Affiliations of authors: Research and Evaluation Department, Kaiser Permanente Southern California, Pasadena, CA (AMG, WC); Departments of Neurology (GMF) and Preventive Medicine (LB), Keck School of Medicine, University of Southern California, Los Angeles
Correspondence to: Ann M. Geiger, PhD, Research and Evaluation Department, Kaiser Permanente Southern California, 100 S Los Robles, Pasadena, CA 91188 (e-mail: ann.m.geiger{at}kp.org)
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ABSTRACT |
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INTRODUCTION |
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However, potentially harmful effects, such as endometrial cancer and venous thromboembolism, may accompany the treatment and prevention benefits of tamoxifen use. Of particular concern is the possibility that tamoxifen use may increase stroke risk. Although an overview of randomized trials of adjuvant tamoxifen for early breast cancer found no increase in stroke-related mortality (1,2), the possibility of an increased incidence of stroke in tamoxifen users was raised in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trialsP-1, the Breast Cancer Prevention Trial (5) and B-24, a trial of tamoxifen for intraductal breast cancer (6). Examining the association between tamoxifen and stroke is challenging because of the small number of strokes occurring in individual trials and because of the difficulties in accurately identifying strokes and gathering information on known stroke risk factors.
To assess the impact of tamoxifen treatment for breast cancer on stroke risk, we conducted a nested casecontrol study among female Los Angeles County residents enrolled in a large health maintenance organization at the time they were diagnosed with breast cancer. Our aims were to determine whether tamoxifen treatment for breast cancer affects stroke risk; to quantify any tamoxifen effects in terms of cumulative dose, duration, and recency of use; and to determine how known stroke risk factors may influence any tamoxifen effects.
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SUBJECTS AND METHODS |
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We conducted a casecontrol study of first stroke after breast cancer nested within a cohort of female Los Angeles County residents who were diagnosed with their first invasive breast cancer while they were members of a large health maintenance organization (Kaiser Permanente Southern California [KPSC]). The study was approved by the Institutional Review Boards for the Protection of Human Subjects at KPSC and the University of Southern California, in accordance with assurances filed with and approved by the U.S. Department of Health and Human Services. The Institutional Review Boards waived informed consent requirements for medical record review. Subjects provided verbal consent at the time of the telephone interview.
The Los Angeles County Cancer Surveillance Program, which is located at the Keck School of Medicine of the University of Southern California, identified all women with a first invasive breast cancer diagnosed at KPSC between January 1, 1980, and July 1, 2000. We linked records of these women with automated KPSC hospitalization data from January 1, 1980, to April 30, 2001, to identify women who possibly had strokes after their breast cancer diagnoses. We also identified women whose cause of death was listed as stroke by linking the breast cancer patient records to cancer registry follow-up data and to California mortality files. Any breast cancer patient with one of the following codes as a hospitalization discharge diagnosis or cause of death was considered a potential stroke case: International Classification of Diseases, 9th Revision (ICD-9) 430.x432.x, 433.x1, 434.x436.x, or ICD-10 I63 or I64.
Case patients were KPSC members throughout the at-risk period, i.e., between their breast cancer diagnoses and their strokes. Patients with a subsequent primary cancer diagnosis (other than a second primary breast cancer, cervical cancer in situ, or basal or squamous cell skin cancer) before their stroke diagnoses were excluded from the study because the other cancer could alter their breast cancer treatment or their stroke risk. Patients with thromboembolic disease diagnoses other than stroke (i.e., myocardial infarction, venous thromboembolism, or pulmonary embolism) were excluded. Case patients with stroke as the underlying cause of death were assumed to have died of stroke. To confirm strokes identified from hospitalization data, a vascular neurologist (G. M. Fischberg) reviewed diagnostic information from medical records, including clinical presentation, and the results of computed tomography and magnetic resonance imaging scans, ultrasound studies, lumbar puncture, angiography, and surgery reports. Stroke was defined as the new onset of rapidly developing symptoms and signs of loss of cerebral function with no apparent cause other than that of vascular origin (7). For this study, we excluded neurologic events resulting from subdural hematoma, brain tumor, metastatic disease, infection, metabolic derangement, and multiple sclerosis. Strokes were classified into one of five groups: transient ischemic, hemorrhagic, thrombotic, embolic, or unable to classify. Two groups of case patients were identified: women who had their first stroke after their breast cancer diagnosis and women who had had a stroke before (i.e., had a history of stroke) and had another stroke after their breast cancer diagnosis.
