ASPIRIN AND NON-STEROIDAL ANTI-INFLAMMATORY DRUG USE AND RISK OF PRECURSORSOF EARLY-ONSET COLORECTAL CANCER

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.

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.