07-2828 1564.1595

Use of Common Medications and Breast Cancer Risk Kirsten B. Moysich,1 Gregory P. Beehler,2 Gary Zirpoli,1,3 Ji-Yeob Choi,1 and Julie A. Baker4 1Department of Epidemiology, Roswell Park Cancer Institute; 2Department of Psychology, VAWestern New York Healthcare System;3Department of Biostatistics, University at Buffalo, Buffalo, New York and 4Department of Obstetrics and Gynecology,Women and Infants Hospital of Rhode Island, Providence, Rhode Island Prescription and over-the-counter medications are breast cancer among aspirin users, most studies that widely used in the United States and many western have examined the potential chemoprotective effect of countries. More than two-thirds of women ages >45 nonsteroidal anti-inflammatory drugs have shown years, who are at greatest risk for breast cancer, take significant risk reductions for regular and prolonged prescription medication. In light of the ubiquitous use of these drugs. The existing literature on the role of nature of medication use and the fact that breast cancer medication use in breast carcinogenesis is complicated.
remains the most common cancer in women, research Interpretation of the evidence is hampered due to on the role of medication use in breast cancer etiology major methodologic differences across studies, includ- is warranted. We summarize the epidemiologic evi- ing exposure assessment, exposure classification, and dence on the association between breast cancer risk adjustment for potential confounding variables. These and use of common medications, including antibiotics, differences largely stem from the fact that the majority antidepressants, statins, antihypertensives, and non- of articles on this topic represent secondary data steroidal anti-inflammatory drugs. Overall, there is analyses from studies with inadequate information little evidence that would implicate the use of anti- on exposure or confounders. Thus, future epidemio- biotics, antidepressants, statins, and antihypertensives logic studies specifically designed to study these in the etiology of breast cancer. Although several ubiquitous and biologically plausible exposures are prospective studies and a randomized low-dose aspirin chemoprevention trial have not shown lower risk of Prescription and over-the-counter medications are very medication use in the United States represents a widely used in the United States and many western ubiquitous exposure. In light of the fact that breast countries. Arecent study of medication use in the cancer remains the most common cancer in women, a ambulatory adult population of the United States careful evaluation of the potential chemopreventive or revealed that 81% of participants have used at least carcinogenetic effects of common medications is war- one medication in the past week and that half of the ranted. In this review, we focus on commonly used sample reported to have taken at least one prescription medications that have been studied previously in medication. This survey also showed that women ages epidemiologic studies of breast cancer. These groups of z65 years were the highest medication users; specifically, medications include antibiotics, antidepressants, statins, 12% of women in this age group took at least 10 different antihypertensives, and nonsteroidal anti-inflammatory medications and 23% took at least 5 prescription drugs (1). More recent data from the Slone Survey (2) indicatethat overall and prescription medication use has increased between 1999 and 2005. This study alsoreinforced earlier estimates that >90% of women ages The existing body of literature concerning the use of z45 years reported any medication use. Further, pre- common medications and breast cancer risk is largely scription medication use for women ages 45 to 64 inconsistent. Aprimary reason for the divergent findings and z65 years was 68% and 82%, respectively. Thus, likely relates to the vast differences in methodologiesemployed in these studies. In addition to the obviousdifferences, such as study design (cohort studies versus Received 11/26/07; revised 4/1/08; accepted 4/15/08.
case-control studies), these previous studies vary greatly Grant support: Susan G. Komen for the Cure as part of the Environmental Factors and with respect to exposure assessment, exposure classifi- Breast Cancer Science Review project led by Silent Spring Institute with collaborating cation, and adjustment for potential confounding varia- investigators at Harvard Medical School, Roswell Park Cancer Institute, andUniversity of Southern California.
bles. For instance, with respect to exposure assessment, Requests for reprints: Kirsten B. Moysich, Department of Cancer Prevention and many studies focused on NSAID use and breast cancer Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
risk have only measured aspirin exposure but have no Phone: 716-845-8004; Fax: 716-845-8487. E-mail: kirsten.moysich@roswellpark.orgCopyright D 2008 American Association for Cancer Research.
data on more recently introduced NSAIDs such as ibu- profen or selective cyclooxygenase-2 (COX-2) inhibitors.
Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 1. Epidemiologic studies of the role of antibiotics use in breast cancer development 157 cases in Finnish Mobile Clinic Health Examination Survey identified via Finnish Cancer Registry 9,304 cancer-free cohort members (total cohort 9,461) Cases: 2,266 women enrolled in large health plan with primary invasive breast cancer identified fromSurveillance, Epidemiology and End Results Controls: 7,953 disease-free health plan members Cases: 2,728 incident cases identified via Controls: 27,280 controls from population-based Civil Registration System matched 10:1 to cases Cases: 3,708 cases identified from General Practice Controls: 20,000 frequency matched cancer-free controls Cases: 1,268 cases identified from those with 6 y recorded medical history in General Practice Research Database Controls: 6,291 cancer-free controls matched to cases Cases: 700 cases(including 5 males) identified from Controls: 700 cancer-free controls matched 1:1 to cases 2,266 women with primary invasive breast cancer enrolled in Group Health Cooperative and identified throughSurveillance, Epidemiology and End Results Highest number of days antibiotic use (z1,001) vs none: 2.07 (1.48-2.89); highest number of prescriptionsfilled (z51) vs none: 2.31 (1.69-3.15) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 1. Epidemiologic studies of the role of antibiotics use in breast cancer development (Cont’d) cancer, high breast density,hysterectomy, menopausalstatus, age at menopause and postmenopausal hormonereplacement therapy (HRT) use 0.9 (0.6-1.2), skin infection1.2 (0.9-1.6), other infection1.0 (0.8-1.3) following covariates: BMI,HRT use, history of benignproliferative breast disease,frequency of mammograms,frequency of visits togeneral practice Grade 4 vs 1: 1.39 (0.47-4.16)ER- vs ER+: 1.17 (0.79-1.75)Lobular vs ductal histology: Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 1. Epidemiologic studies of the role of antibiotics use in breast cancer development (Cont’d) Cohort: 2,130,829 female adult health subscribers Cases: 18,521 women with incident invasive Thus, it is possible that women who do not report aspirin conversion of phytochemicals derived from the con- use but are in fact frequent ibuprofen users will be sumption of plant-based food products into biologically erroneously classified as ‘‘non-NSAID users,’’ because active substances (4-6) suggested to be protective against use of these newer drugs was not assessed in some cancer. For example, phytochemicals, such as lignans, studies. Further, using the existing research on antibiotic can be converted by microflora to enterolactone (7), use and breast cancer risk as an example, there are great which has been correlated with reduced breast cancer differences in exposure assessment. Some studies classify risk (8, 9). Antibiotics could also theoretically decrease antibiotic use as crudely as ‘‘ever versus never,’’ whereas breast cancer risk by affecting the ability of microflora to others have detailed information based on prescription modulate levels of circulating estrogens through decon- data. Results from cohort studies might be difficult to jugation of bound estrogens in the gut, freeing them for interpret, as many studies rely on a single measurement reabsorption and circulation (10-13). However, the of medication use, which does not take into account that disruption of the microflora by antibiotics is not uniform medication use is subject to change over time. Further, and may vary by dose and specific drug formulation (8).
