This Month in Gastroenterology

Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes. Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German population-based case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR = 0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR = 0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR = 0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR = 0.34, 95% CI = 0.18 to 0.65) but not with KRAS- or BRAF-mutated MSI-high CRC (Pheterogeneity < .001). Results for just aspirin use were similar. Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.

This Month in Gastroenterology

Background: Long-term use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be protective against colorectal cancer (CRC). While aspirin is recommended to prevent cardiovascular disease and colorectal cancer in certain subgroups, a broad recommendation is not in place due to concerns about side effects. Evidence from clinical trials among patients with colorectal adenomas suggested stronger effect of aspirin among non-smokers, compared to current smokers; but the effect has not been evaluated for CRC risk. Methods: Using 11,894 cases and 15,999 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR), we performed multivariate logistic regression models to test for the interaction between regular use of NSAIDs (aspirin and non-aspirin NSAIDs) and other CRC risk factors on CRC risk, including age, sex, body mass index (BMI), physical activity, smoking, alcohol consumption, screening, family history of CRC, hormone replacement therapy (HRT) use, as well as intake of fruit, vegetables, red meat, processed meat, dietary fiber, total calcium and total folate. Fixed-effects meta-analyses with inverse variance weighting were used to summarize the estimates from interactions and stratified analyses across studies for each risk factor. A p-value &amp;lt;0.05 was considered statistically significant. Results: Regular use of any NSAID, aspirin, or non-aspirin NSAIDs was statistically significantly associated with a lower risk of CRC across almost all subgroups stratified by sex, body mass index (BMI), smoking, alcohol intake, physical activity and dietary factors. The association between aspirin and CRC risk statistically significantly differed by smoking status after adjusting for other risk factors (p-interaction=0.048). Regular aspirin use was associated with a 25% lower risk of CRC among non-smokers (OR=0.75; 95% CI: 0.64, 0.87), while it was associated with 19% and 16% lower risk of CRC among smokers of lower pack-years (OR=0.81; 95% CI: 0.70, 0.94) and higher pack-years (OR=0.84; 95% CI: 0.73, 0.97), respectively. There was a suggestive interaction between regular use of aspirin and BMI (p-interaction=0.081), where the effect of regular use of aspirin on CRC risk was stronger among individuals with normal BMI (OR=0.77; 95% CI: 0.65, 0.92) and overweight (OR=0.77; 95% CI: 0.66, 0.90), and non-significant among the obese (OR=0.93; 95% CI: 0.80, 1.08). Similarly, the association between any NSAID use and CRC risk was suggested to differ by BMI (p-interaction=0.075). No interaction between non-aspirin NSAIDs and other risk factors of CRC was observed. Conclusions: Our results suggest that the association between regular use of aspirin, but not other NSAIDs, and CRC risk may be modified by smoking status and BMI. The beneficial effect of aspirin on CRC risk appears to be diminished among those with greater CRC risk due to obesity and heavy smoking. The observed effect modifications were borderline significant and did not account for multiple comparisons. This abstract is also being presented as Poster A33. Citation Format: Xiaoliang Wang, Andrew T. Chan, Martha L. Slattery, Jenny Chang Claude, John D. Potter, Steven Gallinger, Caan Bette, Johanna W. Lampe, Polly A. Newcomb, Niha Zubair, Li Hsu, Robert E. Schoen, Hermann Brenner, Loic Le Marchand, Ulrike Peters, Emily White. Interactions between nonsteroidal anti-inflammatory drugs and other risk factors on colorectal cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR06.

