Early-Onset Colorectal Cancer Patients Do Not Require Shorter Intervals for Post-Surgical Surveillance Colonoscopy.

BACKGROUND: Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC to average onset colorectal cancer (AO-CRC) patients to help define surveillance outcomes in these groups. METHODS: Single institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps (adenoma/sessile serrated)) were examined. For each group, three serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards. RESULTS: A total of 1259 CRC patients were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared to AO-CRC patients, EO-CRC patients had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (HR=0.71, 95% CI 0.52 - 1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (p=0.003), and EO-CRC were found to have less advanced neoplasia compared to AO-CRC counterparts (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that while EO-CRC patients returned for follow-up surveillance colonoscopy earlier than AO-CRC patients, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas. CONCLUSIONS: EO-CRC patients do not have an increased risk of advanced neoplasia compared to AO-CRC patients and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend.

CLINICOPATHOLOGICAL CHARACTERISTICS AND RISK FACTORS OF YOUNG-ONSET GASTRIC CARCINOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS.

BACKGROUND: The characteristics of gastric carcinoma in young individuals differ from older individuals. We conducted a systematic review and meta-analysis to explore the clinicopathological features and risk factors associated with young-onset (<50 years) gastric carcinoma. METHODS: We searched for studies published between January 1, 1990, and September 1, 2023, on patients with young-onset gastric carcinoma in PubMed, EMBASE, Web of Science, and MEDLINE to explore clinicopathological characteristics among this specific patient group. Extracted information included the proportion of patients with symptoms or family history of gastric cancer, tumor location, and histological features such as Lauren or WHO histological classification and degree of differentiation. Additional analyses were conducted on risk factors such as a positive family history, Helicobacter pylori (H. pylori) infection, or high-risk nutritional or behavioral factors. The estimates were derived using random or fixed-effect models and included subgroup analyses based on different sex and age groups. This study was registered in PROSPERO (CRD42023466131). RESULTS: We identified 5,696 records, 1,292 were included in the quality assessment stage. Finally, 84 studies from 18 countries or regions including 89,447 patients with young-onset gastric carcinoma were included. Young-onset gastric carcinoma has slight female predominance (53.7%, 95%CI: 51.6-55.7%), with most having symptoms (87.0%, 95%CI: 82.4-91.7%). Family history was reported in 12.1% (95%CI: 9.5-14.7%). H. pylori infection was detected in 60.0% of cases (95%CI: 47.1-72.8%). The majority of these carcinomas were in the non-cardia region (89.6%, 95%CI:82.4-96.8%), exhibiting Lauren diffuse-type histology (71.1%, 95%CI: 66.8-75.3%) and poor/undifferentiated features (81.9%, 95%CI: 79.7-84.2%). A positive family history of gastric cancer was the most important risk factor associated with the development of gastric carcinoma in young individuals (pooled odds ratios [OR] 4.0, 95% CI: 2.8-5.2), followed by H. pylori infection (OR 2.3; 95% CI: 1.4-3.2) and dietary and other lifestyle risk factors. CONCLUSION: Young-onset gastric carcinoma exhibits specific clinicopathological characteristics, with positive family history being the most important risk factor. The majority of patients were symptomatic at diagnosis. These findings could help to inform future strategies for the early detection of gastric carcinoma among young individuals.

Global burden of young-onset gastric cancer: a systematic trend analysis of the global burden of disease study 2019.