many studies of medication use and breast cancer utilize Breast cancer risk may also be mediated by the effect large general practice databases, which improves expo- of antibiotics on the human immune system and sure assessment but does not allow for adjustment for inflammatory response. Numerous specific biological potential confounding variables, as these are generally mechanisms have been suggested, but these remain not available in these data resources. Finally, it should be largely speculative (3). Some antibiotics may have an noted that the vast majority of existing studies represent anti-inflammatory effect by limiting the production of so-called secondary data analyses, indicating that these cytokines or a group of several proteins involved in the various studies were not specifically designed to address immune and inflammatory response (9). Inhibited the relationship between common medications and cytokine production may be important in limiting breast cancer risk. Rather, medication use was collected estrogen synthesis in the peripheral fat (10, 11), poten- as a potential confounder or within the context of a tially decreasing cancer risk. There is also limited medical history in which exposures or confounders is evidence that some antibiotics may increase the produc- often absent. Although it is standard practice in tion of prostaglandins or markers of the inflammatory epidemiologic research to analyze data for secondary associations, such studies are always methodologicallyinferior to those that were specifically designed to assessthe link between specific medications and risk of breast cancer. Summarized below is the existing body ofevidence of the associations between the use of common The potential role of antibiotic use in breast cancer medications, such as antibiotics, antidepressants, statins, etiology gained wide public attention after results from a and NSAIDs, and breast cancer risk, preceded by a brief recent large case-control study became available. In this discussion of the biological mechanism by which these study of 2,266 breast cancer patients and 7,953 controls who were enrolled in a nonprofit health plan, Lawloret al. (14) were able to use computerized pharmacyrecords to assess exposure to antibiotic drugs. Results indicated that compared with women who never usedantibiotics, women with the longest durations of antibi- Biological Mechanisms. Arecent review of the otic use had a 2-fold increase in breast cancer risk biological mechanisms by which antibiotics may influ- [odds ratio (OR), 2.07; 95% confidence interval (95% CI), ence breast cancer risk suggests two main pathways: 1.48-2.89]. Similar risk estimates were observed when disruption of intestinal microflora and effect on immune nonusers were compared with women with the greatest and inflammatory function (3). Naturally occurring gut number of antibiotic prescriptions (OR, 2.31; 95% CI, microflora have been shown to play a role in the 1.69-3.15). Results were very similar for premenopausal Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 1. Epidemiologic studies of the role of antibiotics use in breast cancer development (Cont’d) Use >100 dTetracyclines: 1.23 (1.11-1.36), tetracyclines (excluding everused macrolides): 1.14(0.99-1.31) macrolides (excluding everused tetracycline): 1.18(0.93-1.49) and postmenopausal women and risk was increased for sites as N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethan- all subtypes of antibiotic drugs. These findings, which amine HCl (20). However, the presumed effect of sparked considerable public concern about antibiotic use, antidepressants on tumor growth was not replicated in are somewhat similar to those from a Finish cohort study subsequent in vitro studies of human breast tumor cell (15) where ever use of antibiotics was associated with increased risk of breast cancer among premenopausal The cytochrome P450 enzyme system has been recog- women [relative risk (RR), 1.74; 95% CI, 1.13-2.68] but not nized as an important route of endogenous hormone postmenopausal women (RR, 0.97; 95% CI, 0.59-1.58).
metabolism, potentially affecting estrogen-dependent Subsequent population-based (16) and nested case- breast cancers. Myriad antidepressants have been shown control studies (17-19) did not report strong associations to variably inhibit the cytochrome P450 system (22-25), between antibiotic use and breast cancer risk. Most increasing the availability of endogenous estrogens, recently, Friedman et al. (12) conducted a 9-year thereby increasing the risk of breast cancer. Antidepres- follow-up study of >2 million women enrolled in the sants are also thought to increase levels of prolactin Kaiser Permanente Medical Care Program in northern (26, 27), itself a suspected breast tumor promoter. Finally, California. They observed a modest risk elevation for antidepressants may play a role in immune suppression women with the highest number of days using tetracy- by suppressing lymphocyte proliferation (28-30), sug- clines (RR, 1.23; 95% CI, 1.11-1.36) and an even more gesting an additional route for increased risk.
attenuated, nonsignificant estimate for macrolides (RR,1.16; 95% CI, 0.98-1.36). Finally, in a case-case study, Summary of Existing Research. In a recent article, prolonged antibiotic use was not associated with tumor Lawlor et al. (14) conducted a systematic review of previous stage, grade, histology, or hormone receptor status (13).
