Nonsteroidal anti‐inflammatory drugs and the risk of nonmelanoma skin cancer

Nonsteroidal anti‐inflammatory drugs (NSAIDs) have been assigned a promising role in the chemoprevention of various malignancies. However, epidemiological data on the association between NSAID use and nonmelanoma skin cancer (NMSC) are limited. To explore whether patients regularly exposed to systemic NSAIDs are at a reduced risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), we conducted a population‐based case‐control analysis using the Clinical Practice Research Datalink, a United Kingdom primary care database. We identified 65,398 patients with incident BCC and 7,864 patients with incident SCC diagnosed between 1995 and 2013 and matched 1 and 4 NMSC‐free controls to each BCC and SCC case, respectively, on age, sex, general practice, calendar time and years of history in the database. We compared prior NSAID exposure between cases and controls using multivariate conditional logistic regression analyses controlling for several potential confounders. Overall, we found no association between NSAID use and BCC, but when looking exclusively at users of single NSAID substances there was a suggestion of a reduced BCC risk in regular users of aspirin and ibuprofen (adjusted odds ratio [adj. OR]: 0.92, 95% confidence interval [CI]: 0.85–0.99 and adj. OR: 0.61, 95% CI: 0.48–0.78, respectively). The risk of SCC was slightly decreased in regular users of any NSAIDs (adj. OR: 0.89, 95% CI: 0.82–0.97), with the strongest risk reduction observed in current users of coxibs (adj. OR: 0.77, 95% CI: 0.62–0.95). These findings provide evidence that patients predisposed to NMSC might benefit from chemoprevention with NSAIDs.     

Nonsteroidal anti‐inflammatory drugs and other analgesic use and bladder cancer in northern New England

A few epidemiologic studies have found that use of nonsteroidal anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population‐based case–control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5–9, 10–19 and 20+ years, respectively; p_trend = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (p_trend = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX‐2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX‐2 inhibitors, which merits further evaluation.     

Use of nonsteroidal anti‐inflammatory drugs and prostate cancer risk: A meta‐analysis

The association between use of aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) and the risk of prostate cancer remains controversial despite many observational epidemiological studies. We conducted a systematic meta‐analysis of these studies to examine both the strength and the consistency of the association, and to explore sources of variability between studies. We searched 12 computerized literature databases for reports published before June 2008 and included any epidemiologic studies where the outcome was prostate cancer incidence or mortality, and the exposure was use of NSAIDs. Studies that met the inclusion criteria comprised 10 case–control and 14 cohort studies with a total of 24,230 prostate cancer cases. Studies that assessed the effect of aspirin use on total prostate cancer had a pooled odds ratio (POR) of 0.83 (95%CI: 0.77–0.89), whereas those that assessed the effect of aspirin on advanced prostate cancer had a POR of 0.81 (0.72–0.92). Studies that examined the effects of non‐aspirin NSAIDs or all NSAIDs were less consistent but still suggestive of reduced risks. However, most reviewed studies were limited by exposure and disease misclassification, by inadequate information on dose and duration of use and by the possibility of screening and other biases. In conclusion, the epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive. There is a need for well‐designed observational studies with adequate exposure measurements, accurate case definition, attention to latency effects, and careful adjustment for screening and other biases.     

Nonsteroidal anti‐inflammatory drug use and breast cancer risk in a European prospective cohort study

Experimental studies have shown a protective effect of nonsteroidal anti‐inflammatory drugs (NSAIDs) on breast cancer development. However, results from epidemiological cohort studies are less consistent. Our objective was to assess the association between NSAID use and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Self‐reported information on NSAID use at baseline has been collected in five EPIC countries. Multivariable Cox regression models were used to estimate hazard ratios for the association of NSAID use with breast cancer incidence with adjustment for potential confounders. We also assessed effect modification by breast cancer risk factors and examined the associations within specific breast cancer subtypes. Among the 140,981 women included in the analysis, 7% were regularly using NSAIDs at baseline. During a median follow‐up time period of 13 years, 7,379 incident breast cancer cases were diagnosed (816 in situ and 6,563 invasive). There were no statistically significant associations between NSAID use and breast cancer risk, overall and by subtypes. However, a statistically significant interaction was observed for invasive cases between NSAID use and ever use of menopausal hormonal therapy (MHT) among postmenopausal women [MHT users: HR_{NSAID use} = 0.84 (0.73–0.96); non MHT users: HR_{NSAID use} = 1.08 (0.93–1.25); p_interaction = 0.05]. Our results indicate potential effect modification of MHT use on the association between use of NSAIDs and breast cancer risk which deserves in‐depth investigation in studies with accurate data on both NSAID and MHT use.     

