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Use of Common Medications and Breast Cancer Risk

¹ Department of Epidemiology, Roswell Park Cancer Institute; ² Department of Psychology, VA Western New York Healthcare System; ³ Department of Biostatistics, University at Buffalo, Buffalo, New York and ⁴ Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, Rhode Island

Requests for reprints: Kirsten B. Moysich, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8004; Fax: 716-845-8487. E-mail: kirsten.moysich{at}roswellpark.org

	Abstract

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
Prescription and over-the-counter medications are widely used in the United States and many western countries. More than two-thirds of women ages >45 years, who are at greatest risk for breast cancer, take prescription medication. In light of the ubiquitous nature of medication use and the fact that breast cancer remains the most common cancer in women, research on the role of medication use in breast cancer etiology is warranted. We summarize the epidemiologic evidence on the association between breast cancer risk and use of common medications, including antibiotics, antidepressants, statins, antihypertensives, and nonsteroidal anti-inflammatory drugs. Overall, there is little evidence that would implicate the use of antibiotics, antidepressants, statins, and antihypertensives in the etiology of breast cancer. Although several prospective studies and a randomized low-dose aspirin chemoprevention trial have not shown lower risk of breast cancer among aspirin users, most studies that have examined the potential chemoprotective effect of nonsteroidal anti-inflammatory drugs have shown significant risk reductions for regular and prolonged use of these drugs. The existing literature on the role of medication use in breast carcinogenesis is complicated. Interpretation of the evidence is hampered due to major methodologic differences across studies, including exposure assessment, exposure classification, and adjustment for potential confounding variables. These differences largely stem from the fact that the majority of articles on this topic represent secondary data analyses from studies with inadequate information on exposure or confounders. Thus, future epidemiologic studies specifically designed to study these ubiquitous and biologically plausible exposures are warranted. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1564–95)

	Introduction

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
Prescription and over-the-counter medications are very widely used in the United States and many western countries. A recent study of medication use in the ambulatory adult population of the United States revealed that 81% of participants have used at least one medication in the past week and that half of the sample reported to have taken at least one prescription medication. This survey also showed that women ages 65 years were the highest medication users; specifically, 12% of women in this age group took at least 10 different medications and 23% took at least 5 prescription drugs (1). More recent data from the Slone Survey (2) indicate that overall and prescription medication use has increased between 1999 and 2005. This study also reinforced earlier estimates that >90% of women ages 45 years reported any medication use. Further, prescription medication use for women ages 45 to 64 and 65 years was 68% and 82%, respectively. Thus, medication use in the United States represents a ubiquitous exposure. In light of the fact that breast cancer remains the most common cancer in women, a careful evaluation of the potential chemopreventive or carcinogenetic effects of common medications is warranted. In this review, we focus on commonly used medications that have been studied previously in epidemiologic studies of breast cancer. These groups of medications include antibiotics, antidepressants, statins, antihypertensives, and nonsteroidal anti-inflammatory drugs (NSAID).

	Exposure Definition and Study Designs

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
The existing body of literature concerning the use of common medications and breast cancer risk is largely inconsistent. A primary reason for the divergent findings likely relates to the vast differences in methodologies employed in these studies. In addition to the obvious differences, such as study design (cohort studies versus case-control studies), these previous studies vary greatly with respect to exposure assessment, exposure classification, and adjustment for potential confounding variables. For instance, with respect to exposure assessment, many studies focused on NSAID use and breast cancer risk have only measured aspirin exposure but have no data on more recently introduced NSAIDs such as ibuprofen or selective cyclooxygenase-2 (COX-2) inhibitors. Thus, it is possible that women who do not report aspirin use but are in fact frequent ibuprofen users will be erroneously classified as "non-NSAID users," because use of these newer drugs was not assessed in some studies. Further, using the existing research on antibiotic use and breast cancer risk as an example, there are great differences in exposure assessment. Some studies classify antibiotic use as crudely as "ever versus never," whereas others have detailed information based on prescription data. Results from cohort studies might be difficult to interpret, as many studies rely on a single measurement of medication use, which does not take into account that medication use is subject to change over time. Further, many studies of medication use and breast cancer utilize large general practice databases, which improves exposure assessment but does not allow for adjustment for potential confounding variables, as these are generally not available in these data resources. Finally, it should be noted that the vast majority of existing studies represent so-called secondary data analyses, indicating that these various studies were not specifically designed to address the relationship between common medications and breast cancer risk. Rather, medication use was collected as a potential confounder or within the context of a medical history in which exposures or confounders is often absent. Although it is standard practice in epidemiologic research to analyze data for secondary associations, such studies are always methodologically inferior to those that were specifically designed to assess the link between specific medications and risk of breast cancer. Summarized below is the existing body of evidence of the associations between the use of common medications, such as antibiotics, antidepressants, statins, and NSAIDs, and breast cancer risk, preceded by a brief discussion of the biological mechanism by which these medications might influence risk.