Control subjects had invasive breast cancer but no other primary cancer diagnosis (other than a second primary breast cancer, cervical cancer in situ, or basal or squamous cell skin cancer) and no prebreast cancer diagnosis evidence of stroke or other thromboembolic disease (myocardial infarction, venous thromboembolism, or pulmonary embolism). We used a 2:1 (control:case) matching system, in which two control subjects were selected at random from all breast cancer patients born within 3 years and diagnosed with breast cancer within 1 year of their matched case patient. The at-risk period for each control subject began with her breast cancer diagnosis and extended from breast cancer diagnosis to stroke for her matched case patient. The date the at-risk period ended (i.e., reference date) defined the time point when data collection for control subjects ended. Control subjects were required to be alive and to be members of KPSC throughout the at-risk period. Case patients with stroke and control subjects with evidence of stroke or other thromboembolic disease (myocardial infarction, venous thromboembolism, or pulmonary embolism) were eligible to serve as control subjects up to the day before their thromboembolic event. We confirmed the eligibility of each control subject by reviewing medical records. If a control subject became ineligible for any reason, another control subject was selected randomly, until at least two control subjects were matched to each case patient. When fewer than two control subjects were available to be matched to a case patient, we identified additional control subjects by relaxing the matching criteria for year of birth to within 5 years and the year of diagnosis to within 2 years. Such expanded criteria were used to identify control subjects for three case patients. For five case patients, we were able to identify only one eligible control subject, despite relaxing the matching criteria. Determination of subject eligibility is shown in Fig. 1.
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Details of all breast cancer treatments (surgery, chemotherapy, radiation, and hormonal therapy) received during the at-risk period were abstracted from medical records. In addition, we obtained information on breast tumor characteristics, including estrogen and progesterone receptor status, reproductive history, oral contraceptive and hormone replacement therapy use, height and weight, and histories of hypertension, diabetes, and hypercholesterolemia. Women were classified according to whether they had ever smoked or used oral contraceptives or hormone replacement therapy because we were unable to collect detailed exposure information.
We attempted telephone interviews with study subjects to obtain additional information on breast cancer therapies, smoking status, and medical and reproductive history. Next of kin were interviewed when subjects were deceased or unable to respond. Interviews were conducted for 133 case patients and 234 control subjects; of these, next of kin were interviewed for 69 case patients and 65 control subjects. Interviews could not be conducted for 95 case patients and 169 control subjects for the following reasons: the subject or next of kin refused (50 case patients, 188 control subjects), the subject or next of kin could not be located (41 case patients, 28 control subjects), or permission to contact a patient was denied by her physician (four case patients, 23 control subjects).
We compiled medical record and interview data into a single analytic database, using interview data only when medical record data were missing for a particular factor. We created two categories of recency of tamoxifen use at stroke diagnosis (<1 year and 1 year); "1 year" was chosen to account for annual prescription refills. We created quartiles of cumulative tamoxifen dose, duration of use, and body mass index from the control subjects distribution of these exposures.
Statistical Analyses
We compared case patients with their individually matched control subjects using univariate and multivariable conditional logistic regression methods. Crude and adjusted odds ratios (ORs) were estimated, and 95% confidence intervals (CIs) were calculated (8). These analyses were limited to case patients who had their first stroke after their breast cancer diagnosis and their matched control subjects. In all categorical analyses, women with missing information were included in a separate category. All multivariable analyses included categorical terms for menopausal status (pre- or perimenopausal, naturally postmenopausal, or menopausal because of surgery); history of hypertension (no, yes but not requiring medication, and yes requiring medication); and history of diabetes (no, yes but not requiring medication, and yes requiring medication). To assess the impact of tamoxifen use on stroke risk, we included chemotherapy (yes, no) in multivariable analyses; similarly, to assess the impact of chemotherapy on stroke risk, we included tamoxifen (yes, no) in the analyses. In multivariable analyses assessing the impact of subject characteristics, medical history, breast tumor characteristics, and radiation treatment on stroke risk, we included a combined chemotherapy and tamoxifen use variable (not treated with either, received chemotherapy only, received tamoxifen only, or received both). All analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). All statistical tests were two-sided.