investigations aimed at exploring the association between As outlined in Table 1, there is little consensus on antidepressant use and breast cancer risk. This review whether antibiotic use is associated with breast cancer included seven relevant epidemiologic studies published risk. Any definitive conclusion is complicated by the fact until 2002: two prospective cohorts (31, 32), two retrospective that epidemiologic studies cannot distinguish between cohort studies (15, 16), and three case-control studies (33-35).
the potential carcinogenic effect of antibiotic drugs and None of the case-control studies generated significant the influence of the underlying conditions for which associations between antidepressant use and risk. One these drugs have been prescribed on breast cancer prospective cohort study (17) reported a significant increase in risk with use of any antidepressant at baseline only (RR,1.75; 95% CI, 1.06-2.88). In contrast, a significant decrease inrisk (OR, 0.50; 95% CI, 0.30-0.80) was found in one Antidepressant Use and Breast Cancer Risk retrospective cohort study (15). In light of these inconsistentfindings, the authors concluded in their review that the Biological Mechanisms. There are several tentative current epidemiologic evidence does not support an biological mechanisms by which antidepressants may association between antidepressant use and breast cancer.
play a role in breast cancer development. One frequently Asmall case-control study, nested within a prescription cited laboratory study found that the administration of database, which was not covered by the previous review, antidepressants resulted in a significant increase in the did not reveal an association between antidepressant use and development of mammary tumors in rodents (20). This positive association may be due to the structural Several epidemiologic studies have been published similarities among common antidepressants and the cell subsequent to the review article by Lawlor et al. (ref. 14; growth regulating compound N,N-diethyl-2-[4-(phenyl- Table 2). Results from two population-based (19, 36) and methyl)phenoxy]ethanamine HCl. Tricyclic and selective one hospital-based (37) case-control studies did not show serotonin reuptake inhibitors (SSRI) types of antidepres- elevated breast cancer risk among antidepressant users.
sants have been shown to bind to the same intracellular Similarly, two additional studies using general practice histamine receptors associated with antiestrogen binding (38) and health-care plan (39) databases did not reveal Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 2. Epidemiologic studies of the role of antidepressants use in breast cancer development recurrences or 78 secondprimary cancer cases amongadults with past historybreast, colon, or melanoma sex, original cancer typefrom a cohort of 1,467 patients Cases: 5,882 women with incident invasive DMV and Health Care FinancingAdministration 635 cases identified via Kaiser Permanente Southern California health plan cancerregistry files members with a history ofantidepressant use breast cancer identified via dischargesummaries and pathology reports diagnoses frequency matched to caseson age, study center, and interview year Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 2. Epidemiologic studies of the role of antidepressants use in breast cancer development (Cont’d) specifically about controls,only about entire cohort Genotoxic tricyclic antidepressants: 2.39 (1.30-4.39), nongenotoxic tricyclicantidepressants: 1.02 (0.56-1.86) relative, oral contraceptiveuse, HRT use, educationallevel, BMI, waist-to-hip ratio,alcohol consumption,and cigarette smoking Amitriptyline: 1.10 (0.85-1.42)Imipramine: 0.88 (0.51-1.51)Doxepin: 1.21 (0.70-2.10)Any MAO-I use vs none: 0.87 Sertraline duration z4 y vs none: 1.0 (0.3-4.1) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 2. Epidemiologic studies of the role of antidepressants use in breast cancer development (Con’t) Cases: 2,904 cases of primary invasive or in situ breast cancer in women enrolled ina large HMO, identified via Surveillance,Epidemiology and End Results matched 5:1 to cases on age, calendaryear, and length of HMO membership significant associations with antidepressant use. In Overall, these additional reports also do not provide contrast, a large case-control study using the Saskatch- strong evidence that would implicate antidepressant use ewan Prescription Drug Plan (22) showed significant risk in the etiology of breast cancer. More detailed analyses elevations for women who were prolonged users of by hormone receptor status in existing data sets might be certain genotoxic tricyclic antidepressants (amoxapine, clomipramime, and doxepin; OR, 2.39; 95% CI, 1.30-4.39)but not for nongenotoxic antidepressants (amitriptyline, maprotiline, and nortriptyline; OR, 1.02; 95% CI, 0.56-1.86). Genotoxicity assays were carried out using Biological Mechanisms. There is considerable interest Drosophila melanogaster. Further, Fulton-Kehoe et al. (23) and controversy around whether statins may play a role used a large health-care plan database and reported a in carcinogenesis. An early laboratory study suggested modest increase in risk associated with ever use of that lipid-lowering drugs cause cancer in rodents at amitriptyline (OR, 1.27; 95% CI, 1.10-1.47). However, no amounts that would be comparable with clinically dose-response relationship was noted when number of effective doses in humans (40). However, several studies prescriptions was considered, nor were risk elevations published subsequently have called those findings into observed for tricyclic antidepressants or SSRI. Results question. The best-studied route of action for statins from a small British cohort study did not reveal risk appears to be their inhibition of 3-hydroxy-3-methylglu- elevations for women who reported antidepressant use taryl coenzyme-Areductase, a key enzyme in the at ages 31 or 36 years (24). Finally, Chien et al. (25) mevalonate pathway of cholesterol synthesis. Inhibition reported results from a recent population-based case- of 3-hydroxy-3-methylglutaryl coenzyme-Areductase control study where they observed significant risk thereby inhibits prenylation, a protein synthesis process increases for women with progesterone receptor (PgR) – that leads to cell signaling processes involved in cell negative tumors (OR, 1.8; 95% CI, 1.1-3.6) and estrogen proliferation (28, 41). Preclinical studies have shown receptor (ER) – positive/PgR-negative tumors (OR, 2.0; that a variety of statins working through disruption of the mevalonate pathway decrease cell proliferation by Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 2. Epidemiologic studies of the role of antidepressants use in breast cancer development (Cont’d) database, self-administered vs never: 1.04 (0.94-1.16) Ever amitriptyline: 1.21 (1.03-1.41)Ever doxepine: 0.95 (0.79-1.13)Ever imipramine: 1.04 (0.84-1.29)Ever SSRI vs none: 0.98 (0.80-1.18)Any SSRI + Rx: 1.04 (0.73-1.48)Ever fluoxetine: 1.00 (0.80-1.25)Ever paroxetine: 1.00 (0.70-1.41)Ever sertraline: 1.16 (0.81-1.66) Ever SSRI use vs none: 1.2 (0.8-1.8), ever SSRI among +FHx: 0.4 (0.2-1.0), everSSRI among -FHx: 1.4 (0.9-2.2) promotion of G1 cell cycle arrest and apoptosis in breast many of these studies. Coogan et al. (54) reported cancer cell lines (29-31, 42). Statins have also been shown findings from a hospital-based case-control study in to decrease mammary tumor formation and metastasis in which prolonged statin use was associated with 2-fold increase in breast cancer risk (OR, 2.1; 95% CI, 1.1-4.0).