BACKGROUND: While gastric cancer is generally declining globally, the temporal trend of young-onset (< 40 years) gastric cancer remains uncertain. We performed this analysis to determine the temporal trends of young-onset gastric cancer compared to late-onset cancer (≥ 40 years). METHODS: We extracted cross-sectional data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The burden of gastric cancer from 1990 to 2019 was assessed through indicators including incidence and mortality rates, which were classified at global, national, and regional levels, and according to socio-demographic indexes (SDI) and age or sex groups. Joinpoint regression analysis was used to identify specific years with significant changes. The correlation between AAPC with countries' average SDI was tested by Pearson's Test. RESULTS: The global incidence rate of young-onset gastric cancer decreased from 2.20 (per 100,000) in 1990 to 1.65 in 2019 (AAPC: - 0.95; 95% confidence interval [CI] - 1.25 to - 0.65; P < 0.001). Late-onset cancer incidence also decreased from 59.53 (per 100,000) in 1990 to 41.26 in 2019 (AAPC: - 1.23; 95% CI - 1.39 to - 1.06, P < 0.001). Despite an overall decreasing trend, the incidence rate of young-onset cancer demonstrated a significant increase from 2015 to 2019 (annual percentage change [APC]: 1.39; 95% CI 0.06 to 2.74; P = 0.041), whereas no upward trend was observed in late-onset cancer. Mortality rates of young- and late-onset cancer both exhibited a significant decline during this period (AAPC: - 1.82; 95% CI - 2.15 to - 1.56; P < 0.001 and AAPC: - 1.69, 95% CI - 1.79 to - 1.59; P < 0.001). The male-to-female rate ratio for incidence and mortality in both age groups have been increasing since 1990. While countries with high SDI have had a greater decline in the incidence of late-onset gastric cancer (slope of AAPC change: - 0.20, P = 0.004), it was not observed in young-onset cancer (slope of AAPC change: - 0.11, P = 0.13). CONCLUSIONS: The global incidence and mortality rates of both young- and late-onset gastric cancer have decreased since 1990. However, the incidence rate of young-onset cancer has demonstrated a small but significant upward trend since 2015. There was disparity in the decline in young-onset gastric cancer among male and high SDI countries. These findings could help to inform future strategies in preventing gastric cancer in younger individuals.

Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of precursor lesions for gastric cancer (GC) and the differential burden between countries of varying GC risk is not well-understood. We conducted a systematic review and meta-analysis to estimate the global prevalence of precursor lesions. METHODS: We estimated the prevalence of atrophic gastritis (AG), gastric intestinal metaplasia (IM), and dysplasia in regions with low, medium, and high GC incidence. Because IM is an advanced manifestation of AG, we assessed the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. Prevalence was sub-stratified by Helicobacter pylori infection, symptomatology, and period (<2000, 2000-2010, and >2010). RESULTS: Among the 582 articles that underwent full-text review, 166 studies met inclusion criteria. The global prevalence estimates of AG, IM, and dysplasia were 25.4%, 16.2%, and 2.0%, respectively, on the basis of 126 studies that reported the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. The prevalence of all precursor lesions was higher in high and medium compared with low GC incidence countries (P < .01). Prevalence of AG and IM was significantly higher among H pylori-infected individuals (P < .01) but not statistically different between symptomatic and asymptomatic individuals (P > .17). All precursors demonstrated a secular decrease in prevalence over time. CONCLUSIONS: Gastric precursor lesions have differences in prevalence in regions with differential GC incidence and are associated with H pylori infection. Because of the substantial prevalence of precursor lesions in both symptomatic and asymptomatic individuals, symptomatic evaluation may not be sufficient to identify individuals at risk. These estimates provide important insights for tailoring GC prevention strategies.

Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare & Medicaid Services Coverage Decision.

BACKGROUND & AIMS: A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare & Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective. METHODS: Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis. RESULTS: Without screening, the models predicted 77-88 CRC cases and 32-36 CRC deaths per 1000 individuals, costing $5.3-$5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5-24 QALYG) and less costly (-$3.2 to -$3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT. CONCLUSION: Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Estimated US Cancer Deaths Prevented With Increased Use of Lung, Colorectal, Breast, and Cervical Cancer Screening.

