Limburg, Paul J.

Abstract Commercial insurance covers a follow-up colonoscopy after a positive colorectal cancer–screening test with no patient cost-sharing. Instituting a similar policy for Medicare beneficiaries may increase screening adherence and improve outcomes. The cost-effectiveness of stool-based colorectal cancer screening was compared across adherence scenarios that assumed Medicare coinsurance status quo (20% for follow-up colonoscopy) or waived coinsurance. The CRC-AIM model simulated previously unscreened eligible Medicare beneficiaries undergoing stool-based colorectal cancer screening at age 65 for 10 years. Medicare costs, colorectal cancer cases, colorectal cancer–related deaths, life-years gained (LYG), and quality-adjusted life-years (QALY) were estimated versus no screening. Scenario 1 (S1) assumed 20% coinsurance for follow-up colonoscopy. Scenario 2 (S2) assumed waived coinsurance without adherence changes. Scenarios 3–7 (S3–S7) assumed that waiving coinsurance increased real-world stool-based screening and/or follow-up colonoscopy adherence by 5% or 10%. Sensitivity analyses assumed 1%–4% increased adherence. Cost-effectiveness threshold was ≤$100,000/QALY. Waiving coinsurance without adherence changes (S2) did not affect outcomes versus S1. S3–S7 versus S1 over 10 years estimated up to 3.6 fewer colorectal cancer cases/1,000 individuals, up to 2.1 fewer colorectal cancer deaths, up to 20.7 more LYG, and had comparable total costs per-patient (≤$6,478 vs. $6,449, respectively) as reduced colorectal cancer medical costs offset increased screening and colonoscopy costs. In sensitivity analyses, any increase in adherence after waiving coinsurance was cost-effective and increased LYG. In simulated Medicare beneficiaries, waiving coinsurance for follow-up colonoscopy after a positive stool-based test improved outcomes and was cost-effective when assumed to modestly increase colorectal cancer screening and/or follow-up colonoscopy adherence. Prevention Relevance: Follow-up colonoscopy after a positive stool-based test is necessary to complete the colorectal cancer-screening process. This analysis demonstrated that in a simulated Medicare population, waiving coinsurance for a follow-up colonoscopy improved estimated outcomes and was cost-effective when it was assumed that waiving the coinsurance modestly increased screening adherence. See related Spotlight, p. 641

Abstract Objective: Controversy remains regarding the association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) risk. To clarify and extend the existing data, we prospectively evaluated the association between self-reported type 2 DM (onset at >30 years of age) and incident CRC, overall and by anatomic subsite, among postmenopausal women in the Iowa Women's Health Study (n = 35,230). Methods: After 14 years of follow-up, a total of 870 incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up. CRC risks were estimated using Cox proportional hazards regression models. Results: After adjusting for age, body mass index and other potential confounding variables, the relative risk (RR) for women with DM versus women without DM was modestly increased at 1.4 [95% confidence interval (95% CI), 1.1-1.8]. By anatomic subsite, the RR for proximal colon cancer was statistically significantly increased (RR, 1.9; 95% CI, 1.3-2.6), whereas the RRs for distal colon (RR, 1.1; 95% CI, 0.6-1.8) and rectal cancer (RR, 0.8; 95% CI, 0.4-1.6) were not statistically different from unity. Analyses that included DM ascertained at baseline and follow-up yielded similar results. Conclusion: In this large, prospective study of postmenopausal women, the association between DM and incident CRC was found to be subsite specific. If confirmed by others, this finding implies that CRC prevention strategies among type 2 DM patients should include examination of the proximal colon.

Abstract To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50–69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37–1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38–1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50–1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.