Interest in the mevalonate synthesis as target for However, more detailed analyses revealed that this cancer therapies has grown with the observation that estimate was largely driven by women with in situ statins may show a synergistic effect with chemoradia- disease (OR, 3.4; 95% CI, 1.5-8.0) rather than by women tion (43), chemotherapies (33, 34, 44), and COX-2 with invasive breast cancer (OR, 1.5; 95% CI, 0.7-3.1). In a inhibitors (35). Independent of the mevalonate pathway, more recent report by these investigators, prolonged statins have been suggested to have anticancer properties statin use was not significantly associated with breast through an anti-inflammatory effect and via inhibition of cancer risk (55). These latter findings are consistent with those of a population-based case-control study where Summary of the Existing Evidence. The association ever and prolonged statin use was not associated with between statin use and breast cancer risk has been the excess risk (56). Further, analyses from two large cohort subject in recent attention in the field of pharmacoepi- studies, the Nurses’ Health Study (57) and the Women’s demiology (Table 3). Many of these studies used Health Initiative Observational Study (58), did not reveal prescription or health-care plan record databases. Results significant associations. In contrast, Cauley et al. (59) from these investigations have consistently not revealed described results from a smaller cohort study where ever strong associations between statin use and risk (45-53).
use of statin drugs was associated with a significant risk Although findings from these geographically diverse reduction (OR, 0.28; 95% CI, 0.09-0.86). However, this investigations are consistent, they may have to be estimate was based on a very small number of exposed cautiously interpreted due to significant methodologic breast cancer patients (n = 6) and results should be shortcomings such as lack of adjustment for confounders interpreted cautiously. Finally, two recent meta-analyses and crude exposure assessment (ever versus never) in on this topic did not provide evidence that statin use is Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 3. Epidemiologic studies of the role of statin drug use in breast cancer development population-based prescriptiondatabase and the DanishCancer Registry identified using computerized healthdatabases of the Regie de l’Assurance-Maladie du Quebec Controls: 560 cancer-free controls matched carcinomas from the General PracticeResearch Database Controls: 1,009 cancer-free matched controls Cases: 1,132 primary invasive and in situ breast cancer confirmed by pathology report 244 incident breast cancer cases confirmed identified via tumor registry/Surveillance,Epidemiology and End Results Controls: 1,007 cancer-free general population controls identified via Medicare/Medicaid lists Cases: 3,224 incident cancer cases, including 698 breast cancers from the General PracticeResearch Database Controls: 14,844 cancer-free matched controls Cases: 3,129 incident cancer cases, including 467 breast cancers from the PHARMO drugdispensing database system Controls: 16,976 cancer-free matched controls Cases: 22,512 incident cancer cases, including 3,141 breast cancer cases identified via CentralPopulation Register, Epidemiologic PrescriptionDatabase, and Danish Cancer Registry Controls: 334,754 men and women in general Cases: 3,177 incident cases of breast cancer identified from self-report and medicalrecord review Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 3. Epidemiologic studies of the role of statin drug use in breast cancer development (Cont’d) Ever used statin vs use of bile acid Age at index date, previous neoplasm, year of cohort entry,use of fibric acid, use of otherlipid-reducing agents, and acomorbidity score Past statin use vs none: 1.3 (0.6-2.8)Statin use >5 y vs none: 1.1 (0.4-3.0) variables did not appreciablyeffect risk estimates: HRT at first birth, parity, physicalactivity, and alcoholconsumption Diabetes mellitus, prior hospitalizations, diuretics, ACEi, CCB, hormones,NSAID, and other lipid-loweringtherapy at first birth, height, BMI, first-degree Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 3. Epidemiologic studies of the role of statin drug use in breast cancer development (Cont’d) Cases: 4,383 incident cases of self-reported breast cancer confirmed by medical recordand pathology review Cohort of 31,723 adults with initiation of statin use (24,439) or glaucoma medicationuse (7,284) Cases: 268 individuals with primary invasive 2,707 incidence invasive breast cancer cases identified through Surveillance, Epidemiologyand End Results Cases: 1,185 women with incident invasive breast cancer admitted to a participating hospital Controls: 2,081 women admitted to a participating hospital without cancer or disorders relatedto statin use linked to breast cancer risk (60, 61). Thus, considering ever, as reviewed by Mason et al. (66), the role of this diverse and largely consistent body of evidence, it is calcium ions in apoptosis has been shown to be unlikely that statin drug use is an important factor in inconsistent, with intracellular calcium levels yielding both increased and decreased apoptosis across a rangeof cell types. Additionally, research has shown that CCB Antihypertensive Medication Use and Risk of may actually inhibit carcinogenesis by limiting cell proliferation in breast cell lines (67, 68), making itdifficult to draw firm conclusions about their ultimate Biological Mechanisms. Research into the biological mechanisms by which antihypertensive agents may ACEi have been suggested to offer a potential affect carcinogenesis has focused on calcium channel protective effect against cancer risk through the inhibi- blockers (CCB) and angiotensin II – converting enzyme tion of angiogenesis. More specifically, ACEi target the inhibitors (ACEi). Pahor et al. have suggested that CCB action of angiotensin II, part of the rennin-angiotensin could play a role in increased cancer risk (62) due to system involved with renal blood flow, fluid homeosta- inhibition of apoptosis resulting from diminished sis, and blood pressure control (69). Angiotensin II has intracellular calcium ion concentrations (63-65). How- also been shown to promote neovascularization (70), a Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 3. Epidemiologic studies of the role of statin drug use in breast cancer development (Cont’d) were analyzed, representing86,936 participants