Society: AGA

Background: Aspirin has been known for its chemopreventive effect against various cancers. Evidence for the chemopreventive effect of the very long-term use of aspirin is still uncertain. The current study aims to examine aspirin effect against colorectal cancer (CRC) over 20 years and to determine the optimal age for initiating aspirin for CRC prevention. Methods: Medical data on drug use, disease diagnosis and medical procedures were obtained from the Hospital Authority Hong Kong. Subjects aged 18 or above with aspirin use between January 2000 and June 2019 were included. Non-aspirin users were identified by age-and-gender matching as the sample population. Subjects with any cancer diagnosis, coronary heart disease or stroke prior to the index date were excluded. The index date was set at 6 months after aspirin initiation for aspirin users and the matching date for non-users. All included subjects were followed-up until June 2020. Incidence of CRC was identified as the primary outcome, while cancer-related mortality and bleeding events were identified as the secondary outcomes. The Fine-Gray model was used to calculate the sub-distribution hazard ratio (SHR), with death considered as a competing risk. Propensity score weighting stabilised with trimming was used to adjust for the difference in baseline characteristics. Concurrent medication use during the follow-up period was also adjusted in the model. Results: A total number of 250,765 aspirin users and 925,718 non-users were included in the current study. The mean age was 63.8, with 53.4% male. Forty-five percent of included subjects had hypertension at baseline, while 20% had diabetes and 20% had dyslipidaemia. Cumulative incidence functions for CRC at 20 years were 2.20% (95% CI 2.09-2.33) for aspirin users and 2.31% (95% CI 2.22-2.39) for non-users respectively. Aspirin was associated with a reduced risk of CRC (SHR 0.85, 95% CI 0.82-0.88). The optimal age to initiate aspirin for CRC prevention would be between 40-59 (aged 40-49: SHR 0.70, 95% CI 0.59-0.83; aged 50-59: SHR 0.80, 95% CI 0.73-0.87) (Figure 1). Aspirin was also shown to reduce cancer-related mortality. For bleeding events, aspirin was found to increase the risk of haemorrhagic stroke, upper and lower gastrointestinal bleeding. Conclusion: Aspirin was found to effectively reduce the risk of CRC in 20 years of follow-up. While the long-term chemopreventive effect of aspirin against CRC was certain, its benefit was more prominent in 5-10 years after aspirin initiation. The optimal time to initiate aspirin for CRC prevention can be at the age of around 40-59.

Figure 1. Cumulative Incidence for Colorectal Cancers Stratified by Age. Abbreviation: CI, confidence interval; SHR, sub-distribution hazard ratio.

Figure 1. Cumulative Incidence for Colorectal Cancers Stratified by Age. Abbreviation: CI, confidence interval; SHR, sub-distribution hazard ratio.

Background:
Exploring preventive agents for early-onset colorectal neoplasia is imperative due to the alarming rise in the incidence and mortality of early-onset colorectal cancer (age <50 years) and the limited understanding of the underlying drivers to direct prevention efforts. Emerging data suggest that similar for later-onset colorectal cancer, aspirin use is associated with a lower risk of early-onset colorectal cancer. However, it remains uncertain whether regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a lower risk of early-onset conventional adenomas, especially high-risk adenomas with greater malignant potential, the major precursor of early-onset colorectal cancer.

Methods:
We conducted a prospective analysis using the Nurses’ Health Study II to assess the association between regular aspirin or NSAID use (2+ times/week) with risk of early-onset adenoma overall and by malignant potential (high-risk vs. low-risk) among 32058 women with at least one lower endoscopy before age 50 years (1991-2015). High-risk adenomas included adenomas with size ≥1, tubulovillous/villous histology or high-grade dysplasia, or ≥ 3 adenomas. As secondary analyses, we also assessed the associations for later-onset adenomas among women with lower endoscopy at age 50 and above (1995-2015). Multivariable logistic regressions for clustered data were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI).

Results:
We documented 1247 early-onset adenomas of which 290 were high-risk adenomas. After adjusting for putative risk factors, regular aspirin/NSAID use was associated with a lower risk of adenomas with an OR of 0.85 (95% CI 0.75-0.95) compared with nonregular users. The association was similar for high-risk vs. low-risk adenomas (P for heterogeneity=0.44), but more pronounced for adenomas of tubulovillous/villous histology or with high-grade dysplasia with an OR of 0.67 (95% CI 0.51-0.89) compared to tubular adenomas (OR=0.90; 95% 0.79-1.03; P for heterogeneity=0.02). These findings were similarly observed among women without a family history of CRC or symptom indications for endoscopy.

For later-onset adenomas, although we observed similar findings for overall and high-risk adenomas, the risk reduction was primarily confined to large (OR=0.76; 95% CI 0.62-0.93) or multiple adenomas (OR=0.57; 95% CI 0.40-0.83), but not adenomas of advanced histology (OR=0.92; 95% CI 0.73-1.17).

Conclusions:
Regular aspirin/NSAID use was associated with a lower risk of early-onset conventional adenomas, especially for adenomas of advanced histology. Our findings highlight the urgent need to evaluate aspirin and/or NSAIDs as promising agents for the prevention of early-onset colorectal cancer given the favorable risk-benefit profile in younger individuals.

Abstract
Background Statin use has been associated with a reduced risk of developing advanced colorectal adenomas. However, whether statin use is associated with a decreased risk of colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) remains unclear.

Methods: Using nationwide Swedish healthcare registers, we identified 5,273 new users of statin (mean age: 62.9 years; 56.9% male) in IBD patients from July 2006 to December 2018. Statin users were identified by their first filled prescriptions for 30 or more cumulative defined daily doses and were then matched with 5,273 non-users by 1:1 propensity score matching, with end of follow-up on 31 December 2019. New users and non-users were free of CRC before cohort entry. The primary outcomes were the absolute and relative risks of CRC and CRC-related death. The secondary outcome was death from any cause. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CI).

Results: During a median follow-up of 5.5 years, 70 (21.2 per 10,000 person-years) statin users versus 90 (29.2 per 10,000 person-years) non-statin users were diagnosed with incident CRC (rate difference (RD), -8.0 [95%CI, -15.8 to -0.2 per 10,000 person-years]; aHR, 0.68, [95%CI, 0.49 to 0.95]). Compared with non-statin users, statin users also had a decreased risk for death from CRC (8.4 vs 17.1 per 10,000 person-years, RD, -8.7 [95%CI, -15.3 to -2.2 per 10,000 person-years]; aHR, 0.41 [95%CI, 0.22 to 0.74]) and death from any cause (210.3 vs 307.3 per 10,000 person-years, RD, -97.0 [95%CI, -126.1 to -67.9 per 10,000 person-years]; aHR, 0.62 [95%CI, 0.55 to 0.71]).

Conclusion: In this nationwide cohort of patients with IBD in Sweden, statin use was associated with a lower risk of incident CRC, CRC-related death, and death from any cause.

Figure 1. Cumulative incidence of incident CRC (A), CRC-related death (B), and death from any cause (C) among statin users and non-statin users.

Figure 1. Cumulative incidence of incident CRC (A), CRC-related death (B), and death from any cause (C) among statin users and non-statin users.

INTRODUCTION: Colorectal cancer (CRC) develops mainly from adenomatous polyps as precursor lesions (adenoma-carcinoma sequence), whereas the serrated neoplasm pathway, in which serrated polyps give rise to cancer, has been identified in the last 2 decades. Although the serrated-neoplasia pathway reportedly accounts for 15%-30% of CRC, no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. Connectivity Map (CMAP) is a database established to connect genes, compounds (drugs), and disease, and the CMAP analysis enables to select effective drug from a large number of compounds (e.g., Food and Drug Administration [FDA]-approved drugs). Therefore, we searched for candidate preventive compounds comprehensively from FDA-approved compounds by employing CMAP analysis and investigated their effects using SSL patient-derived organoids (PDOs) in vitro as well as using murine xenograft model in vivo.
METHODS: We obtained biopsies from the SSL and the surrounding normal mucosa in each of the 3 patients under colonoscopy and performed microarray analysis on them to generate SSL-specific gene signatures. We applied them to CMAP analysis with 1309 FDA-approved compounds and ranked effective compounds which should cancel the gene signatures. We established SSL-PDOs from additional SSL patients using biopsy specimens and evaluated their inhibitory effects on SSL-PDOs using a cell viability assay and BrdU assay. We investigated inhibitory effects of compounds in vivo using murine xenograft model.
RESULTS: Based on the CMAP analysis of SSL-gene specific signatures, we identified 221 highly ranked compounds, and narrowed them down to 17 compounds by considering adverse events, oral bioavailability, and costs. The cell viability assay of SSL-PDOs revealed that the IC50 values of these compounds ranged from 47~4902 µM, and IC50 of lansoprazole was the lowest (47 µM) among 17 compounds. Moreover, the BrdU assay revealed that the cell proliferation ability of SSL-PDOs was significantly suppressed in a dose-dependent manner by lansoprazole. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. When lansoprazole was administered to the mice at 50 mg/kg, the growth of SSL xenograft was apparently suppressed, but the tumor in the control mice treated with vehicle alone grew gradually over time.
DISCUSSION: This is the first study to comprehensively analyze compounds for the chemoprevention of SSL, employing CMAP analysis, SSL-PDOs, and murine xenograft model. Our data clearly demonstrate that lansoprazole is the most effective agent for the SSL-neoplasia pathway among 1309 FDA-approved compounds. Because this is a drug-repositioning study, we are able to proceed to human clinical trial soon.