Purpose: Regular NSAID (Non-Steroidal Anti-Inflammatory Drug) use results in an overall reduction in colorectal cancer (CRC) risk; however, this reduction may vary among molecularly defined subsets of CRC. Characterization of patients by regular NSAID use and molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Methods: A sample of patients was selected from the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol, which is designed to molecularly profile tumors of patients with refractory metastatic CRC. Demographic data and NSAID use were collected from a risk-factor survey. Demographic characteristics were compared between 106 non-NSAID users, 75 regular aspirin users and 78 regular non-aspirin NSAID users. Chi-square analysis was used to compare categorical variables and ANOVA was used for continuous variables. Logistic regression was used to assess predictors of aspirin or non-aspirin NSAID use compared to non-use. Results: Preliminary results indicate that aspirin users tend to be older, male and more frequently engage in vigorous physical activity compared to non-users and users of non-aspirin NSAIDs (Table I). In univariate analyses, patients who are older or engage in more frequent vigorous physical activity are at increased odds of using aspirin. When controlling for other variables, only age at diagnosis predicts aspirin use. Table 1.Description and AssociationsNo NSAID useAspirin useNon-Aspirin usep valueN1067578Age at Stage IV Diagnosis, Mean (SE)55.2 (1.0)59.5 (1.1)53.1 (1.3)0.0006Gender, N (%)11884810.0251Male72 (61.0)59 (72.8)44 (52.4)Female46 (39.0)22 (27.2)40 (47.6)Vigorous Physical Activity, N (%)11780840.0214Little or none50 (42.7)18 (22.5)34 (40.5)Once/week10 (8.6)14 (17.5)13 (15.5)Twice/week or more57 (48.7)48 (60.0)37 (44.1)Logistic RegressionUnadjusted Odds of Aspirin UseAdjusted Odds of Aspirin Use*OR (95% CI)p valueOR (95% CI)p valueAge at Stage IV Diagnosis1.047 (1.013, 1.081)0.00571.049 (1.014, 1.085)0.0055Gender (Female)0.584 (0.316, 1.078)0.08550.701 (0.356, 1.379)0.3032Vigorous Physical Activity (overall effect)0.00850.0486Little or none (Ref)1.001.00Once/week3.889 (1.468, 10.300)0.03692.481 (0.892, 6.906)0.2997Twice/week or more2.339 (1.207, 4.533)0.58952.305 (1.137, 4.673)0.2662*Each variable is adjusted for the other variables in the table Conclusions: These preliminary data indicate that we will be able to distinguish aspirin users from non-NSAID users in a sample of late-stage CRC patients. Going forward, we will combine these demographic data with tumor molecular classification to determine the subtypes of CRC that are more or less prevalent in aspirin/NSAID users. Use of NSAIDs and overall survival will also be evaluated among different molecular subtypes of CRC. This data, combined with analysis of risk factors for each molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Citation Format: Jennifer S. Davis, Shailesh Advani, Emilyn Banfield, Michael Overman, Zhi-Qin Jiang, Shanequa Manuel, Carrie Daniel, Shine Chang, Scott Kopetz. Demographics of colorectal cancer patients vary by aspirin use. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3704. doi:10.1158/1538-7445.AM2015-3704

A Large Cohort Study of Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs and Prostate Cancer Incidence

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has consistently been associated with a reduced risk of colon cancer. Recent epidemiologic studies have suggested that the use of NSAIDs, particularly aspirin, may also be associated with a reduced risk of prostate cancer, but the evidence remains limited. We examined the association between NSAID use and prostate cancer incidence among 70 144 men in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. Information on NSAID use was obtained from a questionnaire completed at study enrollment in 1992-1993 and was updated using follow-up questionnaires in 1997 and 1999. We calculated rate ratios (RRs) and 95% confidence intervals (CIs) for prostate cancer incidence associated with NSAID use, adjusting for age and potential prostate cancer risk factors. During follow-up from 1992-1993 through August 31, 2001, 4853 cases of incident prostate cancer were identified. Neither current aspirin use nor current use of NSAIDs (aspirin and other NSAIDs combined) was associated with prostate cancer risk, even at the highest usage level (60 or more pills per month). However, long-duration regular use (30 or more pills per month for 5 or more years) of NSAIDs was associated with reduced risk of prostate cancer (RR = 0.82, 95% CI = 0.71 to 0.94). Long-duration regular use of aspirin was also associated with reduced risk of prostate cancer (RR = 0.85, 95% CI = 0.73 to 0.99). The absolute rate of prostate cancer (standardized to the age distribution of study participants using 5-year age categories) was 1013 per 100,000 person-years among men who had never reported NSAID use, and 847 per 100,000 person-years among long duration regular NSAID users. These results support the hypothesis that long duration regular NSAID use is associated with modestly reduced risk of prostate cancer.

