The effect of prediagnostic aspirin use on the prognosis of stage III colorectal cancer.
ABSTRACT: BACKGROUND:Many studies have suggested that the regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, has a protective effect and survival benefit on colorectal cancer (CRC). However, recent data suggest that CRCs have different responses to NSAIDs depending on the timing of NSAID initiation, duration of NSAID use, and molecular characteristics of the tumor. The aim of this study was to evaluate the effect of long-term prediagnostic aspirin use on the prognosis of stage III CRC. METHODS:From 2007 to 2009, patients who were diagnosed with stage III CRC were recruited, and their medical records were retrospectively analyzed. Patients were divided into prediagnostic aspirin users (who used aspirin for more than three months continuously before CRC diagnosis) and non-users (who did not use of aspirin and NSAIDs). The two groups were compared in terms of recurrence, cancer-specific mortality, disease-free survival (DFS), and cancer-specific survival. In an experimental study, three CRC cell lines (Caco2, SW480, and DLD-1) were pretreated with aspirin (1 mM) for four days or 28 days to make aspirin-resistant cells, treated with 5-fluorouracil (5-FU; 2 µM), and apoptosis was measured with flow cytometry using Annexin-V and propidium iodide double staining. RESULTS:Compared with the aspirin non-users (N=565), the prediagnostic aspirin users (N=121) were not different in terms of baseline characteristics including tumor characteristics, except for comorbidities and diabetes medication and statin use, which were higher in the prediagnostic aspirin users. Recurrence and cancer-specific mortality in stage III CRC were significantly higher in prediagnostic aspirin users than non-users (46.7% vs. 32.3%, P=0.003 and 32.2% vs. 19.8%, P=0.003, respectively). Survival analysis using Cox proportional hazards modeling demonstrated that DFS was significantly worse in prediagnostic aspirin users than non-users (HR, 1.525 (1.018-2.286); P=0.041). In cell line experiments, long-term aspirin pretreatment induced an increase in 5-FU-induced apoptosis in SW480 cells compared with control treatment without aspirin pretreatment. However, Caco2 cells showed a significant decrease of apoptosis in the same experiments and no change in DLD1 cells. CONCLUSION:Prediagnostic long-term aspirin use in stage III CRC could be a negative prognostic factor depending on the characteristics of the CRC.
Project description:Common single nucleotide polymorphisms (SNPs) in SMAD7 (18q21) have been linked to colorectal cancer (CRC) risk in genome-wide association studies, but little is known about their effects on survival. SMAD7 regulates gastrointestinal inflammation by inhibiting transforming growth factor-? (TGFB), which can act as both a tumor suppressor and a promoter of metastasis. Regular use of cyclooxygenase-2 (COX2) inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), reduces the risk of developing CRC. Because COX2 overexpression reduces the growth suppressing effects of TGFB, we hypothesized that survival may depend on both SMAD7 genotype and prediagnostic NSAID use. Postmenopausal women, ages 50-74, diagnosed with incident invasive CRC from 1997 to 2002 were identified using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Information on prediagnostic NSAID use and other risk factors was ascertained by interview, and women were followed-up for survival through December 31, 2009. Seven hundred and twenty-seven cases were genotyped for two GWAS hits in SMAD7 with minor allele frequency > 30%, one with minor allele associated with decreased risk (rs4939827) and one with minor allele associated with increased risk (rs4464148). Two hundred and forty-two deaths occurred, 160 attributable to CRC. Among those without distant disease at diagnosis, CRC-specific survival differed by genotype only for NSAID users: each minor allele of rs4939827 was associated with worse survival [hazard ratio (HR) = 2.67, 95% confidence interval (CI): 1.33-5.37] and each minor allele of rs4464148 was associated with better survival (HR = 0.41, CI 0.18-0.94). SMAD7 variants known to be important for CRC risk were associated with disease-specific survival among prediagnostic NSAID users.
Project description:BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin (acetylsalicylic acid, ASA). Long-term use of NSAIDs has been associated with lowered risk of colorectal cancer (CRC), but the use is hampered by adverse effects. Also, the anti-carcinogenic effects of NSAIDs are incompletely understood. Understanding biological effects of NSAIDs may help developing new preventive medical strategies. AIM: To identify gene-environment interactions between genetic variation and NSAID use in relation to risk of CRC. METHODS: We performed a PubMed literature search and all studies reporting original data on interactions between NSAIDs and polymorphisms in relation to CRC were evaluated. RESULTS: We found indications that aspirin interacted with rs6983267 close to MYC (encoding a transcription factor involved in cell cycle progression, apoptosis and cellular transformation) and NSAIDs interacted with rs3024505 and rs1800872 in or close to IL10 (encoding IL-10) in preventing CRC. Homozygous carriers of the variant allele of rs6983267 (ca. 25% of the population) halved their risk for CRC by aspirin use compared to homozygous wildtype carriers who did not benefit from aspirin intake. No interaction between use of NSAIDs and PTGS-2 (encoding COX-2) in relation to CRC risk was detected. Other findings of interactions between genes in inflammatory and oncogenic pathways and NSAIDs were considered suggestive. CONCLUSIONS: Knowledge of underlying biological effects of NSAIDs in relation to CRC is scarce and the basis for stratifying the patients for preventive treatment is not yet available. Further studies assessing interactions between long-term NSAID exposure and genetic variation in relation to CRC are warranted in large well-characterised prospective cohorts.