	Antibiotics and Breast Cancer Risk

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
Biological Mechanisms
A recent review of the biological mechanisms by which antibiotics may influence breast cancer risk suggests two main pathways: disruption of intestinal microflora and effect on immune and inflammatory function (3). Naturally occurring gut microflora have been shown to play a role in the conversion of phytochemicals derived from the consumption of plant-based food products into biologically active substances (4-6) suggested to be protective against cancer. For example, phytochemicals, such as lignans, can be converted by microflora to enterolactone (7), which has been correlated with reduced breast cancer risk (8, 9). Antibiotics could also theoretically decrease breast cancer risk by affecting the ability of microflora to modulate levels of circulating estrogens through deconjugation of bound estrogens in the gut, freeing them for reabsorption and circulation (10-13). However, the disruption of the microflora by antibiotics is not uniform and may vary by dose and specific drug formulation (8).

Breast cancer risk may also be mediated by the effect of antibiotics on the human immune system and inflammatory response. Numerous specific biological mechanisms have been suggested, but these remain largely speculative (3). Some antibiotics may have an anti-inflammatory effect by limiting the production of cytokines or a group of several proteins involved in the immune and inflammatory response (9). Inhibited cytokine production may be important in limiting estrogen synthesis in the peripheral fat (10, 11), potentially decreasing cancer risk. There is also limited evidence that some antibiotics may increase the production of prostaglandins or markers of the inflammatory response (3).

	Summary of Existing Research

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
The potential role of antibiotic use in breast cancer etiology gained wide public attention after results from a recent large case-control study became available. In this study of 2,266 breast cancer patients and 7,953 controls who were enrolled in a nonprofit health plan, Lawlor et al. (14) were able to use computerized pharmacy records to assess exposure to antibiotic drugs. Results indicated that compared with women who never used antibiotics, women with the longest durations of antibiotic use had a 2-fold increase in breast cancer risk [odds ratio (OR), 2.07; 95% confidence interval (95% CI), 1.48-2.89]. Similar risk estimates were observed when nonusers were compared with women with the greatest number of antibiotic prescriptions (OR, 2.31; 95% CI, 1.69-3.15). Results were very similar for premenopausal and postmenopausal women and risk was increased for all subtypes of antibiotic drugs. These findings, which sparked considerable public concern about antibiotic use, are somewhat similar to those from a Finish cohort study (15) where ever use of antibiotics was associated with increased risk of breast cancer among premenopausal women [relative risk (RR), 1.74; 95% CI, 1.13-2.68] but not postmenopausal women (RR, 0.97; 95% CI, 0.59-1.58). Subsequent population-based (16) and nested case-control studies (17-19) did not report strong associations between antibiotic use and breast cancer risk. Most recently, Friedman et al. (12) conducted a 9-year follow-up study of >2 million women enrolled in the Kaiser Permanente Medical Care Program in northern California. They observed a modest risk elevation for women with the highest number of days using tetracyclines (RR, 1.23; 95% CI, 1.11-1.36) and an even more attenuated, nonsignificant estimate for macrolides (RR, 1.16; 95% CI, 0.98-1.36). Finally, in a case-case study, prolonged antibiotic use was not associated with tumor stage, grade, histology, or hormone receptor status (13).