10529 Background: The Centers for Medicare & Medicaid Services (CMS) recommends covering blood-based biomarker tests with proposed minimum performance thresholds for colorectal cancer (CRC) screening test every 3 years for average-risk, asymptomatic Medicare beneficiaries ages 50–85 years. A blood-based test is a non-invasive screening method to detect CRC but is limited by low sensitivity to detect adenomas. Using the CRC-AIM microsimulation model, predicted life-years gained (LYG) and CRC incidence and mortality reduction were compared between a blood-based test meeting the CMS minimum thresholds and stool-based screening tests (fecal immunochemical test [FIT], fecal occult blood test [FOBT], and multitarget stool DNA [mt-sDNA]). Methods: Outcomes of blood- and stool-based tests were simulated for average-risk individuals free of diagnosed CRC at age 40 and screened between ages 45–75 years per USPSTF recommendations. Per CMS proposed criteria, CRC sensitivity and specificity for a blood-based test were set at 74% and 90%, respectively, and adenoma sensitivity was set at 10%. Published adenoma and CRC sensitivity and specificity were used for each stool test. For the primary analysis, adherence was assumed to be 100%. For secondary analysis, adherence was set at 30–70%, in 10% increments. Outcomes were per 1000 individuals. Results: At 100% adherence, LYG was 229 for a blood test and ≥305 for stool tests, corresponding to at least 25% lower LYG for a blood test relative to all stool tests (Table). Absolute CRC incidence and mortality reductions were at least 19% and 18% lower, respectively, for a blood test vs all stool tests. Secondary analysis indicates that at identical adherence rates that are less than 100%, a blood test had lower LYG vs all stool tests (Table). When the adherence of any test was 50%–70%, a blood test resulted in at least 20% lower LYG vs any stool test, and absolute reductions in CRC incidence and mortality were at least 9% and 10% lower, respectively, vs any stool test. Conclusions: This model suggests that if blood-based CRC screening tests do not sufficiently detect advanced adenomas, clinical outcomes will be inferior to stool-based testing due to lack of cancer prevention. Further discovery efforts to identify blood-based markers associated with both invasive and preinvasive neoplasia are needed to address this deficiency. [Table: see text]

10526 Background: Cancer screening provides a straightforward diagnostic path compared to non-screening, which often requires complex evaluation for patients with non-specific symptoms. The time to diagnosis (from clinical presentation or screening event to definitive diagnosis) captures the clinical efficiency of the journey. The study characterizes time to diagnosis for cancers with and without USPSTF Grade A/B screening recommendations. This could inform the value of screening in diagnostic management and care efficiency improvements. Methods: The Geisinger Health System Phenomics Initiative Database provides deidentified EHR and tumor registry data. Patients aged 50-74 with encounters at least biennially for six years prior to a cancer diagnosis were frequency-matched to a non-cancer control group by diagnosis year. From 18 months prior to diagnosis, equally-sized random samples were drawn (with replacement) from a time-bounded sliding window at monthly intervals. Aggregated procedure and diagnostic code counts for cancer and non-cancer samples were used to calculate the Bray-Curtis dissimilarity (BCd) statistic. The start of the diagnostic path was defined as the earliest date with a monotonically-increasing statistically-significant difference in BCd (95% CI), and was stratified into cancers with and without screening and by stage. Results: 8188 new cancer cases were identified between 2010-2019; 40% had an established screening modality (breast, lung, colorectal, cervical), 55% of which were screened prior to diagnosis. The time to diagnosis for non-screenable cancers was 6 months versus 3 months for screenable cancers. The BCd for procedures differed by 0.029 (95% CI: 0.021-0.037) between the two groups at 6 months prior to diagnosis. Stages I and IV had a time to diagnosis of 3 months across all cancers versus 7 and 6 months for stages II and III, respectively. Conclusions: We report the first known quantification of time to diagnosis across multiple cancers. Screenable cancers were associated with shorter time to diagnosis than non-screenable cancers. Stage II and III cancers took longer to diagnose than stage I and IV, likely related to early detection by screening in the former and severe symptom presentation in the latter. These novel data highlight improved time to diagnosis as another achievable benefit from expanded, multi-cancer screening.

