). For first-time rescreen participants (2nd lifetime mt-sDNA test), the completion rate was 83.1%. For second-time rescreen participants (3rd lifetime mt-sDNA test), the completion rate was even higher at 93.6%. Logistic regression analyses revealed that patients re-screening for a second-time were three times more likely to return the mt-sDNA kit for CRC screening (OR = 3.118; p < 0.001). Conclusions: Data from this large, retrospective cohort study revealed that repeat CRC screening with the mt-sDNA test is associated with high adherence to triennial follow-up among participants. suggesting a high-level of perceived patient confidence in repeat performance of the mt-sDNA test. These novel data provide relevant insights regarding strong patient willingness to continue with home-based, non-invasive mt-sDNA testing over multiple cycles of average-risk CRC screening.