As outlined in Table 1 , there is little consensus on whether antibiotic use is associated with breast cancer risk. Any definitive conclusion is complicated by the fact that epidemiologic studies cannot distinguish between the potential carcinogenic effect of antibiotic drugs and the influence of the underlying conditions for which these drugs have been prescribed on breast cancer development.

	Antidepressant Use and Breast Cancer Risk

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

The cytochrome P450 enzyme system has been recognized as an important route of endogenous hormone metabolism, potentially affecting estrogen-dependent breast cancers. Myriad antidepressants have been shown to variably inhibit the cytochrome P450 system (22-25), increasing the availability of endogenous estrogens, thereby increasing the risk of breast cancer. Antidepressants are also thought to increase levels of prolactin (26, 27), itself a suspected breast tumor promoter. Finally, antidepressants may play a role in immune suppression by suppressing lymphocyte proliferation (28-30), suggesting an additional route for increased risk.

Summary of Existing Research
In a recent article, Lawlor et al. (14) conducted a systematic review of previous investigations aimed at exploring the association between antidepressant use and breast cancer risk. This review included seven relevant epidemiologic studies published until 2002: two prospective cohorts (31, 32), two retrospective cohort studies (15, 16), and three case-control studies (33-35). None of the case-control studies generated significant associations between antidepressant use and risk. One 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 in risk (OR, 0.50; 95% CI, 0.30-0.80) was found in one retrospective cohort study (15). In light of these inconsistent findings, the authors concluded in their review that the current epidemiologic evidence does not support an association between antidepressant use and breast cancer. A small case-control study, nested within a prescription database, which was not covered by the previous review, did not reveal an association between antidepressant use and risk (18).

Several epidemiologic studies have been published subsequent to the review article by Lawlor et al. (ref. 14; Table 2 ). Results from two population-based (19, 36) and one hospital-based (37) case-control studies did not show elevated breast cancer risk among antidepressant users. Similarly, two additional studies using general practice (38) and health-care plan (39) databases did not reveal significant associations with antidepressant use. In contrast, a large case-control study using the Saskatchewan Prescription Drug Plan (22) showed significant risk elevations for women who were prolonged users of 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 Drosophila melanogaster. Further, Fulton-Kehoe et al. (23) used a large health-care plan database and reported a modest increase in risk associated with ever use of amitriptyline (OR, 1.27; 95% CI, 1.10-1.47). However, no dose-response relationship was noted when number of prescriptions was considered, nor were risk elevations observed for tricyclic antidepressants or SSRI. Results from a small British cohort study did not reveal risk elevations for women who reported antidepressant use at ages 31 or 36 years (24). Finally, Chien et al. (25) reported results from a recent population-based case-control study where they observed significant risk increases for women with progesterone receptor (PgR)–negative tumors (OR, 1.8; 95% CI, 1.1-3.6) and estrogen receptor (ER)–positive/PgR-negative tumors (OR, 2.0; 95% CI, 1.1-3.8).

	Statin Drug Use and Breast Cancer Risk

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
Biological Mechanisms
There is considerable interest and controversy around whether statins may play a role in carcinogenesis. An early laboratory study suggested that lipid-lowering drugs cause cancer in rodents at amounts that would be comparable with clinically effective doses in humans (40). However, several studies published subsequently have called those findings into question. The best-studied route of action for statins appears to be their inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, a key enzyme in the mevalonate pathway of cholesterol synthesis. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase thereby inhibits prenylation, a protein synthesis process that leads to cell signaling processes involved in cell proliferation (28, 41). Preclinical studies have shown that a variety of statins working through disruption of the mevalonate pathway decrease cell proliferation by promotion of G₁ cell cycle arrest and apoptosis in breast cancer cell lines (29-31, 42). Statins have also been shown to decrease mammary tumor formation and metastasis in a mouse model (32).

Interest in the mevalonate synthesis as target for cancer therapies has grown with the observation that statins may show a synergistic effect with chemoradiation (43), chemotherapies (33, 34, 44), and COX-2 inhibitors (35). Independent of the mevalonate pathway, statins have been suggested to have anticancer properties through an anti-inflammatory effect and via inhibition of the proteasome (41).