Project description:Frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colorectal adenomas in randomized trials. We examined the persistence of the protective effect after the cessation of randomized aspirin treatment and whether it is affected by the duration and frequency of subsequent NSAID use.We used data from the Aspirin/Folate Polyp Prevention Study (AFPPS), in which 1121 subjects were randomly assigned to receive placebo or aspirin (81 or 325 mg/d) for 3 years. After the end of treatment and a follow-up colonoscopy, AFPPS participants were invited to remain under follow-up until their next surveillance colonoscopies, scheduled 3-5 years later. Information regarding use of NSAIDs during posttreatment follow-up was gathered periodically via questionnaires. Average weekly NSAID use was classified as sporadic (<2 days per week), moderate (2 to <4 days per week), or frequent (>or=4 days per week). The analysis was stratified according to randomized aspirin groups and posttreatment NSAID use; placebo subjects who later were sporadic NSAID users formed the reference group. The primary outcomes were all adenomas and advanced lesions. Adjusted relative risks and 95% confidence intervals were computed with generalized linear models. All statistical tests were two-sided.A total of 850 subjects underwent a posttreatment colonoscopy, on average 4 years after the end of study treatment. The protective effect of 81 mg of aspirin for colorectal adenomas persisted with continued posttreatment NSAID use. The risk of any adenoma among frequent NSAID users was 26.8% vs 39.9% among placebo subjects who later used NSAIDs sporadically (adjusted relative risk = 0.62, 95% confidence interval [CI] = 0.39 to 0.98; P(trend) with NSAID use frequency = .03). The unadjusted absolute risk reduction was 13.1 percentage points (95% CI = -0.3 to 26.5 percentage points) (P = .07). Results for 325 mg of aspirin were similar, although not statistically significant. For advanced lesions, small numbers of endpoints limited the analysis, but findings among subjects randomly assigned to 81 mg of aspirin suggested a protective association regardless of posttreatment NSAID use.Long-term and frequent use of NSAIDs may enhance the chemopreventive effect of aspirin against colorectal neoplasia.
Project description:OBJECTIVE:Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA. METHODS:We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999-2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use. RESULTS:Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs. CONCLUSIONS:This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs.
Project description:<h4>Background</h4>Aspirin use has been shown to lower incidence and mortality in cancer patients. The aim of this population-based study was to determine the effect of postdiagnosis low-dose aspirin use on survival of patients with oesophageal cancer.<h4>Methods</h4>Patients with oesophageal cancer (1998-2010) were selected from the Eindhoven Cancer Registry and linked with outpatient pharmacy data regarding aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Users were subdivided into both prediagnosis and postdiagnosis or only postdiagnosis users. Parametric survival models with an exponential (Poisson) distribution were used with non-specific death as endpoint.<h4>Results</h4>In this study 560 patients were included. Overall, 157 patients (28.0%) were non-users, 293 patients (52.3%) pre- and postdiagnosis (89 aspirin and 204 NSAID users) and 110 patients (19.6%) only postdiagnosis users (16 aspirin and 94 NSAID users). Postdiagnosis aspirin use was associated with overall survival (RR 0.45 (95% CI 0.34-0.60; P<0.001); adjusted rate ratio was 0.42 (95% CI: 0.30-0.57; P<0.001). Postdiagnosis use of NSAIDs was associated with overall survival (RR 0.61 (95% CI 0.49-0.76; <0.001); however, adjusted analyses did not show a significant association with a rate ratio of 0.84 (95% CI 0.66-1.07; P=0.2).<h4>Conclusions</h4>Our study shows that postdiagnosis aspirin use might be associated with a higher survival rate in oesophageal cancer patients. A randomised clinical trial is needed to verify our observations of possible postdiagnosis aspirin use benefit.
Project description:Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all P(trend) > or = 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (P(trend) = 0.04) and estrone sulfate (P(trend) = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (P(trend) = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (P(trend) = 0.001), free estradiol (P(trend) = 0.01), estrone sulfate (P(trend) = 0.03), and the ratio of estradiol to testosterone (P(trend) = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users.
Project description:BACKGROUND:Several frequently used prescription drugs may affect bleeding risk. We investigated use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and statins and risk of postoperative red blood cell transfusion in breast cancer patients. METHODS:Using Danish population-based registries, we identified a cohort of women who underwent surgery for primary breast cancer (n = 22,238) during 2005-2012 and ascertained their use of aspirin, NSAIDs, SSRIs, and statins. For each drug, patients were categorized as users if they filled ≥1 prescription in the 60 days prior to surgery. We calculated the 14-day risk of red blood cell transfusion and relative risks (RRs) with 95% confidence intervals (CIs), comparing users with nonusers for each drug and adjusting for age, cancer stage, and Charlson Comorbidity Index score. RESULTS:In our cohort, 1385 (6.2%) women were aspirin users, 1794 (8.0%) were NSAID users, 1110 (4.9%) were SSRI users, and 2053 (9.1%) were statin users. The overall risk of red blood cell transfusion was 1.3%. The 14-day risk of RBC transfusion was 3.5% among aspirin users versus 1.1% among aspirin nonusers (adjusted RR = 1.9, 95% CI: 1.4-2.7), and 1.8% among SSRI users versus 1.2% among SSRI nonusers (adjusted RR = 1.2, 95% CI: 0.7-1.9). Red blood cell transfusion risk was increased among NSAID users, but not in a sensitivity analysis with a 30-day exposure window. Red blood cell transfusion risk was not increased among SSRI and statin users. CONCLUSIONS:Primary breast cancer surgery confers a low risk of RBC transfusion. Still, use of aspirin and possibly NSAIDs, but not SSRIs and statins, is associated with increased red blood cell transfusion. This increased risk is not explained by differences in age, stage, or comorbidity level.
Project description:<h4>Background</h4>Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.<h4>Methods</h4>We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.<h4>Results</h4>Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.<h4>Conclusions</h4>Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
Project description:Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case-control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): -1.35 (95% CI -5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: -2.68 (95% CI -6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype.