Ebner, Derek W.

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.

Abstract Introduction: Blood-based tests represent a compelling option for early detection and management of cancers and other chronic diseases. While blood-based tests may offer potential to increase patient engagement, the assumption of greater adherence in clinical practice requires further evaluation. This systematic review aimed to evaluate the real-world adherence to established blood-based tests for commonly recommended screening indications, to better inform expectations for proposed application to average-risk colorectal cancer (CRC) screening. Methods: A systematic search of PubMed, Embase, and citations was performed to identify literature published from 2010 to 2023. Studies examined adherence to routine blood-based laboratory tests with a Grade A or B recommendation per the United States Preventive Services Task Force (USPSTF) for diabetes, dyslipidemia, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) in an average-risk patient population were included. In addition, prostate-specific antigen (PSA) testing adherence for prostate cancer screening (Grade-C USPSTF recommendation), the only commonly accessible blood-based single-cancer screening test for average-risk adults, was also included. Studies without venipuncture-derived blood were excluded. Results: Of 53,067 articles screened, 69 were included in the analysis. Overall, adherence rates of blood-based tests were highly variable, with median values (interquartile range, IQR) of 66.3% (11.8%), 67.8% (18.0%), 34% (28.7%), and 36.8% (30%) for diabetes, dyslipidemia, HCV, and HIV, respectively. PSA testing adherence was 37.2% (18.4%). Beyond disease type, adherence varied by study design, data source, patient characteristics, clinical setting, and study country. Information and selection bias were the most common risks of bias. Conclusions: Based on data from this comprehensive systematic review, real-world adherence to currently recommended, blood-based screening strategies is suboptimal. Future research is needed to identify the extent to which these data are generalizable to blood-based CRC screening, and to determine if/how this candidate strategy would impact clinical, economic, and health equity outcomes. Citation Format: Quang A. Le, Takako Kiener, Heather A. Johnson, Rukaiyya S. Khan, Joyce Kong, Kevin H. Li, Gina Thompson, A. Burak Ozbay, Mallik Greene, Paul J. Limburg, A. Mark Fendrick, John B. Kisiel, Derek W. Ebner. Systematic review of real-world adherence to blood-based laboratory tests for average-risk disease screening: potential implications for emerging colorectal cancer screening modalities [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A027.

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.