Preface.

Colon Cancer Screening Models: Lessons and Challenges

Effectiveness of Screening Modalities in Colorectal Cancer: A Network Meta-Analysis

Introduction: Observational and experimental evidence demonstrate that non-steroidal anti-inflammatory drug (NSAID) use reduces the incidence and recurrence of colorectal neoplasia. Consistent with such observations, recent studies have also suggested an inverse association between NSAID use, particularly long-term use, and colorectal cancer (CRC) mortality. We examined the association between aspirin and non-aspirin NSAID use and colorectal mortality among post-menopausal women enrolled in the clinical trial and observational study arms of the Women's Health Initiative (WHI). Methods: We investigated the effect of NSAID use on colorectal cancer mortality among 160,143 women enrolled in the WHI with available follow up data who did not report a prior history of colorectal cancer at the time of study entry. Women provided details on aspirin and non-aspirin NSAID use at both study baseline and three years after enrollment. Reported cases of colorectal cancers were locally confirmed based on medical records and also centrally adjudicated. Cause of death was determined according to centralized medical record and death certificate review; routine linkages were made to National Death Index files to ensure the completeness of vital status information. There were 2,119 confirmed cases of colorectal cancer and 492 deaths among WHI participants where the listed cause of death was colorectal cancer. Cox proportional hazards regression was used to examine the relationship between NSAID use (at study baseline and at year 3 of study follow-up) and colorectal cancer mortality and to estimate hazard ratios and 95% confidence intervals. We conducted a sensitivity analysis that excluded women who developed colorectal cancer within the first three years following study enrollment (n=180) in order to restrict the study question to examining the role of NSAID use prior to diagnosis on colorectal cancer mortality. Results: Reported use of NSAIDs at study baseline, including aspirin, ibuprofen, and prescription NSAIDs, was not associated with colorectal cancer mortality (HR: 0.93; 95% CI 0.76–1.14). However, among women who lived to year 3 after study enrollment (n=156,440; 98% of participants), those who reported use of NSAIDs at both baseline and year 3 experienced reductions in colorectal cancer mortality of approximately 30% (HR: 0.72; 95% CI 0.54–0.95) compared to women who did not report use at both time points. Results from the sensitivity analysis demonstrated that prolonged pre-diagnostic NSAID use (use at both baseline and year 3) was significantly associated with reduced colorectal cancer mortality (HR: 0.70; 95% CI 0.52–0.93). Conclusion: Our results suggest that use of NSAIDs is associated with lower colorectal cancer mortality among post-menopausal women, particularly in women who use these medications for longer periods of time prior to diagnosis. This association may reflect an effect of NSAID use in decreasing the incidence of new tumors and/or an effect in lowering rates of disease progression. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A69.

We aimed to evaluate the association between colonoscopy and colorectal cancer (CRC) occurrence and related mortality in an older population. This retrospective, nationwide, population-based cohort study used data of adults aged ≥40 years from the Health Insurance Review and Assessment Service database. After excluding colonoscopy within 6 months of CRC diagnosis during enrollment, CRC occurrence and related mortality were compared between colonoscopy and non-colonoscopy groups using a time-dependent Cox proportional hazard model. Subgroup analysis was conducted among four age groups: young, middle-aged, old, and very old. Among 748986 individuals followed for 9.64 (SD 0.99) years, the colonoscopy group had a 65% lower CRC occurrence (adjusted hazard ratio [HRa] 0.35, 95%CI 0.32–0.38) and 76% lower CRC-related mortality (HRa 0.24, 95%CI 0.18–0.31) after 5 years compared with the non-colonoscopy group. Colonoscopy was associated with the most significant reduction in CRC occurrence in the middle-aged group (HRa 0.32, 95%CI 0.29–0.35) and in CRC-related mortality in the young group (HRa 0.04, 95%CI 0.01–0.33); the very old group had the least reduction in both CRC occurrence and CRC-related mortality (HRa 0.44, 95%CI 0.33–0.59 and HRa 0.28, 95%CI 0.15–0.53, respectively). We found a significant association between colonoscopy and reduction in CRC occurrence and CRC-related mortality in adults aged ≥40 years after 5 years of follow-up; however, these associations were weaker in the very old group. More research is needed on the association between colonoscopy and older age.