Age, BMI, race, smoking, family history of by dose, duration, and HRTuse at baseline Age, sex, race, Charlson comorbidity score, physician visits, total medications used,hospitalizations, prior nursing home stay,mammography, gynecologic examination,colonoscopy, fecal occult blood testing,osteoporosis drug use, arthritis, diabetes,inflammatory bowel disease, benign breastdisease, HRT use, NSAID use,gastroprotective drug use, obesity,tobacco abuse tobacco use, NSAID use, HRT use, oralcontraceptive use, menopausal status,parity, age at menarche, family historyof breast cancer, religion necessary process for tumor development. Early studies (Table 4). These studies have largely focused on CCB, showed that angiogenesis and tumor growth were h-blockers, and ACEi, and we will restrict our discussion slowed following administration of ACEi in preclinical to these widely studied drugs. As with many pharma- studies (71, 72). Later, Yoshiji et al. (73) hypothesized that coepidemiologic efforts, most of these prior studies were the inhibition of angiotensin II interferes with the action registry based such as general practice database or of vascular endothelial growth factor, a key enzyme in electronic medical records and used data from health- the angiogenesis process. Although cell proliferation care plan records or prescription plan. The limitations of has not shown to be directly effected (74), use of ACEi this approach are outlined above. Nevertheless, results alone or in combination with other agents decreased from these studies do not indicate that ever or prolonged vascular endothelial growth factor concentrations and use of CCB, h-blockers, or ACEi was related to elevated angiogenesis (75-77) and reduced blood vessel and breast cancer risk (45-49, 78, 79). Similarly, results from a large hospital-based case-control study (50), the Nurses’ Summary of Existing Evidence. An increasing num- Health Study cohort (51), and a Dutch cohort study (52) ber of studies have focused on the potential role of do not suggest that these drugs are related to breast antihypertensive drug use in breast cancer development cancer risk. In contrast, findings from a smaller cohort Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 4. Epidemiologic studies of the role of antihypertensive drug use in breast cancer development cancer identified from GeneralPractice Research DatabaseControls: 1,750 total cancer-free controls frequency matched byage and practice location by population-based EpidemiologicPrescription Database and confirmedvia Danish Cancer Registry and women (32,540 person-years offollow-up) enrolled in a breast cancer screeningproject cases confirmed from dischargesummaries and pathology reports population-based EpidemiologicPrescription Database and confirmedvia Danish Cancer Registry cancer identified from GeneralPractice Research DatabaseControls: 14,155 cancer-free controls from cohort matched 4:1 to cases onage, physician practice, index date,number of years of medical historyrecord in database population-based EpidemiologicPrescription Database and confirmedvia Danish Cancer Registry and women (66,827 person-years follow-up) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 4. Epidemiologic studies of the role of antihypertensive drug use in breast cancer development (Cont’d) Ever used CCB vs none: 2.57 (1.47-4.49) Age, race, parity, age at Ever used ACEi vs none: 0.93 (0.37-2.34)Ever used any diuretic vs none: from breast cancer for useof any antihypertensivedrug (data not shown) weight, height, smoking status andmean number of cigarettes smokedper day among women who smokedin 1988, alcohol intake in 1988, physicalactivity, menopausal status in 1988,postmenopausal HRT use, cholesterollevel, systolic and diastolic bloodpressure in 1988, aspirin intake,diabetes, history of stroke, myocardialinfarction, CABG/PTCA, angina,hypertension in or before 1988, familyhistory of breast cancer, history ofbenign breast disease, age at menarche,parity, age at first birth, age at menopause annual visits to physician before diagnosis, race, years of education, breast cancer in mother or sister, benign breast disease, age at menarche, age at first birth, parity, age at menopause, alcohol consumption, durationof oral contraceptive use, duration of HRT use standardized incidence ratio:1.1 (0.9-1.3) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 4. Epidemiologic studies of the role of antihypertensive drug use in breast cancer development (Cont’d) Cases: 3,708 cases of invasive breast cancer identified from General Practice Research DatabaseControls: 20,000 cancer-free controls from cohort matched to cases on age andcalendar year (study cohort = 734,899 women) Cases: 975 cases of invasive breast cancer identified via Cancer Surveillance System,a population-based cancer registry Controls: 1,007 cancer-free controls identified from list of Medicare/Medicaid recipients,selected for similar age population-based EpidemiologicPrescription Database and confirmed viaDanish Cancer Registry 49,950 women in total cohort (19,284 statin users contributing 109,985 person-yearsof follow-up) Cases: 523 women age 50-75 y with incident Controls: 131 women ages 50-75 y old identified through random-digit dialing, matched tocases on age study (53) have linked ever use of CCB to a significant prolonged use of h-blockers (82). Thus, future studies increase in risk (OR, 2.57; 95% CI, 1.47-4.49). No risk employing solid epidemiologic designs and sophisticated elevations were observed for use of h-blockers and ACEi.
exposure assessment might be needed to definitively rule Li et al. (80), in a large population-based case-control out the role of antihypertensive medication use in breast study, observed a significant increase in risk for prolonged use (z15 years) of h-blockers (OR, 2.1; 95%CI, 1.2-3.7) but no associations with long-term use of CCB and ACEi. Finally, Largent et al. (81) recently reportedresults from another population-based case-control Biological Mechanism. NSAIDs, including aspirin, study. Results indicated that ever (OR, 1.79; 95% CI, ibuprofen, and naproxen, appear to exert an anticancer 1.07-3.01) and prolonged (OR, 3.50; 95% CI, 1.64-7.50) use effect through inhibition of the COX enzyme system.
of diuretics was associated with excess risk. No such risk COX-2, in particular, promotes the synthesis of prosta- elevations were observed for nondiuretic antihyperten- glandins, such as prostaglandin E2, thought to play an etiologic role in tissue generation and tumorigenesis.
