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Background: Prior epidemiological and intervention studies have not been able to separate independent effects of dose, timing, and duration of aspirin use in colorectal cancer (CRC) chemoprevention. We examined aspirin-based CRC chemoprevention according to timing in the Nurses' Health Study and Health Professionals Follow-Up Study.Methods: The exposures include cumulative average dose and total duration of aspirin use in more than 10 years before follow-up started (remote period) and in the immediate 10 years before follow-up started (recent period). Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for exposures and CRC risk.Results: Aspirin use of longer than 10 years before follow-up started (HR = 0.88, 95% CI = 0.83 to 0.94) per 5-year increment and the immediate 10 years before follow-up started (HR = 0.90, 95% CI = 0.84 to 0.96) were similarly important in CRC chemoprevention, though a 5-year lag was required for a clear benefit in the recent period. In the remote period, the association was not dose dependent; compared with less than 0.5 standard-dose (325 mg) tablets per week; hazard ratios were 0.78 (95% CI = 0.63 to 0.98), 0.81 (95% CI = 0.72 to 0.91), and 0.74 (95% CI = 0.64 to 0.86) for doses of 0.5 to less than 1.5, 1.5 to less than 5, and 5 and more tablets per week, respectively. However, there was dose dependency in the recent period (with respective HR = 0.91, 95% CI = 0.79 to 1.06; HR = 0.87, 95% CI = 0.77 to 0.98; and HR = 0.76, 95% CI = 0.64 to 0.91).Conclusions: A suggestive benefit necessitates at least 6-10 years and most clearly after approximately 10 years since initiation of aspirin. Remote use and use within the previous 10 years both contribute independently to decrease risk, though a lower dose may be required for a benefit with longer term use. [ABSTRACT FROM AUTHOR]

Introduction: The relationships among PIK3CA mutations, medication use and tumor progression remains poorly understood. Aspirin use post-diagnosis may modify components of the PI3K pathway, including AKT and mTOR, and has been associated with lower risk of breast cancer recurrence and mortality. We assessed time to metastasis (TTM) and survival with respect to aspirin use and tumor PIK3CA mutations among women with metastatic breast cancer.Methods: Patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer treated in 2009-2016 who received tumor genotyping were included. Aspirin use between primary and metastatic diagnosis was extracted from electronic medical records. TTM and survival were estimated using Cox proportional hazards regression.Results: Among 267 women with metastatic breast cancer, women with PIK3CA mutated tumors had longer TTM than women with PIK3CA wildtype tumors (7.1 vs. 4.7 years, p = 0.008). There was a significant interaction between PIK3CA mutations and aspirin use on TTM (p = 0.006) and survival (p = 0.026). PIK3CA mutations were associated with longer TTM among aspirin non-users (HR = 0.60 95% CI:0.44-0.82 p = 0.001) but not among aspirin users (HR = 1.57 0.86-2.84 p = 0.139). Similarly, PIK3CA mutations were associated with reduced mortality among aspirin non-users (HR = 0.70 95% CI:0.48-1.02 p = 0.066) but not among aspirin users (HR = 1.75 95% CI:0.88-3.49 p = 0.110).Conclusions: Among women who develop metastatic breast cancer, tumor PIK3CA mutations are associated with slower time to progression and mortality only among aspirin non-users. Larger studies are needed to confirm this finding and examine the relationship among aspirin use, tumor mutation profile, and the overall risk of breast cancer progression. [ABSTRACT FROM AUTHOR]