Background: Colorectal cancer (CRC) is a leading cancer worldwide. Incidence varies greatly by country and racial group. We present recent CRC incidence and mortality rates among American Indian/Alaska Native (AI/AN) persons in Alaska and compare them to rates among other racial groups in Alaska and AI/AN persons in other regions of the United States, and to published CRC incidence rate estimates for other countries around the world. Methods: To calculate CRC incidence in the United States, we used U.S. Cancer Statistics data, which includes cancer registry data from the Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Cancer data for AI/AN persons in Alaska came from the Alaska Cancer Registry as well as the Alaska Native Tumor Registry. Death data came from the CDC’s National Death Index, which was linked with the Indian Health Service patient registry database to address race misclassification in AI/AN populations, to create the United States Cancer Statistics American Indian and Alaska Native Mortality Database. This database was used to calculate CRC mortality rates for AI/AN persons in this study. Rates were age-adjusted using the World Health Organization’s World Standard Population (2000-2025), so that rates for AI/AN persons in the United States could be more comparable to rates that have been estimated for countries around the world. Estimates of worldwide CRC incidence came from the International Agency for Research on Cancer Global Cancer Observatory GLOBOCAN 2020 database. Results: AI/AN persons in Alaska (males and females combined) had the highest CRC incidence rate (58.4 per 100,000 people) in the year 2020, when compared to AI/AN persons in every other region of the United States. Within Alaska, AI/AN persons had a higher CRC incidence rate than persons of any other racial group. When compared with published CRC incidence rates worldwide, the rate for AI/AN persons in Alaska was higher than the rates reported for any country in the world in 2020. The country with the highest recorded CRC incidence rate in 2020 was Hungary (45.3 per 100,000 people). AI/AN persons in Alaska also had the highest CRC mortality rate (27.1 per 100,000 people) in 2020. Worldwide, the country with the highest recorded CRC mortality rate in 2020 was Slovakia (21.0 per 100,000 people). Conclusions: This review of CRC incidence and mortality rates from populations in the US and worldwide showed that AI/AN persons in Alaska had the highest documented incidence and mortality rates of CRC in the world in 2020. Health systems serving AI/AN persons in Alaska could implement policies and interventions that support colorectal cancer screening, to reduce the burden of this preventable disease. Citation Format: Donald Haverkamp, Diana Redwood, Elena Roik, Stephen Vindigni. Elevated colorectal cancer incidence among American Indian/Alaska Native persons in Alaska compared to other populations worldwide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4872.

Family History of Colorectal Cancer: It Is Time to Rethink Screening Recommendations

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Evidence for colorectal cancer screening

Background and aims: Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide, and fecal immunochemical testing (FIT) is most widely used for population-based screening. Reduced long-term CRC mortality has been reported only scarcely in response to early detection with FIT screening. We aimed to elucidate whether and how FIT screening led to overall and site-specific reduction of advanced stage CRC incidence and mortality after the first decade of Taiwan's screening program, which offers biennial FIT screening for people aged 50-69 years. Method: The study cohort comprised eligible subjects who did (screened group) and did not (unscreened group) participate in FIT screening during the inaugural 5 years (2004-2009) with follow up until 2014. FIT-positive subjects were offered colonoscopy as a confirmatory exam. The primary outcome was incidence of advanced stage CRC and CRC mortality. Results: Among 5,417,699 eligible subjects, 3,072,164 (56.6%) had at least once FIT screening, and 1,605,200 (52.3%) received 2 or more screenings during the study period. During mean follow-up of 9.78 years, 5716 screened and 20,962 unscreened subjects developed incident advanced stage cancers [adjusted relative risk (aRR) = 0.76; 95% CI, 0.72-0.79] after controlling for self-selection to attend screening and increasing CRC incidence. CRC deaths during follow-up included 3077 screened and 15,550 unscreened subjects (aRR = 0.56, 95% CI, 0.53-0.59). Effectiveness was greater for distal cancers (advanced cancer incidence aRR = 0.68, 95% CI, 0.65-0.71); mortality aRR = 0.52 95% CI, 0.49-0.55) than for proximal cancers (advanced cancer incidence aRR = 0.99 95% CI, 0.92-1.07; mortality aRR = 0.69 95% CI, 0.63-0.75). Conclusion: FIT screening effectively reduces risk of advanced stage CRC and CRC mortality, with effectiveness consistently stronger for distal CRC than proximal CRC.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and second most common cause of cancer death. The relationship between socio-economic deprivation and CRC incidence is unclear and previous findings have been inconsistent. There is stronger evidence of an association between area-level deprivation and CRC survival; however, few studies have investigated the association between individual-level socio-economic status (SES) and CRC survival.Data from the Office for National Statistics Longitudinal Study (LS) in England and Wales was used. LS members aged 50+ were stratified by individual-level educational attainment, social class, housing tenure and area deprivation quintile, measured at the 2001 Census. Time-to-event analysis examined associations between indicators of SES and CRC incidence and survival (all-cause and CRC death), over a 15-year follow-up period.Among 178116 LS members, incidence of CRC was lower among those with a degree, compared to those with no degree and higher among those employed in manual occupations compared to non-manual occupations. No clear relationship was observed between CRC incidence and the area-based measure of deprivation.Disparities were greater for survival. Among 5016 patients diagnosed with CRC aged 50+, probability of death from all-causes was lower among those with a degree, compared to no degree and higher among those employed in manual occupations, compared to non-manual occupations and among those living in social-rented housing, compared to owner-occupiers. Individual indicators of SES were also associated with probability of death from CRC. Those living in the most deprived areas had a higher probability of death (from all-causes and CRC) compared to those in the least deprived areas.Both individual and area-based indicators of SES were associated with CRC survival, and the relationships were stronger than those observed for CRC incidence. These findings could help inform more effective targeting of public health interventions for CRC.