Summary of the Existing Evidence
The association between statin use and breast cancer risk has been the subject in recent attention in the field of pharmacoepidemiology (Table 3 ). Many of these studies used prescription or health-care plan record databases. Results from these investigations have consistently not revealed strong associations between statin use and risk (45-53). Although findings from these geographically diverse investigations are consistent, they may have to be cautiously interpreted due to significant methodologic shortcomings such as lack of adjustment for confounders and crude exposure assessment (ever versus never) in many of these studies. Coogan et al. (54) reported findings from a hospital-based case-control study in which prolonged statin use was associated with 2-fold increase in breast cancer risk (OR, 2.1; 95% CI, 1.1-4.0). However, more detailed analyses revealed that this estimate was largely driven by women with in situ disease (OR, 3.4; 95% CI, 1.5-8.0) rather than by women with invasive breast cancer (OR, 1.5; 95% CI, 0.7-3.1). In a more recent report by these investigators, prolonged statin use was not significantly associated with breast cancer risk (55). These latter findings are consistent with those of a population-based case-control study where ever and prolonged statin use was not associated with excess risk (56). Further, analyses from two large cohort studies, the Nurses' Health Study (57) and the Women's Health Initiative Observational Study (58), did not reveal significant associations. In contrast, Cauley et al. (59) described results from a smaller cohort study where ever use of statin drugs was associated with a significant risk reduction (OR, 0.28; 95% CI, 0.09-0.86). However, this estimate was based on a very small number of exposed breast cancer patients (n = 6) and results should be interpreted cautiously. Finally, two recent meta-analyses on this topic did not provide evidence that statin use is linked to breast cancer risk (60, 61). Thus, considering this diverse and largely consistent body of evidence, it is unlikely that statin drug use is an important factor in breast cancer development.

	Antihypertensive Medication Use and Risk of Breast Cancer

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

ACEi have been suggested to offer a potential protective effect against cancer risk through the inhibition of angiogenesis. More specifically, ACEi target the action of angiotensin II, part of the rennin-angiotensin system involved with renal blood flow, fluid homeostasis, and blood pressure control (69). Angiotensin II has also been shown to promote neovascularization (70), a necessary process for tumor development. Early studies showed that angiogenesis and tumor growth were slowed following administration of ACEi in preclinical studies (71, 72). Later, Yoshiji et al. (73) hypothesized that the inhibition of angiotensin II interferes with the action of vascular endothelial growth factor, a key enzyme in the angiogenesis process. Although cell proliferation has not shown to be directly effected (74), use of ACEi alone or in combination with other agents decreased vascular endothelial growth factor concentrations and angiogenesis (75-77) and reduced blood vessel and formation around tumors (74).

Summary of Existing Evidence
An increasing number of studies have focused on the potential role of antihypertensive drug use in breast cancer development (Table 4 ). These studies have largely focused on CCB, β-blockers, and ACEi, and we will restrict our discussion to these widely studied drugs. As with many pharmacoepidemiologic efforts, most of these prior studies were registry based such as general practice database or electronic medical records and used data from health-care plan records or prescription plan. The limitations of this approach are outlined above. Nevertheless, results from these studies do not indicate that ever or prolonged use of CCB, β-blockers, or ACEi was related to elevated breast cancer risk (45-49, 78, 79). Similarly, results from a large hospital-based case-control study (50), the Nurses' Health Study cohort (51), and a Dutch cohort study (52) do not suggest that these drugs are related to breast cancer risk. In contrast, findings from a smaller cohort study (53) have linked ever use of CCB to a significant increase in risk (OR, 2.57; 95% CI, 1.47-4.49). No risk elevations were observed for use of β-blockers and ACEi. Li et al. (80), in a large population-based case-control study, observed a significant increase in risk for prolonged use (15 years) of β-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 reported results from another population-based case-control study. Results indicated that ever (OR, 1.79; 95% CI, 1.07-3.01) and prolonged (OR, 3.50; 95% CI, 1.64-7.50) use of diuretics was associated with excess risk. No such risk elevations were observed for nondiuretic antihypertensive medications.