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer. To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent. Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. Colorectal cancer. Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

Non-steroidal anti-inflammatory drugs (NSAIDs) comprise the group of structurally diverse but similarly acting compounds that are used for relieving signs and symptoms of inflammation, especially in treatment of rheumatic diseases. Recent reports suggested potential association between regular use of NSAIDs and the risk of development of hematological malignancies. However, the data distinctly differ depending on type of NSAID used, period of its administration and type of malignancy. Regular use of aspirin and other NSAIDs was shown to correlate with reduced risk of lymphoid malignancies. Frequent use of aspirin was found to be associated with decreased risk of acute leukemia (AL) development. In contrast, correlation between long-term acetaminophen usage and increased incidence of AL and multiple myeloma (MM) was indicated. On the other hand, NSAIDs were found to exert anti-cancer effects, inhibiting proliferation and invasive growth or inducing cell apoptosis in several tumors, including hematologic malignancies. One of those agents, non-cyclooxygenase 2-inhibiting R-enantiomer of etodolac (SDX-101), exerts cytotoxic effects against chronic lymphocytic leukemia (CLL) and MM cells, and is currently investigated in phase II clinical trial in CLL. The indole-pyran analogue of SDX-101, SDX-308 (CEP-18082), showed more potent cytotoxicity than SDX-101 against MM cells and inhibited osteoclast formation and activity of mature osteoclasts. Thus, SDX-308 may be an ideal agent for bone disease in MM and related diseases. Another analogue of SDX-101, SDX-309, showed also significant anti-tumor activity in first preclinical studies. The potential role of NSAIDs in prevention and treatment of hematologic malignancies is the subject of this review.

Nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a reduced risk of colon cancer; further epidemiologic data appear consistent for stomach and esophageal adenocarcinomas. Yet, data on potential confounding effects by upper gastrointestinal tract (UGI) disorders on adenocarcinomas of the UGI are limited. This study recruited newly diagnosed patients with esophageal adenocarcinoma (n = 220), gastric cardia adenocarcinoma (n = 277), or distal gastric adenocarcinoma (n = 441) as well as 1,356 control subjects in Los Angeles County. Unconditional multivariable logistic regression analyses were done to evaluate the association between regular NSAID use, at least two pills per week for 1 month, and these cancers. Duration of regular use of aspirin and non-aspirin NSAIDs was associated with reduced relative odds of distal gastric adenocarcinoma [>5 years use versus no regular use: odds ratio (OR), 0.61; 95% confidence interval, 0.40-0.92; P(trend) = 0.009] and esophageal adenocarcinoma (OR, 0.60; 95% confidence interval, 0.38-0.95; P(trend) = 0.04) in multivariable models that included history of UGI disorders and other potential confounding factors. Daily regular use was also associated with statistically significant reduced ORs of these two tumor types. No significant heterogeneity in risk estimates was noted after stratification by history of UGI disorders for any of the sites studied. However, irregular users of NSAIDs also had reduced risk of these cancers when compared with nonusers. Results from this study support an inverse association between regular NSAID use and risk of esophageal and distal gastric adenocarcinomas in individuals with and without a history of UGI disorders with long duration and daily use, providing the greatest risk reduction. Reduced risk in irregular users suggests that factors other than an effect on cyclooxygenase may also be important.

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. 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. 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. 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.

The use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is widespread for treatment of common symptoms such as headaches, muscular pain, and inflammation. In addition, the chemopreventive use of NSAIDs is increasingly common for heart disease and colon cancer. Evidence of a protective association with breast cancer risk has been inconsistent, and few data exist for premenopausal women. We assessed the associations for use of aspirin, other NSAIDs, and acetaminophen with breast cancer risk among premenopausal women in the prospective Nurses' Health Study II. In total, 112,292 women, aged 25 to 42 years and free of cancer in 1989, were followed up until June 2003. Multivariate relative risks and 95% confidence intervals were calculated by Cox proportional hazards models, adjusting for age and other important breast cancer risk factors. Overall, 1345 cases of invasive premenopausal breast cancer were documented. Regular use of aspirin (> or = 2 times per week) was not significantly associated with breast cancer risk (relative risk, 1.07; 95% confidence interval, 0.89-1.29). Regular use of either nonaspirin NSAIDs or acetaminophen also was not consistently associated with breast cancer risk. Results did not vary by frequency (days per week), dose (tablets per week), or duration of use. Furthermore, associations with each drug category did not vary substantially by estrogen and progesterone receptor status of the tumor. These data suggest that the use of aspirin, other NSAIDs, and acetaminophen is not associated with a reduced risk of breast cancer among premenopausal women.