Yogurt consumption and colorectal cancer incidence and mortality in the Nurses’ Health Study and the Health Professionals Follow-Up Study

Oncologists encounter patients with pathogenic variants (PVs) in ATM, CHEK2, or PALB2, but little is known about their cancer mortality. Patients who were 20 years or older, diagnosed in 2013-2019 with breast, colorectal, or pancreatic cancer, and reported to SEER registries in California and Georgia were linked to germline genetic testing results from four clinical laboratories and followed through 2021. Multivariable models of cancer mortality were fit; for each cancer, the reference group was the average hazard across all genetically tested patients with that diagnosis. Each cancer was modeled separately, followed by a single model that interacted the cancer type with all covariates. In addition to fixed effects models, random effects models were used as a regularization approach to reduce overfitting. A total of 70,272 tested patients with breast (48,473 estrogen receptor-/progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative; 9,957 HER2-positive; 11,842 triple-negative) cancer, 5,822 with colorectal cancer, and 1,861 with pancreatic cancer were analyzed; the mean follow-up was 3.9 years. Patients with ATM, CHEK2, or PALB2 PVs had no differences in breast, colorectal, or pancreatic cancer mortality. Patients with ATM PVs in triple-negative breast cancer appeared to have higher mortality in fixed effects models (hazard ratio [HR], 3.7 [95% CI, 1.8 to 7.8]), but not in random effects models (HR, 1.2 [95% CI, 0.8 to 1.6]) that reduce overfitting. Patients with BRCA1/2 PVs had lower triple-negative breast cancer mortality in both models (fixed HR, 0.6 [95% CI, 0.5 to 0.9], random HR, 0.7 [95% CI, 0.6 to 0.8]). Patients with Lynch syndrome gene PVs had lower colorectal cancer mortality in both models (fixed HR, 0.5 [95% CI, 0.4 to 0.8], random HR, 0.7 [95% CI, 0.5 to 0.9]). Patients with ATM, CHEK2, or PALB2 PVs had similar breast, colorectal, and pancreatic cancer mortality to the average genetically tested patient with their cancer type.

BackgroundThe purpose of this study was to study the role of thymidylate synthetase (TYMS) and B-cell lymphoma-2 like 1 (BCL2L1) in the occurrence and development of colorectal cancer and its potential regulatory mechanism.MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to examine the expression and prognostic value of TYMS and BCL2L1 in colorectal cancer. C-BioPortal analysis was used to detect the TYMS and BCL2L1 alterations. Through The Human Protein Atlas (THPA), the TYMS and BCL2L1 protein levels were also assessed. The protein protein interaction (PPI) network was built using GeneMANIA analysis, while co-expression genes correlated with TYMS and BCL2L1 were identified using LinkedOmics analysis. Finally, we collected clinical samples to verify the expressions of TYMS and BCL2L1 in colorectal cancer.ResultsTYMS and BCL2L1 were up-regulated, and TYMS and BCL2L1 genomic alterations were not associated with the occurrence of colorectal cancer. TYMS and BCL2L1 were significantly connected with the prognosis of colorectal cancer patients. The genes interacted with TYMS and BCL2L1 were linked to functional networks involving pathway of apoptosis, apoptosis-multiple species, colorectal cancer, platinum drug resistance and p53 signaling pathway. qRT-PCR verification results of TYMS were consistent with the result of TCGA and GEO analysis.ConclusionsThis study display that data mining can efficiently provide information on expression of TYMS and BCL2L1, correlated genes of TYMS and BCL2L1, core pathways and potential functional networks in colorectal cancer, suggesting that TYMS and BCL2L1 may become new prognostic and therapeutic targets for colorectal cancer.