Aspirin,nonsteroidal anti‐inflammatory drugs,paracetamol and risk of endometrial cancer: A case–control study,systematic review and meta‐analysis

Aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) have been associated with reduced risk of a number of cancer types, however, previous studies of endometrial cancer have yielded inconclusive results. We analyzed data from the Australian National Endometrial Cancer Study (ANECS), a population‐based case–control study (1,398 cases, 740 controls). We systematically reviewed all the evidence linking aspirin/NSAIDs use with endometrial cancer and conducted a meta‐analysis. For ANECS, unconditional logistic regression was used to estimate odds ratios (OR) adjusting for potential confounders. For the systematic review, we searched Pubmed, Embase, Web of Science and conducted a review of citations from retrieved articles. The meta‐analysis risk estimates were pooled using a random‐effects model. In our case–control study, women who had ever used aspirin in the last 5 years had a significantly lower risk of endometrial cancer OR = 0.78 [95% confidence interval (CI): 0.63‐0.97]. There was a significant inverse dose–response (p‐trend <0.001) such that women who reported using ≥2 aspirin/week had almost half the risk OR = 0.54 (0.38–0.78). No significant associations were observed between use of half‐aspirin/day, non‐aspirin NSAIDs or paracetamol and endometrial cancer risk. The results were similar when examined by cancer subtype. Nine studies were included in the meta‐analysis. The overall pooled risk estimate for any versus no use of aspirin was 0.87 (0.79–0.96) with no evidence of heterogeneity. The pooled risk estimate for obese women (BMI ≥ 30 kg/m²) was 0.72 (0.58–0.90) but there was no association for non‐obese women. Overall these results suggest that aspirin may reduce the risk of endometrial cancer, particularly among obese women.     

Nonsteroidal anti-inflammatory drugs and the risk of developing breast cancer in a population-based prospective cohort study in Washington County, MD

The objective of this study was to examine the association between nonsteroidal anti-inflammatory drug (NSAID) use and the development of breast cancer, and to assess whether this association differed by estrogen receptor (ER) subtype. Data were analyzed from 15,651 women participating in CLUE II, a cohort study initiated in 1989 in Washington County, MD. Medication data were collected at baseline in 1989 and in 1996. Incident cases of invasive breast cancer occurring from baseline to March 27, 2006 were identified through linkage of cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Cox proportional hazards modeling was used to calculate the risk ratios (RR) and 95% confidence intervals (95% CI) for breast cancer associated with medication use. Among women in the CLUE II cohort, 418 invasive breast cancer cases were identified during the follow-up period. The results showed that self-reported use of NSAIDs in both 1989 and in 1996 was associated with a 50% reduction in the risk of developing invasive breast cancer compared with no NSAID use in either 1989 or 1996 (RR = 0.50; 95% CI 0.28, 0.91). The protective association between NSAID use and the risk of developing breast cancer was consistent among ER-positive and ER-negative breast cancers, although only the RR for ER-positive breast cancer was statistically significant. Overall, findings from this study indicate that NSAID use is associated with a decrease in breast cancer risk and that the reduction in risk is similar for ER-positive and ER-negative tumors.     

Non‐steroidal anti‐inflammatory drugs and cancer risk in women: Results from the Women's Health Initiative

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site‐specific cancer incidence in the large, prospective Women's Health Initiative (WHI). Women (129,013) were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow‐up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site‐specific cancer risk. Relative to non‐use, consistent use (i.e., use at baseline and year 3 of follow‐up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94–1.06). Results for individual NSAIDs were similar to the aggregate measure. In site‐specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs' benefit on cancer risk was therefore limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.     

Associations of aspirin,nonsteroidal anti‐inflammatory drug and paracetamol use with PSA‐detected prostate cancer: Findings from a large,population‐based,case–control study (the ProtecT study)

Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti‐inflammatory drugs may protect against prostate cancer development. We analysed data from a cross‐sectional case–control study (n_cases= 1,016; n_controls= 5,043), nested within a UK‐wide population‐based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to investigate the relationship of aspirin, nonsteroidal anti‐inflammatory drug (NSAID) and paracetamol use with prostate cancer. In conditional logistic regression models accounting for stratum matching on age (5‐year age bands) and recruitment centre, use of non‐aspirin NSAIDs [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.04–1.67] or all NSAIDs (OR = 1.25; 95% CI = 1.07–1.47) were positively associated with prostate cancer. There were weaker, not conventionally statistically significant, positive associations of aspirin (OR = 1.13; 95% CI = 0.94–1.36) and paracetamol (OR = 1.20; 95% CI = 0.90–1.60) with prostate cancer. Mutual adjustment for aspirin, non‐aspirin NSAIDs or paracetamol made little difference to these results. There was no evidence of confounding by age, family history of prostate cancer, body mass index or self‐reported diabetes. Aspirin, NSAID and paracetamol use were associated with reduced serum PSA concentrations amongst controls. Our findings do not support the hypothesis that NSAIDs reduce the risk of PSA‐detected prostate cancer. Our conclusions are unlikely to be influenced by PSA detection bias because the inverse associations of aspirin, NSAID and paracetamol use with serum PSA would have attenuated (not generated) the observed positive associations.     