Importance: Increased use of recommended screening could help achieve the Cancer Moonshot goal of reducing US cancer deaths. Objective: To estimate the number of cancer deaths that could be prevented with a 10-percentage point increase in the use of US Preventive Services Task Force (USPSTF)-recommended screening. Design, Setting, and Participants: This decision analytical model study is an extension of previous studies conducted for the USPSTF from 2018 to 2023. This study simulated contemporary cohorts of US adults eligible for lung, colorectal, breast, and cervical cancer screening. Exposures: Annual low-dose computed lung tomography among eligible adults aged 50 to 80 years; colonoscopy every 10 years among adults aged 45 to 75 years; biennial mammography among female adults aged 40 to 74 years; and triennial cervical cytology screening among female adults aged 21 to 29 years, followed by human papillomavirus testing every 5 years from ages 30 to 65 years. Main Outcomes and Measures: Estimated number of cancer deaths prevented with a 10-percentage point increase in screening use, assuming screening commences at the USPSTF-recommended starting age and continues throughout the lifetime. Outcomes were presented 2 ways: (1) per 100 000 and (2) among US adults in 2021; and they were expressed among the target population at the age of screening initiation. For lung cancer, estimates were among those who will also meet the smoking eligibility criteria during their lifetime. Harms from increased uptake were also reported. Results: A 10-percentage point increase in screening use at the age that USPSTF recommended screening commences was estimated to prevent 226 lung cancer deaths (range across models within the cancer site, 133-332 deaths), 283 (range, 263-313) colorectal cancer deaths, 82 (range, 61-106) breast cancer deaths, and 81 (1 model; no range available) cervical cancer deaths over the lifetimes of 100 000 persons eligible for screening. These rates corresponded with an estimated 1010 (range, 590-1480) lung cancer deaths prevented, 11 070 (range, 10 280-12 250) colorectal cancer deaths prevented, 1790 (range, 1330-2310) breast cancer deaths prevented, and 1710 (no range available) cervical cancer deaths prevented over the lifetimes of eligible US residents at the recommended age to initiate screening in 2021. Increased uptake was also estimated to generate harms, including 100 000 (range, 45 000-159 000) false-positive lung scans, 6000 (range, 6000-7000) colonoscopy complications, 300 000 (range, 295 000-302 000) false-positive mammograms, and 348 000 (no range available) colposcopies over the lifetime. Conclusions and Relevance: In this decision analytical model study, a 10-percentage point increase in uptake of USPSTF-recommended lung, colorectal, breast, and cervical cancer screening at the recommended starting age was estimated to yield important reductions in cancer deaths. Achieving these reductions is predicated on ensuring equitable access to screening.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Personalized Multilevel Intervention for Improving Appropriate Use of Colorectal Cancer Screening in Older Adults: A Cluster Randomized Clinical Trial.

Importance: Despite guideline recommendations, clinicians do not systematically use prior screening or health history to guide colorectal cancer (CRC) screening decisions in older adults. Objective: To evaluate the effect of a personalized multilevel intervention on screening orders in older adults due for average-risk CRC screening. Design, Setting, and Participants: Interventional 2-group parallel unmasked cluster randomized clinical trial conducted from November 2015 to February 2019 at 2 US Department of Veterans Affairs (VA) facilities: 1 academic VA medical center and 1 of its connected outpatient clinics. Randomization at the primary care physician/clinician (PCP) level, stratified by study site and clinical full-time equivalency. Participants were 431 average-risk, screen-due US veterans aged 70 to 75 years attending a primary care visit. Data analysis was performed from August 2018 to August 2023. Intervention: The intervention group received a multilevel intervention including a decision-aid booklet with detailed information on screening benefits and harms, personalized for each participant based on age, sex, prior screening, and comorbidity. The control group received a multilevel intervention including a screening informational booklet. All participants received PCP education and system-level modifications to support personalized screening. Main Outcomes and Measures: The primary outcome was whether screening was ordered within 2 weeks of clinic visit. Secondary outcomes were concordance between screening orders and screening benefit and screening utilization within 6 months. Results: A total of 436 patients were consented, and 431 were analyzed across 67 PCPs. Patients had a mean (SD) age of 71.5 (1.7) years; 424 were male (98.4%); 374 were White (86.8%); 89 were college graduates (21.5%); and 351 (81.4%) had undergone prior screening. A total of 258 (59.9%) were randomized to intervention, and 173 (40.1%) to control. Screening orders were placed for 162 of 258 intervention patients (62.8%) vs 114 of 173 control patients (65.9%) (adjusted difference, -4.0 percentage points [pp]; 95% CI, -15.4 to 7.4 pp). In a prespecified interaction analysis, the proportion receiving orders was lower in the intervention group than in the control group for those in the lowest benefit quartile (59.4% vs 71.1%). In contrast, the proportion receiving orders was higher in the intervention group than in the control group for those in the highest benefit quartile (67.6% vs 52.2%) (interaction P = .049). Fewer intervention patients (106 of 256 [41.4%]) utilized screening overall at 6 months than controls (96 of 173 [55.9%]) (adjusted difference, -13.4 pp; 95% CI, -25.3 to -1.6 pp). Conclusions and Relevance: In this cluster randomized clinical trial, patients who were presented with personalized information about screening benefits and harms in the context of a multilevel intervention were more likely to receive screening orders concordant with benefit and were less likely to utilize screening. Trial Registration: ClinicalTrials.gov Identifier: NCT02027545.

Projected long-term effects of colorectal cancer screening disruptions following the COVID-19 pandemic.

The aftermath of the initial phase of the COVID-19 pandemic may contribute to the widening of disparities in colorectal cancer (CRC) outcomes due to differential disruptions to CRC screening. This comparative microsimulation analysis uses two CISNET CRC models to simulate the impact of ongoing screening disruptions induced by the COVID-19 pandemic on long-term CRC outcomes. We evaluate three channels through which screening was disrupted: delays in screening, regimen switching, and screening discontinuation. The impact of these disruptions on long-term CRC outcomes was measured by the number of life-years lost due to CRC screening disruptions compared to a scenario without any disruptions. While short-term delays in screening of 3-18 months are predicted to result in minor life-years loss, discontinuing screening could result in much more significant reductions in the expected benefits of screening. These results demonstrate that unequal recovery of screening following the pandemic can widen disparities in CRC outcomes and emphasize the importance of ensuring equitable recovery to screening following the pandemic.

Young-onset colorectal cancer.

In the past decades the incidence of colorectal cancer (CRC) in people under the age of 50 years has increased, which is referred to as early-onset CRC or young-onset CRC (YO-CRC). YO-CRC is expected to account for 11% of colon cancers and 23% of rectal cancers by 2030. This trend is observed in different parts of the world and in both men and women. In 20% of patients with YO-CRC, a hereditary cancer syndrome is found as the underlying cause; however, in the majority of patients no genetic predisposition is present. Beginning in the 1950s, major changes in lifestyle such as antibiotic use, low physical activity and obesity have affected the gut microbiome and may be an important factor in YO-CRC development. Owing to a lack of screening, patients with YO-CRC are often diagnosed with advanced-stage disease. Long-term treatment-related complications should be taken into account in these younger patients, making the more traditional sequential approaches of drug therapy not always the most appropriate option. To better understand the underlying mechanism and define relationships between environmental factors and YO-CRC development, long-term prospective studies are needed with lifestyle data collected from childhood.

Factors associated with detection of hereditary diffuse gastric cancer on endoscopy in individuals with germline CDH1 mutations.

BACKGROUND AND AIMS: Individuals with germline pathogenic CDH1 variants have a high risk of hereditary diffuse gastric cancer. The sensitivity of EGD in detecting signet ring cell carcinoma (SRCC) in this population is low. We aimed to identify endoscopic findings and biopsy practices associated with detection of SRCC. METHODS: This retrospective cohort included individuals with a germline pathogenic/likely pathogenic CDH1 variant undergoing at least 1 EGD at Memorial Sloan Kettering Cancer Center between January 1, 2006, and March 25, 2022. The primary outcome was detection of SRCC on EGD. Findings on gastrectomy were also assessed. The study included periods before and after implementation of the Cambridge protocol for endoscopic surveillance, allowing for assessment of a spectrum of biopsy practices. RESULTS: Ninety-eight CDH1 patients underwent at least 1 EGD at our institution. SRCC was detected in 20 (20%) individuals on EGD overall and in 50 (86%) of the 58 patients undergoing gastrectomy. Most SRCC foci were detected in the gastric cardia/fundus (EGD, 50%; gastrectomy, 62%) and body/transition zone (EGD, 60%; gastrectomy, 62%). Biopsy results of gastric pale mucosal areas were associated with detection of SRCC (P < .01). The total number of biopsy samples taken on EGD was associated with increased detection of SRCC (P = .01), with 43% detected when ≥40 samples were taken. CONCLUSIONS: Targeted biopsy sampling of gastric pale mucosal areas and increasing number of biopsy samples taken on EGD were associated with detection of SRCC. SRCC foci were mostly detected in the proximal stomach, supporting updated endoscopic surveillance guidelines. Further studies are needed to refine endoscopic protocols to improve SRCC detection in this high-risk population.