NSAIDs and a Lower Risk of Prostate Cancer: Causation or Confounding?

Objective To evaluate the relation between Parkinson’s disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men.Design Case-control analysis nested in the Physicians’ Health Study....

Epidemiologic studies of the association between nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, and breast cancer risk have yielded inconsistent results. We investigated the association of NSAID use with risk of breast cancer in the California Teachers Study cohort, with special attention to risk of specific breast cancer subtypes and to type of NSAID used. We analyzed data on 114 460 women in the California Teachers Study cohort who were aged 22 to 85 years and free of breast cancer at baseline in 1995 to 1996. Information on frequency and duration of NSAID use was collected through a self-administered questionnaire. A total of 2391 women were diagnosed with breast cancer during the follow-up period from 1995 to 2001. We used Cox proportional hazards regression to estimate relative risks (RR) and 95% confidence intervals (CI) of breast cancer subtypes with NSAID use. Neither regular use (more than once a week) of any NSAID (aspirin and ibuprofen combined) nor regular use of aspirin was associated with breast cancer risk (RR = 1.09, 95% CI = 0.97 to 1.21 for daily versus no regular use of NSAIDs and RR = 0.98, 95% CI = 0.86 to 1.13 for daily versus no regular use of aspirin). However, long-term (> or = 5 years) daily aspirin users had a non-statistically significant decreased risk of estrogen receptor and progesterone receptor (ER/PR)-positive breast cancer (RR = 0.80, 95% CI = 0.62 to 1.03). In contrast, we observed a statistically significantly increased risk of ER/PR-negative breast cancer with long-term daily use of aspirin (RR = 1.81, 95% CI = 1.12 to 2.92). In this population, 11 fewer ER/PR-positive breast cancer cases and seven excess ER/PR-negative breast cancer cases may be due to daily long-term aspirin use among 2391 breast cancer cases observed over 6 years if the association were proven to be causal. Long-term daily use of ibuprofen was also associated with an increased risk of breast cancer (RR = 1.51, 95% CI = 1.17 to 1.95), particularly of nonlocalized tumors (RR = 1.92, 95% CI = 1.24 to 2.97). If causality were subsequently proven, 16 of the observed 2391 breast cancer cases and 8 of the 713 non-localized breast cancer cases would be attributable to long-term daily use of ibuprofen. Long-term daily use of NSAIDs was not associated with breast cancer risk overall. Ibuprofen use was associated with an increased risk of breast cancer, and long-term daily aspirin use was associated with an increased risk of ER/PR-negative breast cancer. However, it is not clear if the observed association is causal.

Several studies have suggested that use of nonsteroidal antiinflammatory drugs (NSAIDs) may reduce the risk of breast cancer. Reductions in risk may vary according to the hormone receptor status of the tumor or the type of NSAID used. The authors extended a previous US hospital-based case-control study (the Case-Control Surveillance Study) to include 444 additional cases, for a total of 7,006 incident breast cancer cases (1976-2002). They examined the relation between regular NSAID use and breast cancer risk using logistic regression to adjust for confounding. The odds ratio for regular use of NSAIDs was 0.78 (95% confidence interval: 0.63, 0.97), and a trend of decreasing risk with increasing duration of use was statistically significant (p for trend = 0.02). The inverse association with regular use of NSAIDs was stronger among premenopausal women (odds ratio = 0.62). The overall odds ratios for regular use of aspirin and ibuprofen were 0.86 and 0.85, respectively. The effect of NSAID use on breast cancer risk did not vary according to the hormone receptor status of the tumor. In conclusion, long-term regular use of NSAIDs was associated with decreased risk of breast cancer. The type of NSAID used or the hormone receptor status of the tumor did not modify the effect.