Use of non‐steroidal anti‐inflammatory drugs and risk of non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Epidemiological study findings regarding the association between use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and risk of non‐Hodgkin lymphoma (NHL) have been inconsistent. We aimed to systematically review epidemiological studies of the association and calculate pooled relative risks using meta‐analytic methods. We searched eight electronic literature databases and three clinical trial registers to identify all studies (including observational studies and randomized clinical trials) of the association published prior to October 2013. Identified studies were independently reviewed by two researchers. We used a random effects model to calculate pooled odds ratio (PORs). Heterogeneity amongst studies was examined using Cochran's Q and I‐squared (I²) tests; and sources of heterogeneity were explored using subgroup and meta‐regression analyses. A total of 17 studies (12 case‐control studies and five cohort studies), all adult studies, were included. Use of NSAIDs was not associated with overall risk of NHL [POR = 1.05, and 95% confidence interval (95% CI) 0.90–1.22] or NHL subtypes including B‐cell lymphoma, T‐cell lymphoma, follicular lymphoma, diffuse large B‐cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aspirin use was associated with reduced risk of CLL/SLL (POR = 0.70, 95% CI 0.54–0.91) but not with the risk of all NHLs (POR = 1.02, 95% CI 0.89–1.17). Use of non‐aspirin NSAIDs was associated with increased risk of NHL (POR = 1.41, 95% CI 1.01–1.97) amongst females only. The epidemiologic evidence remains inconclusive. Effects of NSAIDs may differ by drug type, NHL subtype, and sex and more studies taking into consideration these differences are needed. Copyright © 2014 John Wiley & Sons, Ltd.     

Use of nonsteroidal anti-inflammatory drugs and risk of basal cell carcinoma in the United States Radiologic Technologists study

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with reduced risk of colorectal and other cancers, but the association with basal cell carcinoma (BCC) is unclear. Previous epidemiological studies have been small in size, conducted in especially vulnerable populations, or have not accounted for solar ultraviolet exposure, a major risk factor for BCC. In the United States Radiologic Technologists cohort, we followed subjects to assess NSAID use on risk of first incident BCC. We included Caucasian participants who responded to both second and third questionnaires (administered from 1994 to 1998 and 2003 to 2005, respectively), and who reported no cancer at the time of the second questionnaire, N = 58,213. BCC, constituent risk factors (e.g., eye color, complexion, hair color) and sun exposure history were assessed through self-administered survey. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Of the 58,213 people in the study population, 2,291 went on to develop BCC. Any NSAID use was not associated with subsequent incidence of BCC (HR = 1.04, 95% CI: 0.92-1.16) after adjusting for age, sex and estimated lifetime summer sun exposure. Neither association was observed when stratified by NSAID type (aspirin and other NSAIDs), nor did dose-response patterns emerge by frequency of use (average days per month). Further analyses did not reveal interaction with sex, birth cohort, smoking, alcohol consumption, sun exposure, occupational radiation exposure or personal risk factors for BCC. In this large nationwide study, we observed no association between NSAID use and subsequent BCC risk.     

Baseline serum C‐reactive protein and death from colorectal cancer in the NHANES III cohort

Several prospective studies suggest that C‐reactive protein (CRP), a nonspecific serologic marker of inflammation, might be linked to risk of colorectal cancer (CRC), whereas others have reported null or protective effects. We analyzed data from 7,072 participants (50–85 years) in the U.S. National Health and Nutrition Examination Survey III (1988–1994), a nationally representative cohort (n = 33,994; 2 months–85 years) with vital status follow‐up to 2000. Hazard ratios (HRs) for mortality associated with baseline clinically raised (≥1.00 mg/dL) and intermediate (≥0.22–0.99 mg/dL) CRP levels were estimated using Cox proportional hazards regression controlling for CRC risk factors. There were 59 deaths from CRC, 106 from other obesity‐related cancers (other‐ORCs) and 1,130 from cardiovascular disease (CVD). Participants with clinically raised CRP at baseline were found to have a statistically significant greater risk of CRC death (HRs = 2.36–2.47) in comparison to persons with undetected levels. HRs were lower for death from other‐ORC and CVD (1.82, 95% CI 1.05–3.15; 1.53, 95% CI 1.29–1.81, respectively). Intermediate CRP level was associated with a nonsignificant 10–21% increased risk for CRC death. HR for CRC death was higher among persons with a normal BMI (2.16, 95% 0.96–4.87, p = 0.06) compared to those who were overweight (1.22, 95% CI 0.53–2.78) or obese (1.23, 95% CI, 0.37–4.08). A similar pattern was observed for waist circumference. This effect modification suggests that the impact of chronic inflammation may be independent of excess body fat. Future research is recommended to confirm emerging data that elevated serologic CRP might reflect underlying colonic inflammation.     

Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy

In this review, we discuss the available experimental evidences supporting the chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and the biological basis for their possible role as anticancer agents. Although the comprehension of the mechanisms underlying the effects of these drugs on colon cancer cells is incomplete, research efforts in identifying the biochemical pathway by which NSAIDs exert their chemopreventive effect have provided a rationale for the potential use of NSAIDs alone or in combination with conventional and experimental anticancer agents in the treatment of colorectal cancer. In this paper, we review three main issues: (i) the role of COX-2 in colon cancer; (ii) the common death pathways between NSAIDs and anticancer drugs; and (iii) the biological basis for the combination therapy with COX-2 selective inhibitors and new selective inhibitors of growth factor signal transduction pathways.     

Inhibition of store-operated calcium entry contributes to the anti-proliferative effect of non-steroidal anti-inflammatory drugs in human colon cancer cells

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation and angiogenesis in colorectal cancer. We examined a possible involvement of store-operated calcium (SOC) entry in human colon carcinoma cells (HRT-18), which require calcium for proliferation. Acetyl-salicylic-acid (ASA), mefenamic acid (MEF) and sulindac sulfide (SUS) inhibited cell proliferation with the following order of potency: SUS > MEF > ASA. SUS but not MEF and ASA induced apoptosis following low-dose treatment. Furthermore, SUS and MEF significantly altered the cell cycle distribution. The ability of NSAIDs to inhibit SOC entry was assessed by measuring the intracellular calcium concentration ([Ca2+]i) in response to calcium store depletion using the endoplasmic calcium ATPase inhibitor thapsigargin. SUS and MEF, but not ASA significantly inhibited SOC entry. A causal link between SOC entry inhibition and anti-proliferative activity was tested using the inorganic SOC entry inhibitor La3+ and the specific organic inhibitor N-1-n-octyl-3,5-bis-(4-pyridyl)triazole (DPT). Both La3+ and DPT inhibited cell proliferation and SOC entry. Analogous to MEF, the anti-proliferative effect of DPT was mediated by cell cycle arrest and not by induction of apoptosis. These data indicate a role of SOC entry for cell proliferation in cancer cells and suggest a novel anti-proliferative NSAID mechanism in addition to its known influence on lipid metabolism.     

Low‐serum GTA‐446 anti‐inflammatory fatty acid levels as a new risk factor for colon cancer

Gastrointestinal tract acid‐446 (GTA‐446) is a long‐chain polyunsaturated fatty acid present in the serum. A reduction of GTA‐446 levels in colorectal cancer (CRC) patients has been reported previously. Our study compared GTA‐446 levels in subjects diagnosed with CRC at the time of colonoscopy to the general population. Serum samples and pathology data were collected from 4,923 representative subjects undergoing colonoscopy and from 964 subjects from the general population. Serum GTA‐446 levels were determined using a triple‐quadrupole tandem mass spectrometry method. A low‐serum GTA‐446 level was based on the bottom tenth percentile of subjects with low risk based on age (40–49 years old) in the general population. Eighty‐six percent of newly diagnosed CRC subjects (87% for stages 0–II and 85% for stages III–IV) showed low‐serum GTA‐446 levels. A significant increase in the CRC incidence rate with age was observed in subjects with low GTA‐446 levels (p = 0.019), but not in subjects with normal levels (p = 0.86). The relative risk of CRC given a low GTA‐446 level was the highest for subjects under age 50 (10.1, 95% confidence interval [C.I.] = 6.4–16.4 in the reference population, and 7.7, 95% C.I. = 4.4–14.1 in the colonoscopy population, both p < 0.0001), and declined with age thereafter. The CRC incidence rate in subjects undergoing colonoscopy with low GTA‐446 levels was over six times higher than for subjects with normal GTA‐446 levels and twice that of subjects with gastrointestinal symptoms. The results show that a low‐serum GTA‐446 level is a significant risk factor for CRC, and a sensitive predictor of early‐stage disease.