Critical Appraisal of Decision Models Used for the Economic Evaluation of Bladder Cancer Screening and Diagnosis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Bladder cancer is common among current and former smokers. High bladder cancer mortality may be decreased through early diagnosis and screening. The aim of this study was to appraise decision models used for the economic evaluation of bladder cancer screening and diagnosis, and to summarise the main outcomes of these models. METHODS: MEDLINE via PubMed, Embase, EconLit and Web of Science databases was systematically searched from January 2006 to May 2022 for modelling studies that assessed the cost effectiveness of bladder cancer screening and diagnostic interventions. Articles were appraised according to Patient, Intervention, Comparator and Outcome (PICO) characteristics, modelling methods, model structures and data sources. The quality of the studies was also appraised using the Philips checklist by two independent reviewers. RESULTS: Searches identified 3082 potentially relevant studies, which resulted in 18 articles that met our inclusion criteria. Four of these articles were on bladder cancer screening, and the remaining 14 were diagnostic or surveillance interventions. Two of the four screening models were individual-level simulations. All screening models (n = 4, with three on a high-risk population and one on a general population) concluded that screening is either cost saving or cost effective with cost-effectiveness ratios lower than $53,000/life-years saved. Disease prevalence was a strong determinant of cost effectiveness. Diagnostic models (n = 14) assessed multiple interventions; white light cystoscopy was the most common intervention and was considered cost effective in all studies (n = 4). Screening models relied largely on published evidence generalised from other countries and did not report the validation of their predictions to external data. Almost all diagnostic models (n = 13 out of 14) had a time horizon of 5 years or less and most of the models (n = 11) did not incorporate health-related utilities. In both screening and diagnostic models, epidemiological inputs were based on expert elicitation, assumptions or international evidence of uncertain generalisability. In modelling disease, seven models did not use a standard classification system to define cancer states, others used risk-based, numerical or a Tumour, Node, Metastasis classification. Despite including certain components of disease onset or progression, no models included a complete and coherent model of the natural history of bladder cancer (i.e. simulating the progression of asymptomatic primary bladder cancer from cancer onset, i.e. in the absence of treatment). CONCLUSIONS: The variation in natural history model structures and the lack of data for model parameterisation suggest that research in bladder cancer early detection and screening is at an early stage of development. Appropriate characterisation and analysis of uncertainty in bladder cancer models should be considered a priority.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data.

BACKGROUND & AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

Elucidating the Drivers for the Rising Incidence of Early-Onset Colorectal Cancer: How Ecologic Studies Could Help and What Is Next.

The incidence of colorectal cancer diagnosed before age 50, often referred to as early-onset colorectal cancer, has been increasing, whereas the overall colorectal cancer incidence has declined. Elucidating the drivers for the rising burden of early-onset colorectal cancer is a priority in cancer epidemiology and prevention. In this issue of Cancer Epidemiology, Biomarkers & Prevention, Chen and colleagues demonstrated that ecologic studies are a helpful method to reveal emerging risk factors at the population level and concluded that alcohol use might be a potential contributor to the rising incidence of early-onset colorectal cancer. Moving forward, because of the observed birth cohort effect in early-onset colorectal cancer, where younger generations have a steeper increase, hypothesis-driven investigations on emerging risk factors in recent generations, especially during early life, are warranted. Ultimately, the identified risk factors could be integrated with well-established microsimulation models of colorectal cancer, powerful tools that can simultaneously capture population-level secular changes in risk factors, relative risk estimates for each risk factor, and the natural history of colorectal cancer. This would allow us to quantitatively estimate the explained and unexplained portion of the rising incidence of early-onset colorectal cancer by calendar period and birth cohorts, and to help identify priorities in etiologic research, prevention, and early detection. See related article by Chen et al., p. 217.

The Impacts of Computer-Aided Detection of Colorectal Polyps on Subsequent Colonoscopy Surveillance Intervals: Simulation Study.

BACKGROUND: Computer-aided detection (CADe) of colorectal polyps has been shown to increase adenoma detection rates, which would potentially shorten subsequent surveillance intervals. OBJECTIVE: The purpose of this study is to simulate the potential changes in subsequent colonoscopy surveillance intervals after the application of CADe in a large cohort of patients. METHODS: We simulated the projected increase in polyp and adenoma detection by universal CADe application in our patients who had undergone colonoscopy with complete endoscopic and histological findings between 2016 and 2020. The simulation was based on bootstrapping the published performance of CADe. The corresponding changes in surveillance intervals for each patient, as recommended by the US Multi-Society Task Force on Colorectal Cancer (USMSTF) or the European Society of Gastrointestinal Endoscopy (ESGE), were determined after the CADe was determined. RESULTS: A total of 3735 patients who had undergone colonoscopy were included. Based on the simulated CADe effect, the application of CADe would result in 19.1% (n=714) and 1.9% (n=71) of patients having shorter surveillance intervals, according to the USMSTF and ESGE guidelines, respectively. In particular, all (or 2.7% (n=101) of the total) patients who were originally scheduled to have 3-5 years of surveillance would have their surveillance intervals shortened to 3 years, following the USMSTF guidelines. The changes in this group of patients were largely attributed to an increase in the number of adenomas (n=75, 74%) rather than serrated lesions being detected. CONCLUSIONS: Widespread adoption of CADe would inevitably increase the demand for surveillance colonoscopies with the shortening of original surveillance intervals, particularly following the current USMSTF guideline.

Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.