Background: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory but have been linked in some studies to Crohn disease (CD) and ulcerative colitis (UC). Objective: To assess the association between aspirin and NSAID use and incident CD and UC. Design: Prospective cohort study. Setting: Nurses' Health Study I. Patients: 76 795 U.S. women who provided biennially updated data about aspirin and NSAID use. Measurements: Incident CD and UC between 1990 and 2008 (outcome) and NSAID and aspirin use (exposure). Results: 123 incident cases of CD and 117 cases of UC occurred over 18 years and 1 295 317 person-years of follow-up. Compared with nonusers, women who used NSAIDs at least 15 days per month seemed to have increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100 000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56]) and UC (absolute difference, 7 cases per 100 000 personyears [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99]). Less frequent NSAID use was not clearly associated with risk for CD or UC, and there was no clear association between aspirin use and disease. Limitations: Cohort participants were exclusively women, most of whom were white. Aspirin and NSAID use were self-reported. Conclusion: Frequent use of NSAIDs but not aspirin seemed to be associated with increased absolute incidence of CD and UC. The findings have more mechanistic than clinical implications, because the absolute incidence of CD or UC associated with NSAIDs was low and the increase in risk for CD or UC associated with NSAIDs is unlikely to alter the balance of more common and clinically significant risks and benefits associated with these agents. Primary Funding Source: American Gastroenterological Association, IBD Working Group, Broad Medical Research Program, and National Institutes of Health. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been implicated in diverticular complications. We examined the influence of aspirin and NSAID use on risk of diverticulitis and diverticular bleeding in a large prospective cohort. Methods: We studied 47,210 US men in the Health Professionals Follow-up Study cohort who were 40–75 years old at baseline in 1986. We assessed use of aspirin, nonaspirin NSAIDs, and other risk factors biennially. We identified men with diverticulitis or diverticular bleeding based on responses to biennial and supplementary questionnaires. Results: We documented 939 cases of diverticulitis and 256 cases of diverticular bleeding during a 22-year period of follow-up evaluation. After adjustment for risk factors, men who used aspirin regularly (≥2 times/wk) had a multivariable hazard ratio (HR) of 1.25 (95% confidence interval [CI], 1.05–1.47) for diverticulitis and a HR of 1.70 (95% CI, 1.21–2.39) for diverticular bleeding, compared with nonusers of aspirin and NSAIDs. Use of aspirin at intermediate doses (2–5.9 standard, 325-mg tablets/wk) and frequency (4–6 days/wk) were associated with the highest risk of bleeding (multivariable HR, 2.32; 95% CI, 1.34–4.02, and multivariable HR, 3.13; 95% CI, 1.82–5.38, respectively). Regular users of nonaspirin NSAIDs also had an increased risk of diverticulitis (multivariable HR, 1.72; 95% CI, 1.40–2.11) and diverticular bleeding (multivariable HR, 1.74; 95% CI, 1.15–2.64), compared with men who denied use of these medications. Conclusions: Regular use of aspirin or NSAIDs is associated with an increased risk of diverticulitis and diverticular bleeding. Patients at risk of diverticular complications should carefully consider the potential risks and benefits of using these medications. [Copyright &y& Elsevier]

Context Randomized trials of short-term aspirin use for prevention of recurrent colorectal adenoma have provided compelling evidence of a causal relationship between aspirin and colorectal neoplasia. However, data on long-term risk of colorectal cancer according to dose, timing, or duration of therapy with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) remain limited. Objective To examine the influence of aspirin and NSAIDs in prevention of colorectal cancer. Design, Setting, and Participants Prospective cohort study of 82 911 women enrolled in the Nurses’ Health Study providing data on medication use biennially since 1980 and followed up through June 1, 2000. Main Outcome Measure Incident colorectal cancer. Results Over a 20-year period, we documented 962 cases of colorectal cancer. Among women who regularly used aspirin (≥2 standard [325-mg] tablets per week), the multivariate relative risk (RR) for colorectal cancer was 0.77 (95% confidence interval [CI], 0.67-0.88) compared with nonregular users. However, significant risk reduction was not observed until more than 10 years of use (P≤.001 for trend). The benefit appeared related to dose: compared with women who reported no use, the multivariate RRs for cancer were 1.10 (95% CI, 0.92-1.31) for women who used 0.5 to 1.5 standard aspirin tablets per week, 0.89 (95% CI, 0.73-1.10) for 2 to 5 aspirin per week, 0.78 (95% CI, 0.62-0.97) for 6 to 14 aspirin per week, and 0.68 (95% CI, 0.49-0.95) for more than 14 aspirin per week (P<.001 for trend). Notably, women who used more than 14 aspirin per week for longer than 10 years in the past had a multivariate RR for cancer of 0.47 (95% CI, 0.31-0.71). A similar dose-response relationship was found for nonaspirin NSAIDs (P = .007 for trend). The incidence of reported major gastrointestinal bleeding events per 1000 person-years also appeared to be dose-related: 0.77 among women who denied any aspirin use; 1.07 for 0.5 to 1.5 standard aspirin tablets per week; 1.07 for 2 to 5 aspirin per week; 1.40 for 6 to 14 aspirin per week; and 1.57 for more than 14 aspirin per week. Conclusions Regular, long-term aspirin use reduces risk of colorectal cancer. Nonaspirin NSAIDs appear to have a similar effect. However, a significant benefit of aspirin is not apparent until more than a decade of use, with maximal risk reduction at doses greater than 14 tablets per week. These results suggest that optimal chemoprevention for colorectal cancer requires long-term use of aspirin doses substantially higher than those recommended for prevention of cardiovascular disease, but the dose-related risk of gastrointestinal bleeding must also be considered. [ABSTRACT FROM AUTHOR]

Background: In vitro experiments and limited animal studies suggest that aspirin and nonsteroidal anti-inflammatory drugs may inhibit pancreatic carcinogenesis. Because few studies have examined the association between aspirin use and pancreatic cancer in humans and the results have been inconsistent, we examined the relationship between aspirin use and the development of pancreatic cancer in the Nurses' Health Study. Methods: Among 88 378 women without cancer at baseline, we documented 161 cases of pancreatic cancer during 18 years of follow-up. Aspirin use was first assessed at baseline in 1980 and updated biennially thereafter. All statistical tests were two-sided. Results: Participants were classified according to history of aspirin use. In a multivariable analysis, the risk of pancreatic cancer was not associated with current regular aspirin use (defined as two or more standard tablets per week; relative risk [RR] = 1.20, 95% confidence interval [CI] = 0.87 to 1.65), compared with use of fewer than two tablets per week. Increasing duration of regular aspirin use, compared with non-use, was associated with a statistically significant increase in risk: Women who reported more than 20 years of regular aspirin use had an increased risk of pancreatic cancer (RR = 1.58, 95% CI = 1.03 to 2.43; Ptrend = .01). Among women who reported aspirin use on at least two of three consecutive biennial questionnaires compared with consistent non-users of aspirin, the risk increased with dose (one to three tablets per week: RR = 1.11% 95% CI = 0.70 to 1.76; four to six tablets per week: RR = 1.29, 95% CI = 0.70 to 2.40; seven to 13 tablets per week: RR = 1.41, 95% CI = 0.76 to 2.61; and ≥14 tablets per week: RR = 1.86, 95% CI = 1.03 to 3.35) (Ptrend = .02). Conclusion: Extended periods of regular aspirin use appear to be associated with a statistically significantly increased risk of pancreatic cancer among women. [ABSTRACT FROM AUTHOR]

There is a wealth of experimental, epidemiological, and most recently, randomized trial evidence that suggests that aspirin and other NSAIDs can reduce the risk of colorectal adenoma and cancer. As a result, these medications have emerged as promising chemopreventative agents. However, routine use has not been recommended in large part due to a lack of information on the optimal dose and duration of treatment. In this issue, observational data drawn from a cohort within the Polyp Prevention Trial strongly support the effectiveness of aspirin and NSAIDs in reducing the risk of recurrent colorectal adenoma, including those with morphologically or histologically advanced features. In particular, the investigators demonstrate that participants who consumed more than one standard aspirin tablet per day had the greatest reduction in risk. Because much potential toxicity of these agents are dose-related, these findings highlight the need for further investigation into the optimal dose and duration of the medications before consideration of their use in widespread chemoprevention efforts. The combination of future epidemiological data, in concert with continuing experimental developments, will guide further research initiatives and better inform cost-benefit and decision analyses. Hopefully, interpretation of this large body of evidence ultimately will lead to concrete clinical guidelines which will define a role, if any, for these medications as anticancer agents. [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants" is presented.

Background: More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection.Methods: Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.Results: With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4).Conclusions: In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.). [ABSTRACT FROM AUTHOR]