1 Clinical Epidemiology Research and Training Unit, School of Medicine, Boston University, Boston, MA
2 Slone Epidemiology Center, Boston University, Boston, MA
3 Center for Clinical Epidemiology and Biostatistics; Department of Biostatistics and Epidemiology; Center for Education and Research on Therapeutics; and Division of General Internal Medicine, Department of Medicine; University of Pennsylvania School of Medicine, Philadelphia, PA
Correspondence to Dr. Yuqing Zhang, Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, 715 Albany Street, Room A203, Boston, MA 02118 (e-mail: yuqing{at}bu.edu).
Received for publication November 30, 2004. Accepted for publication March 22, 2005.
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ABSTRACT |
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anti-inflammatory agents, non-steroidal; breast neoplasms; case-control studies
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INTRODUCTION |
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In an earlier report based on 6,558 breast cancer patients recruited into the Case-Control Surveillance Study from 1976 to 1996, we found equivocal evidence of an association between NSAID use and breast cancer risk (9). There was a decreasing odds ratio with increasing duration of use, but it was found mostly at one study center. In the current analysis, we extended the time of subject recruitment to the year 2002 and the number of cases to 7,006. In addition to assessing the effect of all NSAID use, we also examined the effect of individual NSAIDs and whether the relation of NSAID use to breast cancer risk varied according to the hormone receptor status of the tumor or menopausal status. The use of NSAIDs, especially nonaspirin NSAIDs, has increased in the United States because of the increasing use of over-the-counter drugs; thus, the data that were collected more recently increased our ability to examine the effects of long-term NSAID use and type of NSAID use on the risk of breast cancer.
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MATERIALS AND METHODS |
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Information was collected on demographic factors, medical and reproductive history, family history of cancer, lifestyle factors, and medication use. Histories of medication use were elicited through questions about 42 indications, including those for which NSAIDs are used (e.g., pain, headache, and arthritis). For each episode of use, the name of the medication and the duration, timing, and frequency of use were recorded.
After discharge, the diagnosis that led to the patient's hospital admission was abstracted from the hospital record; discharge summaries were obtained for all patients, and pathology reports were obtained for patients with cancer. Information on hormone receptor status (estrogen receptor and progesterone receptor) was obtained for 1,294 breast cancer cases. These cases tended to be patients interviewed in the later years of the study, because hormone receptor status was not usually reported in the earlier years.
NSAID use
NSAID use was defined as use of any drug in the following classes: salicylates (e.g., aspirin), indoles (e.g., indomethacin), propionic acids (e.g., ibuprofen), fenamates (e.g., mefenamic acid), pyrazolines (e.g., phenylbutazone), oxicams (e.g., piroxicam), and cyclooxygenase-2 inhibitors (e.g., celecoxib). Most NSAID use was sporadic. We theorized that if NSAID use had a preventive role, it would most likely be regular use of long duration. We defined regular NSAID use as use of any NSAID at least four times per week for 3 or more continuous months. All other use was considered nonregular. Regular use was further subdivided according to when NSAIDs were first and last used. Only use that began a year or more before hospital admission was considered etiologically relevant.
Cases
Eligible cases were 7,006 women aged 3079 years who met the following criteria: 1) a diagnosis of breast cancer recorded in the discharge summary or pathology report that had been made within the year before the current admission and 2) no other primary cancer or history of cancer.
Controls
Controls were selected from a pool of 3,906 women aged 3079 years with no history of cancer who had been admitted to the hospital for nonmalignant diseases that we considered unrelated to NSAID use. Eligible diagnoses included appendicitis, hernia of the abdominal cavity, and traumatic injury. Subjects with missing information on NSAID use were not eligible as potential controls. The potential controls were frequency matched to the cases at a ratio of up to 4:1 on 5-year age group, study center (New York, Boston, Philadelphia, or Baltimore), and year of interview (in 5-year categories). The final control series comprised 3,622 women. In our previous study (9), we also used a control series of women with cancer. However, because cancers at various sites have been linked to NSAID use, we did not use cancer controls in the present study.
The prevalences of regular NSAID use that began at least 1 year before admission, standardized by age and geographic region, were similar among controls admitted for appendicitis or hernia of the abdominal cavity and controls admitted for traumatic injury. The prevalences of never use of NSAIDs, nonregular use of NSAIDs, and regular use of NSAIDs were 37.0 percent, 51.5 percent, and 11.5 percent, respectively, in the first group and 37.8 percent, 50.6 percent, and 11.5 percent, respectively, in the second group. The two subgroups of controls were also similar in terms of mean number of years of regular NSAID use (5.2 years vs. 6.1 years).
Data analysis
We assessed the relation of NSAID use to the risk of breast cancer using multiple logistic regression models. In a multivariable model, we adjusted for age, year of interview, study center, race, years of education, benign breast disease, number of physician visits 2 years before hospitalization, duration of female hormone supplement use, duration of oral contraceptive use, age at menarche, age at menopause, age at first birth, parity, alcohol consumption, family history of breast cancer (breast cancer in a mother or sister), practice of breast self-examination, and body mass index. We included a term for duration of regular NSAID use in the model to test for a trend across duration of use. We assessed regular use of all NSAIDs and use of ibuprofen and aspirin specifically. In all analyses, the reference group comprised women who had never used any NSAIDs.
We assessed the effect of regular NSAID use according to the hormone receptor status of the tumor and menopausal status. As in the previous study of NSAIDs and tumor receptor status (18), a tumor was classified as hormone receptor positive if it was positive for either estrogen receptor or progesterone receptor; otherwise, it was classified as hormone receptor negative.