	NSAID Use and Breast Cancer Risk

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
Biological Mechanism
NSAIDs, including aspirin, ibuprofen, and naproxen, appear to exert an anticancer effect through inhibition of the COX enzyme system. COX-2, in particular, promotes the synthesis of prostaglandins, such as prostaglandin E₂, thought to play an etiologic role in tissue generation and tumorigenesis. COX-2-derived prostaglandin E₂ may stimulate estrogen biosynthesis in breast tissue (83). Additionally, COX-2 has been found to be overexpressed in human breast tumors in multiple studies (84-86). The observation that COX-2 expression is correlated with aromatase expression in breast cancer allows one to formulate the hypothesis that COX-2 increases estrogen production via up-regulation of aromatase expression. Preclinical research has shown that the administration of NSAID inhibits production of COX enzymes with resulting reduction in mammary carcinogenesis (87-89). Moreover, NSAIDs have been suggested to reduce neovascularization and promote apoptosis (63, 90). Some NSAIDs that do not affect the COX system have been shown to induce cell cycle arrest and apoptosis in breast cancer cell lines (64). Taken together, multiple lines of research into the biological mechanisms by which NSAIDs affect cancer risk point to a potentially valid agent in chemoprevention.

Summary of Existing Evidence
A large and diverse body of literature exists on the potential chemopreventive effect of NSAID use on breast cancer development (Table 5 ). Exposure assessment, however, differs widely across studies, including the definition of regular and prolonged use. Nevertheless, results from most studies have been remarkably consistent. Three registry-based studies (91-93) showed significant risk reductions for prolonged NSAID use. Several hospital-based (65, 94-97) and population-based (98-102) studies have generated statistically significant risk reductions for regular and prolonged aspirin use, except for a recent one (103). Less consistent evidence exists for ibuprofen use, which was associated with decreased risk in two investigations (104, 133) but not in others (131, 136, 138). Such discrepancy might not be surprising, given that ibuprofen is still a relatively new drug, and to date, few people have had significant exposures to this agent. Findings from the Women's Health Initiative observational study indicated that prolonged use (10 years) of any NSAID or aspirin was associated with statistically significant risk reductions (RR, 0.72; 95% CI, 0.56-0.91 and RR, 0.79; 95% CI, 0.60-1.03, respectively; ref. 105). Similarly, findings from the CLUE cohort in Washington county (106) point to a chemoprotective effect of aspirin use in breast cancer etiology (RR, 0.46; 95% CI, 0.22-0.98), but results were not influenced by hormone receptor status or COX-2 genetic polymorphisms (107). Other studies have also attempted to assess the effect of the COX-2 gene on the association between NSAID use and breast cancer risk, but results have been inconsistent (108, 109). Further support for a chemopreventive role of aspirin comes from the National Health and Nutrition Examination Survey I cohort (110) and Iowa Women's cohort (111) where current or prolonged (6 years) use were associated with significant risk decreases (RR, 0.70; 95% CI, 0.56-0.96 and RR, 0.71; 95% CI, 0.58-0.87, respectively). In the Iowa Women's cohort, these risk reductions were still apparent in subsequent analyses based on more breast cancer patients (112). These findings are similar to those of a smaller cohort from Ohio (113), where frequent NSAID use was associated with a significant risk reduction (RR, 0.57; 95% CI, 0.44-0.74). Recently, Ready et al. (114) found significant risk reduction for frequent and long-term use of low-dose aspirin (4 days/wk over 10 years) in the Vitamins and Lifestyle cohort (RR, 0.65; 95% CI, 0.43-0.91).

Finally, four meta-analyses showed significant chemopreventive effects of aspirin or NSAIDs against breast cancer. The first considered 14 studies published until 2000 (120) and showed a significant risk reduction associated with NSAID use (OR, 0.82; 95% CI, 0.75-0.89). A more recent meta-analysis restricted to 10 epidemiologic studies published from 2001 to 2005 (121) supported a protective association between aspirin intake and breast cancer (RR, 0.74; 95% CI, 0.69-0.79) with significant dose-response relationship. The protective effect was similar when cohort and case-control studies were examined separately (120, 121). Similar results were observed in two literature-based meta-analyses (122, 160).