Although most studies on this topic generated null COX-2-derived prostaglandin E2 may stimulate estrogen findings, the majority of these investigations could only biosynthesis in breast tissue (83). Additionally, COX-2 crudely classify participants as ever or never users of has been found to be overexpressed in human breast these drugs. Further, one study with more sophisticated tumors in multiple studies (84-86). The observation exposure assessment showed an association between that COX-2 expression is correlated with aromatase Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 4. Epidemiologic studies of the role of antihypertensive drug use in breast cancer development (Cont’d) use, HRT use, first-degree familyhistory of breast cancer, smokingstatus, average daily alcoholintake, and BMI effected by number of prescriptions,years of follow-up, type of diuretic,or type of calcium antagonist expression in breast cancer allows one to formulate the across studies, including the definition of regular and hypothesis that COX-2 increases estrogen production via prolonged use. Nevertheless, results from most studies up-regulation of aromatase expression. Preclinical re- have been remarkably consistent. Three registry-based search has shown that the administration of NSAID studies (91-93) showed significant risk reductions for inhibits production of COX enzymes with resulting prolonged NSAID use. Several hospital-based (65, 94-97) reduction in mammary carcinogenesis (87-89). Moreover, and population-based (98-102) studies have generated NSAIDs have been suggested to reduce neovasculariza- statistically significant risk reductions for regular and tion and promote apoptosis (63, 90). Some NSAIDs that prolonged aspirin use, except for a recent one (103). Less do not affect the COX system have been shown to induce consistent evidence exists for ibuprofen use, which was cell cycle arrest and apoptosis in breast cancer cell associated with decreased risk in two investigations lines (64). Taken together, multiple lines of research into (104, 133) but not in others (131, 136, 138). Such the biological mechanisms by which NSAIDs affect discrepancy might not be surprising, given that ibupro- cancer risk point to a potentially valid agent in chemo- fen is still a relatively new drug, and to date, few people have had significant exposures to this agent. Findingsfrom the Women’s Health Initiative observational study Summary of Existing Evidence. Alarge and diverse indicated that prolonged use (z10 years) of any NSAID body of literature exists on the potential chemopreven- or aspirin was associated with statistically significant risk tive effect of NSAID use on breast cancer development reductions (RR, 0.72; 95% CI, 0.56-0.91 and RR, 0.79; 95% (Table 5). Exposure assessment, however, differs widely CI, 0.60-1.03, respectively; ref. 105). Similarly, findings Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development breast cancer identified by collaboratinghospitals in northeastern United States (2,303 confirmed with medical records and111 cases identified by questionnaire response) Controls: 1,534 cancer-free women from central 393 breast cancers have been detected32,505 women enrolled in the mammography screening program of The Ohio State UniversityComprehensive Cancer Center (4.7 yaverage follow-up) Cases: 6,558 women with a first occurrence of primary breast cancer diagnosed within theprevious year, confirmed by path report, andno concurrent or previous cancer Controls: 3,296 patients with other cancers not associated with NSAID use, 2,925 noncancer patients Cases: 5,882 women diagnosed with histologically Controls: 23,517 controls frequency matched on Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) (0.74-0.93), lung cancer: 0.68(0.49-0.94), breast cancer inwomen: 0.70 (0.50-0.96), andcolorectal cancer in youngermen: 0.35 (0.17-0.73) effect risk estimates: age,education, parity, menopausalstatus, and family history ofbreast cancer Age, study center, interview year, Adjustment for the following Saskatchewan Prescription NSAID exposure 2-5 y ADD = 0: 0.52 (0.37-0.73),0.1 < ADD V 0.3 vs ADD = 0: 0.53 (0.30-0.92), andADD > 0.3 vs ADD =0: 0.49 (0.24-0.99) studies, and 0.87 (0.84-0.91)in 8 case-control studies Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) Cases: 3,133 random women diagnosed with a first primary cancer of the breast, 25-74 y identifiedvia Ontario Cancer Registry Controls: 3,062 age-matched random sample of the Cases: 3,706 women with incident breast cancerControls: 14,155 age, years of medical history in the computer record, general practice attended,and calendar time matched controls 1,392 self-reported incident cases confirmed by 80,741 women in total cohort (43-mo average Cases: 930 cases of invasive breast cancer identified via North Carolina Central Cancer Registry Controls: 754 controls selected from DMV and Health Care Financing Administration, frequency matchedto cases on age and ethnicity Cases: 3,708 cases of invasive breast cancer identified DatabaseControls: 20,000 cancer-free controls from cohort matched to cases on age and calendar year (studycohort = 734,899 women) Cases: 1,508 invasive or in situ breast cancer cases Controls: 1,556 controls selected though random-digit dialing methods and Health Care FinancingAdministration lists, frequency matched to casesin 5-y age intervals Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) Age, history of arthritis, benign Confounders evaluated include history of breast cancer, othermedication use, dietary fat intake Age, ethnicity, education, BMI, Additional analyses stratified HRT use, education, BMI,waist-to-hip ratio, smokingstatus, and offset term from 1966 to 2002 for cohort 0.77 (0.66-0.88)or case-control studies use z4 y vs none: 0.94 (0.74-1.21) remaining NSAID receptor positive vs none:0.74 (0.60-0.93) receptor negative vs none:0.97 (0.67-1.40) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) 3008 incident cases identified via self-report and confirmed via medical record or state cancer registries Cases: 7,006 primary breast cancer cases confirmed from discharge summaries and pathology reports Controls: 3,622 controls admitted for nonmalignant Cases: 1,478 primary, incident cases confirmed Controls: 3,383 cancer-free controls frequency Cases: 2,391 primary incident cases confirmed Cases: 1,090 incident cases identified from mammography screening group(418,458 women in total cohort) Cases: 763 cases of invasive or in situ breast Controls: 678 disease-free African American Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) Age, year of interview, study center, race, year of education, benign breast disease, duration of oral contraceptive use, age at birth, parity, alcohol consumption, family history of breast cancer, practice of breast