e13631 Background: Colorectal cancer (CRC) screening disruptions have been observed with the COVID-19 pandemic, putting patients at risk for more advanced-stage disease at the time of diagnosis. We estimated the impact of increased use of stool-based tests for screening during the COVID-19 pandemic on near-term clinical outcomes in a simulated United States (US) population. Methods: A previously developed budget impact model was adapted to assess the impact of increasing use of multi-target stool DNA [mt-sDNA] or fecal immunochemical [FIT] tests to offset the COVID-19 related disruption in colonoscopy screening. Adults, ages 50 – 75 years, at average risk for CRC were included over a 3-year time horizon (2020 – 2023) to explore the impact of increased screening for CRC using mt-sDNA or FIT, from the perspective of a US payer. Compared to the base case (S0; 85% colonoscopy and 15% non-invasive tests), the estimated number of missed CRCs and advanced adenomas (AAs) were determined for four COVID-19-affected screening scenarios: S1, 9 months of CRC screening at 50% capacity, followed by 21 months at 75% capacity; S2, S1 followed by increasing stool-based testing by an average of 10% over 3-years; S3, 18 months of CRC screening at 50% capacity, followed by 12 months of 75% capacity; and S4, S3 followed by increasing stool-based testing by an average of 13% over 3-years. Results: Increasing the proportional use of mt-sDNA, the detection of AAs improved by 6.0% (Scenario 2 versus 1) to 8.4% (Scenario 4 versus 3) and the number of missed CRCs decreased by 15.1% to 17.3% respectively. Increasing FIT utilization improved the detection of AAs by 3.3% (Scenario 2 versus 1) to 4.6% (Scenario 4 versus 3) and the number of missed CRCs decreased by 12.9% (Scenario 2 versus 1) to 14.9% (Scenario 4 versus 3). Across all scenarios, the number of AAs detected was higher for mt-sDNA than for FIT, and the number of missed CRCs was lower for mt-sDNA than for FIT. Conclusions: Using home-based stool tests for average-risk CRC screening can mitigate the consequences of reduced colonoscopy screening resulting from the COVID-19 pandemic. Use of mt-sDNA led to fewer missed CRCs and more AAs detected, compared to FIT.

e13624 Background: Commercial insurance plans are required to cover, with no patient cost sharing, a follow-up colonoscopy (COL) after a positive stool-based colorectal cancer (CRC) screening test. Medicare beneficiaries may still be responsible for 20% coinsurance for a follow-up COL, posing a financial barrier to screening completion. Removing the coinsurance may increase screening adherence and improve outcomes. The estimated cost-effectiveness of stool-based CRC screening was compared among adherence scenarios that assumed the status quo (20% coinsurance for follow-up COL) or waived follow-up COL coinsurance. Methods: The CRC-AIM microsimulation model simulated US Medicare beneficiaries undergoing stool-based CRC screening between ages 65-75 years. Outcomes of total costs, total quality adjusted life years (QALYs), life-years gained (LYG), CRC incidence reductions (IR), and CRC mortality reductions (MR) were calculated per 1000 individuals versus no screening using the weighted average of the outcome with multitarget stool DNA, fecal immunochemical test, and fecal occult blood test, scaled by their estimated use. Costs of follow-up COL were assumed to have 20% coinsurance in the status quo scenario. Four comparative scenarios assumed that waiving coinsurance increased published, real-world stool-based screening or follow-up COL adherence rates by 5% or 10%. Results: In scenarios where waiving coinsurance was assumed to increase screening and/or follow-up COL adherence, up to 21 more LYG and greater IR and MR were observed vs the status quo (Table). Total costs in waived coinsurance scenarios (≥$6,398) were comparable to the status quo ($6,449) as the cost savings in CRC care offset the increased COL costs. Total QALYs in waived coinsurance scenarios (≥9.3671) were greater than the status quo (9.3643) because of improved clinical outcomes. Stool-based testing in waived coinsurance scenarios was either dominant (more effective and less costly) or cost-effective at $50,000/QALY with minimal incremental costs vs the status quo. Conclusions: In a simulated Medicare population, clinical CRC outcomes improved and stool-based screening was cost-effective or cost-saving when waiving the 20% coinsurance was assumed to modestly (5%) increase adherence rates for total CRC screening and/or a COL following a positive test. [Table: see text]

