Fendrick, A. Mark

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.

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.

Abstract Background Recommended noninvasive strategies for average-risk colorectal cancer (CRC) screening include multitarget stool DNA and fecal immunochemical test from ages 45 to 75 years. With new clinical trials, performance data for next-generation multitarget stool DNA, multitarget stool RNA, and blood-based screening tests are now available. This decision analytical model study evaluated the estimated benefit-to-burden ratio by means of efficient frontiers for noninvasive established and emerging CRC screening strategies. Methods Outcomes were estimated using the Colorectal Cancer and Adenoma Incidence and Mortality microsimulation model for average-risk individuals in the United States. Screening strategies were next-generation multitarget stool DNA (an updated marker panel), fecal immunochemical tests, multitarget stool RNA, or blood-based tests every 1-3 years, over various age ranges. Test performance inputs were derived from recent large clinical trials. A strategy was deemed efficient if no other strategy provided more life-years gained with equivalent or fewer lifetime colonoscopies and near-efficient if within 3 days of life-years gained of the efficient frontier. Results All modeled screening strategies resulted in life-years gained vs no screening. No strategy using blood-based tests was efficient or near-efficient. Overall, 10 strategies were efficient (6 next-generation multitarget stool DNA and 4 fecal immunochemical tests), including 2 strategies among those ages 45-75 years (biennial and triennial next-generation multitarget stool DNA). Overall, 22 strategies were near-efficient, including 4 strategies among those ages 45-75 years (annual, biennial, or triennial fecal immunochemical test; annual next-generation multitarget stool DNA). Conclusion Based on this modeling study, next-generation multitarget stool DNA was the only noninvasive screening test at guideline-endorsed interval and age-recommended ranges that was deemed efficient. Blood-based and multitarget stool RNA strategies were deemed not efficient for primary screening.

Background Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related deaths in the United States. Screening can prevent CRC by detecting advanced precancerous lesions. Adherence to screening is crucial in reducing CRC disease burden; however, there is limited research on the impact of digital outreach screening uptake and adherence. Objective This study evaluated the impact of different digital outreach channels on patient adherence to CRC screening with a multi-target stool DNA (mt-sDNA) test in a real-world setting. Methods Patients were individuals aged 45 to 85 years with a valid mt-sDNA test order from Exact Sciences Laboratories, LLC (Jan. 1, 2023–Sept. 23, 2023). All patients received letters and phone calls; some received short message service (SMS), email, or both. Adherence and time to test return were compared across digital outreach categories stratified by patient characteristics. Multivariable regression evaluated the association of digital outreach methods with adherence and time to test return. Results Among 2 425 308 patients (43.5% between 50 and 64 years, 58.2% female), digital SMS only (62.7%) was the most common outreach method. Overall adherence was 70.1%, with highest adherence in the digital SMS-plus-email group (72.9%). Mean time to test return from shipment of mt-sDNA kit to receipt of valid test was 25.8 days. In adjusted analyses, patients receiving digital SMS plus email had the highest odds of test return (odds ratio, 1.75; 95% confidence interval [CI], 1.73-1.78; P <.001) and had return times 8.7% shorter than the no-digital-outreach group (95% CI, 8.2-9.2; P <.001). Discussion Among nationally insured individuals within the recommended age range for CRC screening, overall adherence to the mt-sDNA test was in the 70s, with the highest rates in the digital (SMS and email) outreach group and the lowest in the no-digital-outreach group. Conclusions These findings highlight the importance of multichannel navigation in facilitating completion of CRC screening with the mt-sDNA test.

Abstract The substantial carbon footprint imparted by medical services warrants increased attention to their environmental impact. National guideline organizations such as the US Preventive Services Task Force (USPSTF) recommend multiple modalities for average-risk colorectal cancer (CRC) screening with varying resource intensity. The aim of this study was to quantify the environmental burden for 2 of the most used CRC screening modalities, colonoscopy and the multi-target stool DNA (mt-sDNA) test. A validated CRC microsimulation model was used to estimate the number of screening and follow-up tests for a cohort of 1 million average-risk individuals who underwent screening between ages 45 and 75. Component resources used for mt-sDNA, including waste products, energy, and transportation for colonoscopy and mt-sDNA, were collected from January 1, 2023, to January 1, 2024, and converted to carbon-equivalent emissions. Resources used for colonoscopy were captured from the literature. Resources devoted to screening colonoscopy were substantially (59%) higher than those to mt-sDNA, even when including follow-up colonoscopy. Of note, follow-up colonoscopy accounted for the majority (64%) of total emissions for the mt-sDNA screening strategy. Compared with colonoscopy screening, mt-sDNA substantially reduces the carbon emissions attributable to population-level CRC screening. Environmental impact should be included as a factor when choosing among guideline-recommended CRC screening strategies.

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.