Age at menarche, age at first birth, BMI, history of first-degree relative with breast cancer, and history of benign breast disease menopausal and hormone therapy use status, smoking, alcohol intake, physical activity, mammography history, breast biopsy history, (1.12-2.92); ER/PgR positive andibuprofen use z5 y daily vs Age, mammography in year 2 or 3 before index date, breast procedure in the prior 3 y, benign neoplasm of the breast in prior 3 y, other breast disease in the prior 3 y, HRT in prior year, visit to gynecologist in prior year Age, offset term for oversampling younger and regular NSAID use vs none:0.3 (0.2-0.6) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) aspirin (19,934) and placebo (19,942) armsfollowed for self-reported cancer endpointsverified by medical record review Cases: 323 cases of histologically confirmed invasive matched controlsfrom hospital mammography service Cases: 91 cases of invasive or in situ breast cancer identifiedvia county and state cancer registries identified fromlarger CLUE II cohort of 14,625 women Cases: 1,067 in situ or invasive breast cancer cases includedin the Long Island Breast Cancer Study Project Controls: 1,110 frequency matched on age identified 1,830 breast cancer cases in the Multiethnic cohort 571 breast cancer cases in Cancer Prevention Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) aspirin use and smokingstatus, P < 0.09 former smokers: 0.84 (0.70-1.01),and current smokers: 0.93(0.69-1.25) Self-report questionnaire, Aspirin use in 1989 vs none: risk among those with COX-2rs2143416 variant CC genotypeand nonuse of NSAIDs alcohol, race, education,religion, marital status NSAID use vs none: 0.7 (0.5-1.0)P for the interaction = 0.02 No association between breast cancer Age, ethnicity, BMI, family history hormone receptor status, theprotective effect limited toCaucasians or African Americansor to women with at least onepositive hormone receptor Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) 35,323 total postmenopausal women in cohort 430 cases of primary invasive breast cancer 3,487 incident cancer cases and 3,581 deaths were observed in the cohort of 22,507 postmenopausalwomen Controls: 647 from the Seattle metropolitan area, identified by random-digit dialing and frequencymatched by 5-y age groups Cases: 798 Hispanic/Native American and 1,527 non-Hispanic White women diagnosed with firstprimary breast cancer Controls: 935 Hispanic/Native American and 1,671 non-Hispanic White women from the targetpopulations matched on ethnicity and 5-yearage distribution of cases Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) 2 y before baseline, age at menarche, age at first birth, age at menopause, history All NSAIDs (except for low-dose aspirin) of surgical menopause, years of combined All NSAIDs (except for low-dose aspirin) therapy, multivitamin use and alcohol history of fibrocysticdisease, family historyof breast cancer, age atfirst menarche, hormoneuse, oral contraceptiveuse, menopausal status,parity, BMI Age, education status, physical activity, No information according osteoarthritis, and history ofrheumatoid arthritis <2 y diagnosis vs never: 1.0 (0.7-1.3)Among cases with localized disease, women with recent hormoneexposure or premenopausal/perimenopausal women was notassociated with breast cancer risk association between aspirin andbreast cancer among postmenopausalwomen with no recent hormoneexposure (P for interaction = 0.04for Hispanic/Native American and0.06 for non-Hispanic White) Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) 847 cases identified via the Danish Cancer Registry 39,876 women randomized into low-dose aspirin (19,934) and placebo (19,942) arms followed forself-reported cancer endpoints verified by medicalrecord review from the CLUE cohort in Washington county (106) point between aspirin and breast cancer but found that current to a chemoprotective effect of aspirin use in breast cancer other NSAID use was protective among Caucasian and etiology (RR, 0.46; 95% CI, 0.22-0.98), but results were not African American as well as among women with at least influenced by hormone receptor status or COX-2 genetic one positive hormone receptor. In a randomized low- polymorphisms (107). Other studies have also attempted dose aspirin (100 mg) chemoprevention trial (118), with to assess the effect of the COX-2 gene on the association an average of 10 years of follow-up, women who were between NSAID use and breast cancer risk, but results randomized to the aspirin intervention arm were not at have been inconsistent (108, 109). Further support for a lower risk of breast cancer compared with women who chemopreventive role of aspirin comes from the National received the placebo (RR, 0.98; 95% CI, 0.87-1.09). In Health and Nutrition Examination Survey I cohort (110) subgroup analyses, low-dose aspirin showed no effects and Iowa Women’s cohort (111) where current or by tumor characteristics at diagnosis (83) but suggested prolonged (z6 years) use were associated with signifi- protective effects by smoking status (RR, 0.84; 95% CI, cant risk decreases (RR, 0.70; 95% CI, 0.56-0.96 and RR, 0.70-1.01; ref. 118). Consistently, the Iowa Women’s 0.71; 95% CI, 0.58-0.87, respectively). In the Iowa Health Study showed that the inverse association Women’s cohort, these risk reductions were still appar- between total cancer incidence (and mortality) and ent in subsequent analyses based on more breast cancer aspirin use was stronger among former and never patients (112). These findings are similar to those of a smokers than current smokers (112). However, results smaller cohort from Ohio (113), where frequent NSAID from the Women’s Health Study, a randomized preven- use was associated with a significant risk reduction tion trial, did not reveal lower risk of breast cancer in the (RR, 0.57; 95% CI, 0.44-0.74). Recently, Ready et al. (114) treatment group after an average of 10 years of follow-up found significant risk reduction for frequent and long- of almost 40,000 women (83, 118). It should be noted, term use of low-dose aspirin (z4 days/wk over 10 years) though, that low-dose aspirin (100 mg every other day) in the Vitamins and Lifestyle cohort (RR, 0.65; 95% CI, was administered in this trial. Jacobs et al. (119) conducted further analyses in the Cancer Prevention In contrast, initial analyses from the Cancer Prevention Study II Nutrition cohort and focused on long-term Study II Nutrition cohort (115) as well as results from the (z5 years) daily use of adult-strength aspirin prepara- California Teachers (116) and Nurses’ Health Study (117) tions (z325 mg). The authors speculated that the lack of a cohorts did not show associations between use of aspirin protective effect in the randomized trial might be due to or other NSAIDs and breast