Introduction: Reactive aldehydes, such as iso-levuglandins (isoLGs), are generated from lipid peroxidation and these electrophiles form covalent adducts with amine-containing macromolecules and lead to oxidative damage. We recently reported that an experimental scavenger of electrophiles reduces tumorigenesis in a murine model of colitis-associated carcinogenesis (CAC). The natural product 2-hydroxybenzylamine (2-HOBA) is derived from buckwheat seeds and reacts with all aldehydes at a rate 3 orders of magnitude faster than with lysine. Two Phase I clinical trials have demonstrated its safety in humans. Our goal was to determine if the clinically available electrophile scavenger, 2-HOBA, is protective in the development and growth of colorectal cancer (CRC). Methods: We used i) C57BL/6 mice ± AOM-DSS as a model of CAC; and ii) C57BL/6 mice with tamoxifen (TAM)-inducible disruption of Apc using the intestinal epithelial cell-specific CDX2 Cre (CDX2P-CreER^T2;Apc^fl/fl), i.p. injected or not with 4.5 mg/kg TAM as a genetic model of CRC. Mice were treated or not with1 mg/ml 2-HOBA in the drinking water. Histology and tumorigenesis were assessed. Lysyl-LG adducts were detected by immunohistochemistry; mRNA expression was determined by RT-real-time PCR. 2-HOBA concentrations were measured by LC/ESI-MS/MS. Also, the human CRC cell line HCT116 was transplanted into the flank of athymic nude mice; xenograft tumors were measured, and oral 2-HOBA was initiated when tumors reached 100 mm³. Results: The bioavailability of 2-HOBA was confirmed in mouse colons. In the AOM-DSS model, 2-HOBA reduced tumor size (P<0.0001) and tumor burden (P<0.01), without affecting inflammation. The number of tumors (P<0.01) and the tumor burden (P<0.01) observed in TAM-treated CDX2P-CreER^T2;Apc^fl/fl mice were also both reduced by 2-HOBA. Further, tumor burden was inversely correlated with colon 2-HOBA levels (r=–0.66; P=0.026). Histology revealed less histologic adenomas in the 2-HOBA-treated group (P<0.05), associated with a reduction of the prevalence of high-grade dysplasia. The moderate inflammation in the non-tumor area and the expression of the pro-inflammatory genes induced in the tumors of TAM-treated CDX2P-CreER^T2;Apc^fl/fl mice were not affected by 2-HOBA. Nuclear lysyl-LG adduct levels were increased in the non-tumor areas of TAM-treated CDX2P-CreER^T2;Apc^fl/fl mice, and were markedly reduced by 2-HOBA supplementation. In the human xenografts, weekly measurements showed a decrease of tumor growth in 2-HOBA-treated mice and the tumor volume at the end of experiments was reduced by 1.8-fold (P<0.05); the tumor growth inhibition index was 51%. Conclusions: The electrophile scavenger 2-HOBA reduces colon tumorigenesis and growth of tumor cells in three distinct models of CRC. Thus, this nutraceutical supplement could be useful for the prevention and treatment of CRC.

Backgound & Aims: Previous research on the potential chemoprotective effect of aspirin for colorectal cancer (CRC) shows conflicting results. We aimed to emulate a trial of aspirin intiation in individuals with incident polyps.
Methods: We identified individuals registered with their first colorectal polyp in the nationwide gastrointestinal ESPRESSO histopathology cohort in Sweden. Individuals aged 45-79 years diagnosed with colorectal polyps 2006-2016 in Sweden without CRC or contraindications for preventive aspirin (cerebrovascular disease, heart failure, aortic aneurysms, pulmonary emboli, myocardial infarction, gastric ulcer, dementia, liver cirrhosis, or any other metastatic cancer) registered until the month of first polyp detection were eligible. Using duplication and inverse probability weighting, we emulated a target trial of aspirin initiation within 2 years of initial polyp detection. The main outcome measures were incident CRC, CRC mortality and all-cause mortality registered until 2019.
Results: Of 31,633 individuals meeting our inclusion criteria, 1,716 (5%) initiated aspirin within 2 years of colon polyp diagnosis. Median follow-up was 8.07 years. The 10-year cumulative incidence in initiators vs. non-initiators was 6% vs. 8% for CRC incidence, 1% vs. 1% for CRC mortality and 21% vs. 18% for all-cause mortality. The corresponding hazard ratios were 0.88 (95% confidence interval, 95%CI=0.86-0.90), 0.90 (95%CI=0.75-1.06) and 1.18 (95%CI=1.12-1.24).
Conclusion: Aspirin initiation in individuals with polyp removal was linked to 2% lower cumulative incidence of CRC after 10 years but did not alter CRC mortality. We also observed a 3% increased risk difference of all-cause mortality at 10 years after the initiation of aspirin.
Key Words: cancer prevention; precision medicine; target trial emulation; causal inference

Jonas Ludvigsson

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