Background: Colorectal cancer mortality can be reduced through risk factor modification (adherence to lifestyle recommendations), screening, and improved treatment. This study estimated the potential of these three strategies to modify colorectal cancer mortality rates in Norway.Methods: The potential reduction in colorectal cancer mortality due to risk factor modification was estimated using the software Prevent, assuming that 50% of the population in Norway-who do not adhere to the various recommendations concerning prevention of smoking, physical activity, body weight, and intake of alcohol, red/processed meat, and fiber-started to follow the recommendations. The impact of screening was quantified assuming implementation of national flexible sigmoidoscopy screening with 50% attendance. The reduction in colorectal cancer mortality due to improved treatment was calculated assuming that 50% of the linear (positive) trend in colorectal cancer survival would continue to persist in future years.Results: Risk factor modification would decrease colorectal cancer mortality by 11% (corresponding to 227 prevented deaths: 142 men, 85 women) by 2030. Screening and improved treatment in Norway would reduce colorectal cancer mortality by 7% (149 prevented deaths) and 12% (268 prevented deaths), respectively, by 2030. Overall, the combined effect of all three strategies would reduce colorectal cancer mortality by 27% (604 prevented deaths) by 2030.Conclusions: Risk factor modification, screening, and treatment all have considerable potential to reduce colorectal cancer mortality by 2030, with the largest potential reduction observed for improved treatment and risk factor modification.Impact: The estimation of these health impact measures provides useful information that can be applied in public health decision-making. Cancer Epidemiol Biomarkers Prev; 26(9); 1420-6. ©2017 AACR.

INTRODUCTION: Colorectal cancer (CRC) is the third common cause of cancer death in the US. The incidence of CRC is higher in minority racial and ethnic groups. Traditionally, CRC has had a higher mortality rate in men when compared to women. However, studies assessing trends among sex and racial groups on the incidence and mortality of CRC is lacking. We aim to investigate disparities in CRC by reviewing a large national cancer registry. METHODS: This is a retrospective cross-sectional study of the Surveillance, Epidemiology and End Results Registry (SEER) of individuals aged 45–79 years from 2000 to 2017. Race was classified as White, Black, American Indian/Alaska Native, and Asian or Pacific Islander. Annual percent change (APC) and incidence risk ratios (IRR) were calculated for sex and race. Kaplan-Meier estimations and log-rank tests were used to evaluate cancer-specific survival outcomes. Statistical significance was set at P < 0.05. RESULTS: Among 690,450 patients, there were 512,285 patients age 45–79 years diagnosed with CRC from 2000 to 2017. A higher proportion of patients had distal tumors versus proximal tumors (62% vs 38%, P < 0.001). SEER summary staging showed that most tumors were localized (40%) compared to regional (35%), distant cancer (20%), and unknown (4%). Approximately 23% of tumors on presentation occurred in the rectum (n = 114,873), followed by 21% in the sigmoid (102,850), 14% in the cecum (70,084), 12% in the ascending colon (n = 60,227), and 29.5% other locations. During the study period, the incidence of CRC decreased for both males and females, respectively (APC −2.14 vs −1.81). Amongst all racial groups, African American showed the least decline in incidence of CRC. African American females showed the highest risk for CRC (IRR 1.34; 95% CI 1.32–1.36, P < 0.001) compared to other females or males from different racial groups [Figure 1]. Subgroup analysis using Kaplan Meier estimations showed that African American females had the poorest 5-year survival rate (56%) compared to White females (66%), American Indian/Alaska Native females (58%), and Asian or Pacific Islander females (66%). Among males, American Indian/Alaska Natives had the poorest 5-year survival (54%) compared to African American males (61%), White males (66%), and Asian or Pacific Islander males (66%). CONCLUSION: Overall, the incidence of colorectal cancer is declining. However, the incidence of CRC remains highest in African Americans females who are also burden with poor survival rates.Figure 1.: Forest plot for Incidence Rate Ratios (IRR) for colorectal cancer (CRC) based on gender and race/ethnicity.Table 1.: One through 5-year survival rates based on gender and race/ethnicity.