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RESULTS |
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DISCUSSION |
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To date, epidemiologic findings regarding the effect of NSAID use on breast cancer risk have been equivocal. While the majority of case-control studies have shown that regular use of NSAIDs is associated with decreased risk of breast cancer, results from cohort studies are conflicting. Of seven cohort studies (13
, 6
, 8
, 16
, 19
) that evaluated the association, only two had more than 100 incident breast cancer cases (6
, 16
). In the Nurses' Health Study (2,414 incident breast cancer cases), no relation was found between aspirin use and the risk of breast cancer (odds ratio = 1.01, 95 percent CI: 0.80, 1.27) (6
). Investigators from the Women's Health Initiative Observational Study (1,252 incident breast cancer cases) reported relative risks of 0.79 (95 percent CI: 0.60, 1.04) for women who used NSAIDs regularly for 59 years and 0.72 (95 percent CI: 0.56, 0.91) for women who used NSAIDs regularly for 10 years or more (16
). The effect appeared to be stronger for ibuprofen use (relative risk = 0.51, 95 percent CI: 0.28, 0.96) than for aspirin use (relative risk = 0.79, 95 percent CI: 0.60, 1.03) (16
).
To our knowledge, no epidemiologic study has assessed whether the relation between regular NSAID use and breast cancer risk varies according to menopausal status. In the Nurses' Health Study, the relative risk of breast cancer for regular aspirin use among women aged 3449 years was 0.79 (95 percent CI: 0.43, 1.45), whereas the corresponding effect estimate among women aged 50 years or more was 1.06 (95 percent CI: 0.83, 1.35) (6). These results suggest that regular use of aspirin is associated with lower risk of breast cancer among younger women, and probably most of them were premenopausal. Nevertheless, the number of cases was small (99 cases), and the confidence interval was wide. In our study, the breast cancer odds ratios for regular use of NSAIDs were 0.69 and 0.90 among pre- and postmenopausal women, respectively. It is unclear why an effect of regular NSAID use would vary by menopausal status. The effect of NSAID use on the risk of breast cancer is relatively small, and it is possible that a weak association was simply more likely to be detected among low-risk women, that is, premenopausal women (20
).
The inconsistent findings among the different studies may reflect differences in the definitions of regular NSAID use and of nonuse. For example, in the Nurses' Health Study, regular use of aspirin was defined as two or more aspirin taken per week, and the reference group included both nonregular users and never users. The Women's Health Initiative used the same definition of regular NSAID use as the Nurses' Health Study, but the referent group included women who had used NSAIDs regularly for less than 1 year in addition to nonregular and never users (16). The definition of regular use of NSAIDs in the Long Island Breast Cancer Study Project (18
) was similar to that in our study. However, it is unclear what the reference group was when the effect of each individual NSAID was assessed. In addition, the studies that reported an inverse association between NSAID use and breast cancer risk (3
, 5
, 8
, 10
, 12
, 14
16
) assessed the dose-response relations of frequency of use and duration of use separately. None addressed this issue with a variable that combines both frequency of use and duration of use. Thus, there is a lack of informative evidence on a possible dose-response relation between NSAID use and risk of breast cancer.
Several biologic mechanisms have been proposed to explain why NSAID use may reduce the risk of breast cancer. Studies have demonstrated that NSAIDs inhibit the synthesis of prostaglandins through interference with cyclooxygenase-2. Prostaglandins play a key role in the proliferation of tumor tissue (21). Other studies indicate that NSAIDs may have the ability to induce apoptosis and inhibit angiogenesis (22
). Whether these proposed mechanisms influence breast carcinogenesis is still not clear; however, cyclooxygenase-2 has been found to be overexpressed in breast tumors but not in normal breast tissues (23
).
Several characteristics of our study are noteworthy. Controls were selected from women whose diagnoses were unrelated to NSAID use. The distributions of NSAID use among subgroups of the controls were similar, suggesting the absence of selection bias. Important breast cancer risk factors were controlled simultaneously in multivariable analysis. The data on medication use were collected in the context of questions about many drug indications, and the participants and interviewers were unaware of the hypotheses at issue; thus, recall bias is unlikely to have played a role.
Information on the dosage of the NSAID taken was not collected in our study, nor was information on the number of pills taken per day. We used frequency of use as a surrogate for intensity of exposure. Misclassification could have influenced the relation between regular NSAID use and breast cancer risk in either direction. Nevertheless, there is evidence of the validity of the data: With the same database, we found a significant reduction in the risk of colon cancer for regular NSAID usea finding confirmed in many other studies (2426
).
Data on the hormone receptor status of the tumor were obtained from only 26 percent of the cases in our study. However, the distributions of data on important risk factors for breast cancer, such as duration of female hormone supplement use, duration of oral contraceptive use, age at menarche, age at menopause, age at first birth, parity, alcohol consumption, and body mass index, were similar among cases with data on hormone receptor status and cases without such data, suggesting the absence of selection bias.
In summary, the present study found that regular use of NSAIDs is associated with a decreased risk of breast cancer, but the effect is relatively weak. Given the conflicting results from large cohort studies and the varying definitions of NSAID use, it is still too early to suggest that regular use of NSAIDs could help prevent breast cancer.
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ACKNOWLEDGMENTS |
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Dr. Brian Strom has been a consultant for most of the manufacturers of nonsteroidal antiinflammatory drugs and has received funding from many for research, though not on this topic.
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References |
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