Most observational studies and meta-analyses showed consistent and statistically significant risk reductions in human breast cancer with exposure to NSAIDs; however, interpretation of the existing body of literature on the associations between various NSAIDs and breast cancer risk is not straightforward. Although most studies on this topic have shown statistically significant risk reductions, the majority of these studies were either registry-based or employed a case-control design. The former approach is methodologically limited due to insufficient adjustment for potential confounders, whereas the latter study design is known to be prone to selection and information bias. Further, studies using only prescription records or health plan data will misclassify over-the-counter medication users as unexposed and thereby may underestimate exposure prevalence. Four large follow-up studies (82, 115, 150, 151) found no evidence of reduced risk of breast cancer among aspirin users, yet the majority of cohort studies found significant risk reductions among aspirin users (83, 139-141, 144-146, 148, 153). Importantly, however, two randomized trials, considered the gold standard in epidemiologic study designs, did not show a chemoprotective effect of aspirin use. It is possible, as suggested by Jacobs et al. (119) that higher-dose aspirin preparations may be needed to produce a chemoprotective effect. However, because they are the most common cause of serious gastrointestinal complications in the United States (161-163), chemopreventive trial of adult-dose (e.g., 325 mg) aspirin might be problematic. It is also possible that selective COX-2 inhibitors have much stronger chemopreventive properties than aspirin. Although previous trials revealed the serious side effects related to cardiovascular events with these drugs (164-166), recent reviews and meta-analyses of controlled observational studies (167) and randomized trials (123) confirmed that only rofecoxib was associated with the risk of cardiovascular events and suggests that celecoxib and other COX-2 inhibitors in commonly used doses may not increase the risk. Thus, additional randomized trials with these COX-2 inhibitors may be needed to resolve these questions. In conclusion, although the lack of a protective effect of aspirin in randomized trials is somewhat worrisome, the overwhelming majority of the existing evidence points to a chemoprotective role of aspirin in breast cancer etiology.

	Conclusions and Future Directions

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
The existing literature on the use of common over-the-counter and prescription medications has not definitively linked any of the drugs covered in this review to either increased or decreased risk of breast cancer. Important contributing factors to this apparent inconsistency are likely the numerous methodologic issues, discussed throughout this review, associated with the various study designs employed in these investigations. Thus, in conclusion, there is inconclusive evidence on the association between antibiotic use and breast cancer risk, no strong evidence pointing to a significant role of antidepressant and statin drugs in breast cancer development, somewhat inconclusive evidence on the effect of antihypertensive drugs, and significant chemoprotective evidence implicating aspirin use against breast cancer. Future studies with detailed lifetime medication histories are needed to further clarify these important associations. It is unlikely that such an assessment can be accomplished with a cohort study design, where repeated detailed medication measurement would be difficult to achieve. Thus, future case-control studies should consider in their design strategies for obtaining detailed and valid lifetime medication histories, which will likely involve a combination between self-report and prescription and/or health-care plan data. Further, in light of the strong and largely consistent findings from epidemiologic studies that link prolonged higher-dose aspirin use to reduce risk of breast cancer, a chemoprevention trial of NSAIDs or COX-2 inhibitors with similar chemopreventive properties to aspirin but without severe adverse gastrointestinal effects might be warranted. As pointed out above, medication use constitutes a ubiquitous exposure in the United States and in many countries worldwide. Given that breast cancer is the most common cancer in the United States and elsewhere, it is essential that we increase our understanding on the role of these commonly used drugs in the etiology of this disease.

	Disclosure of Potential Conflicts of Interest

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 
No potential conflicts of interest were disclosed.

	Footnotes

 
Grant support: Susan G. Komen for the Cure as part of the Environmental Factors and Breast Cancer Science Review project led by Silent Spring Institute with collaborating investigators at Harvard Medical School, Roswell Park Cancer Institute, and University of Southern California.

Received 11/26/07; revised 4/ 1/08; accepted 4/15/08.

	References

Top Abstract Introduction Exposure Definition and Study... Antibiotics and Breast Cancer... Summary of Existing Research Antidepressant Use and Breast... Statin Drug Use and... Antihypertensive Medication Use... NSAID Use and Breast... Conclusions and Future... Disclosure of Potential... References

 

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