Importance Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal adenomas and cancer. Combination sulindac and erlotinib was previously shown to reduce duodenal polyp burden but was associated with a relatively high adverse event (AE) rate. Objective: To evaluate if a once weekly dosing schedule for erlotinib intervention improves the AE profile, while still providing efficacy with respect to reduced polyp burden, in participants with FAP. Design, setting and participants: Single-arm trial, enrolling 46 participants with FAP, conducted from October 2017 to September 2019 in eight academic cancer centres. Exposures Participants self-administered 350 mg of erlotinib by mouth, one time per week for 6 months. Main outcomes and measures: Duodenal polyp burden (sum of polyp diameters) was assessed in the proximal duodenum by esophagogastroduodenoscopy performed at baseline and 6 months, with mean per cent change defined as the primary efficacy outcome of interest. Rate of grade 2–3 AEs was evaluated as a co-primary outcome. Secondary outcomes included changes in total duodenal polyp count, along with changes in lower gastrointestinal (GI) polyp burden and count (for participants examined by optional lower endoscopy). Results Forty-six participants (mean age, 44.1 years (range, 18–68); women, 22 (48%)) were enrolled; 42 participants completed 6 months of intervention and were included in the per-protocol analysis. Duodenal polyp burden was significantly reduced after 6 months of weekly erlotinib intervention, with a mean per cent change of −29.6% (95% CI, −39.6% to −19.7%; p<0.0001). Similar results were observed in subgroup analyses defined by participants with advanced duodenal polyposis (Spigelman 3) at baseline (mean, −27%; 95% CI, −38.7% to −15.2%; p<0.0001). Post-intervention Spigelman stage was downstaged in 12% of the participants. Lower GI polyp number was also decreased after 6 months of intervention (median, −30.8%; IQR, −47.4% to 0.0%; p=0.0256). Grade 2 or 3 AEs were reported in 71.7% of subjects, with only two experiencing grade 3 toxicity at least possibly related to intervention. Conclusion In this single-arm, multi-centre trial of participants with FAP, erlotinib one time per week resulted in markedly lower duodenal polyp burden, and modestly reduced lower GI polyp burden, after 6 months of intervention. While AEs were still reported by nearly three-quarters of all participants, these events were generally lower grade and well-tolerated. These findings support further investigation of erlotinib as an effective, acceptable cancer preventive agent for FAP-associated GI polyposis. Trial registration number NCT02961374 .

Abstract Few studies compare fecal immunochemical test (FIT) and multi-target stool DNA (mt-sDNA) outcomes in practice. We compared colonoscopy yield following FIT+ or mt-sDNA+ tests to colonoscopies without preceding stool tests in the comprehensive population-based New Hampshire Colonoscopy Registry (NHCR). Outcomes were any neoplasia and an ordered outcome: adenocarcinoma, advanced neoplasia (adenoma/serrated polyp ≥ 1 cm/villous/high-grade dysplasia), nonadvanced neoplasia, or normal. Our total sample included 306 mt-sDNA+ (average age ± SD 67.0 ± 7.9), 276 FIT+ (66.6 ± 8.7), and 50,990 colonoscopy-only patients (61.8 ± 8.1). Among average-risk patients (N = 240 mt-sDNA+, N = 194 FIT+, N = 26,221 colonoscopy only), mt-sDNA+ patients had a higher risk for any neoplasia (67.1%) compared with FIT+ (54.6%, P = 0.00098) or colonoscopy (40.8%, P &lt; 0.0001). Severity of findings and histology subtypes differed across the three groups (P &lt; 0.0001 for both), with a higher yield of advanced findings in mt-sDNA+ patients. In particular, clinically relevant serrated polyps (hyperplastic polyps ≥10 mm/traditional serrated adenomas/sessile serrated polyps) were detected at a higher frequency in mt-sDNA+ patients as compared with FIT+ or colonoscopy-only patients. Even after adjustment, patients with positive mt-sDNA [OR = 2.82; 95% confidence interval (CI), 2.00–4.02] or FIT+ tests (OR = 1.67; 95% CI, 1.19–2.36) were more likely to have histologically more advanced findings than colonoscopy alone. At follow-up colonoscopy, mt-sDNA+ tests were more likely to predict neoplasia than FIT+, largely due to increased detection of serrated polyps. Prevention Relevance: Colorectal cancer screening options include colonoscopy and stool-based tests, including the fecal immunochemical test (FIT) and the multi-target stool DNA (mt-sDNA) test which, if positive, must be followed by a colonoscopy. Assessing “real-world” outcomes of colonoscopies following positive stool tests can inform their clinical use. See related Spotlight, p. 417