cancer risk. In fact, in the the administration of low-dose aspirin tablets, which California Teachers cohort, prolonged use (z5 years) of may not have been sufficient to produce a chemo- both aspirin and ibuprofen was associated with signif- protective effect. Results indicated that daily long-term icant risk elevations for women with hormone receptor- use was associated with a nonsignificant risk reduction negative tumors (RR, 1.8; 95% CI, 1.12-2.92 and RR, 1.50; 95% CI, 1.1-2.03, respectively). The Danish Diet, Cancer Finally, four meta-analyses showed significant chemo- and Health cohort study (82) also showed increased preventive effects of aspirin or NSAIDs against breast breast cancer incidence among both any NSAID and cancer. The first considered 14 studies published until aspirin-only users (RR, 1.27; 95% CI, 1.10-1.45 and RR, 2000 (120) and showed a significant risk reduction 1.31; 95% CI, 1.12-1.53, respectively), although this cohort associated with NSAID use (OR, 0.82; 95% CI, 0.75- women had higher breast cancer incidence than women 0.89). Amore recent meta-analysis restricted to 10 in the general Danish population and most chronic epidemiologic studies published from 2001 to 2005 aspirin use came from low-dose aspirin. In the Multieth- (121) supported a protective association between aspirin nic cohort [153], authors observed no association intake and breast cancer (RR, 0.74; 95% CI, 0.69-0.79) with Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Table 5. Epidemiologic studies of the role of NSAID use in breast cancer development (Cont’d) frequency, recency, or duration ofNSAID use or by hormone receptorstatus of breast tumors 10 studies were analyzedSelf-administered effect of breast cancer in the subgroupanalysis by tumor characteristicsat diagnosis significant dose-response relationship. The protective doses may not increase the risk. Thus, additional effect was similar when cohort and case-control studies randomized trials with these COX-2 inhibitors may be were examined separately (120, 121). Similar results needed to resolve these questions. In conclusion, were observed in two literature-based meta-analyses although the lack of a protective effect of aspirin in randomized trials is somewhat worrisome, the over- Most observational studies and meta-analyses showed whelming majority of the existing evidence points to a consistent and statistically significant risk reductions in chemoprotective role of aspirin in breast cancer etiology.
human breast cancer with exposure to NSAIDs; however,interpretation of the existing body of literature on the associations between various NSAIDs and breast cancerrisk is not straightforward. Although most studies on this The existing literature on the use of common over-the- topic have shown statistically significant risk reductions, counter and prescription medications has not definitively the majority of these studies were either registry-based or linked any of the drugs covered in this review to either employed a case-control design. The former approach is increased or decreased risk of breast cancer. Important methodologically limited due to insufficient adjustment contributing factors to this apparent inconsistency are for potential confounders, whereas the latter study likely the numerous methodologic issues, discussed design is known to be prone to selection and information throughout this review, associated with the various bias. Further, studies using only prescription records study designs employed in these investigations. Thus, or health plan data will misclassify over-the-counter in conclusion, there is inconclusive evidence on the medication users as unexposed and thereby may under- association between antibiotic use and breast cancer estimate exposure prevalence. Four large follow-up risk, no strong evidence pointing to a significant role of studies (82, 115, 150, 151) found no evidence of reduced antidepressant and statin drugs in breast cancer devel- risk of breast cancer among aspirin users, yet the opment, somewhat inconclusive evidence on the effect of majority of cohort studies found significant risk reduc- antihypertensive drugs, and significant chemoprotective tions among aspirin users (83, 139-141, 144-146, 148, 153).
evidence implicating aspirin use against breast cancer.
Importantly, however, two randomized trials, considered Future studies with detailed lifetime medication histories the gold standard in epidemiologic study designs, did are needed to further clarify these important associations.
not show a chemoprotective effect of aspirin use. It is It is unlikely that such an assessment can be accom- possible, as suggested by Jacobs et al. (119) that higher- plished with a cohort study design, where repeated dose aspirin preparations may be needed to produce a detailed medication measurement would be difficult to chemoprotective effect. However, because they are the achieve. Thus, future case-control studies should consid- most common cause of serious gastrointestinal compli- er in their design strategies for obtaining detailed and cations in the United States (161-163), chemopreventive valid lifetime medication histories, which will likely trial of adult-dose (e.g., 325 mg) aspirin might be involve a combination between self-report and prescrip- problematic. It is also possible that selective COX-2 tion and/or health-care plan data. Further, in light of the inhibitors have much stronger chemopreventive proper- strong and largely consistent findings from epidemio- ties than aspirin. Although previous trials revealed the logic studies that link prolonged higher-dose aspirin use serious side effects related to cardiovascular events with to reduce risk of breast cancer, a chemoprevention trial of these drugs (164-166), recent reviews and meta-analyses NSAIDs or COX-2 inhibitors with similar chemopreven- of controlled observational studies (167) and randomized tive properties to aspirin but without severe adverse trials (123) confirmed that only rofecoxib was associated gastrointestinal effects might be warranted. As pointed with the risk of cardiovascular events and suggests that out above, medication use constitutes a ubiquitous celecoxib and other COX-2 inhibitors in commonly used exposure in the United States and in many countries Cancer Epidemiol Biomarkers Prev 2008;17(7). July 2008 Cancer Epidemiology,Biomarkers & Prevention worldwide. Given that breast cancer is the most common 22. Sharpe C, Collet JP, Belzile E, Hanley J, Boivin JF. The effects of cancer in the United States and elsewhere, it is essential tricyclic antidepressants on breast cancer risk. Br J Cancer 2002;86:92 – 7.
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No potential conflicts of interest were disclosed.
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