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RESULTS |
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Almost 90% of the case patients and control subjects were aged 50 years or older (Table 1), whereas 76% of eligible women with breast cancer were in this age group (data not shown). Strokes occurred 19 years after breast cancer diagnosis in 66.5% of the case patients, 14.5% of strokes occurred within 1 year, and 19% occurred more than 10 years after the breast cancer diagnosis. Ischemic strokes, including transient ischemic attacks, were the most common form of stroke, occurring in 67.6% of case patients. We identified 21 (11.7%) case patients from mortality records.
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We also compared characteristics among case patients with incident strokes and case patients with stroke history. Case patients with strokes before and after their breast cancer experienced their postbreast cancer strokes closer in time to their breast cancer diagnoses and were older than case patients who had their first stroke after breast cancer (Table 4). Compared with first-stroke case patients, recurrent-stroke case patients were less likely to have received chemotherapy and more likely to have been treated for hypertension and diabetes and to have received tamoxifen therapy.
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DISCUSSION |
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Although a systematic overview of randomized trials of adjuvant tamoxifen therapy for early breast cancer found no increase in stroke mortality (1,2) and a meta-analysis of randomized trials of tamoxifen for breast cancer prevention found no increased stroke risk (9), concern regarding an association between tamoxifen and stroke has remained because of results from two randomized controlled trials. In the NSABP B-24 trial of tamoxifen for the treatment of intraductal breast cancer (3), five strokes were reported among women in the tamoxifen group compared with one stroke among women in the placebo group. However, no statistical test was reported (6). Although only about one-third of the participants in NSABP B-24 were older than 60 years, the median age at stroke in that study was 67.1 years (range = 54.176.0 years), consistent with the age of our case patients. To examine the possible association between tamoxifen and stroke, the NSABP P-1 Breast Cancer Prevention Trial was designed to identify strokes prospectively using specific definitions; thus, women with previous stroke and uncontrolled hypertension or diabetes were excluded from the study (6). Although the results did not achieve statistical significance, they suggested a possible increased incidence of stroke among women randomly assigned to the tamoxifen arm. After 69 months of follow-up, there were 38 strokes among women in the tamoxifen group compared with 24 strokes among women in the placebo group, for a risk ratio of 1.59 (95% CI = 0.93 to 2.77). When the analysis was restricted to strokes among women aged 50 years or older, the group most similar to our study subjects, the risk ratio was 1.75 (95% CI = 0.98 to 3.20) (5).
Our results provide no support for an association between first stroke after breast cancer and tamoxifen use to prevent recurrence but cannot fully address associations with preventive use of tamoxifen. Whereas a minimal increase in stroke risk may be acceptable for breast cancer treatment, women using tamoxifen for prevention must carefully weigh the possible slight increase in stroke found in the P-1 trial, which reported an excess of five strokes per 10 000 women of all ages in the tamoxifen arm.
Tamoxifen belongs to the class of drugs known as selective estrogen receptor modulators (SERMs). Some information exists regarding the risk of stroke among women taking exogenous estrogen and a different SERM, raloxifene. Two recent literature reviews (10,11), one a quantitative meta-analysis, found that users of high-dose oral contraceptives have an increased risk of stroke but strongly questioned the reported increased risk of stroke in users of low-dose oral contraceptives. A consistent but modest increase in stroke risk among users of a variety of hormone replacement therapy regimens has been reported in multiple trials and in observational studies (11,12). Raloxifene does not appear to increase the risk of stroke and, in fact, may decrease stroke risk among women at increased risk (13).
Evidence of an association between chemotherapy and stroke after breast cancer is limited. A systematic review of randomized trials of polychemotherapy for early-stage breast cancer did not identify an increase in all-cause nonbreast cancer mortality in the tamoxifen treatment arms (14). Among seven trials of adjuvant breast cancer therapy, polychemotherapy was associated with an increase in venous and arterial thromboemboli. In addition, premenopausal women who received the combination of chemotherapy and tamoxifen had an increased risk of arterial thromboemboli during treatment (15). In a trial of concurrent tamoxifen and chemotherapy treatment for breast cancer, there was an increase in total thromboemboli, most of which occurred during treatment, but no increase in stroke incidence in women receiving both treatments (16). Among 1014 women enrolled in two trials of polychemotherapy, eight strokes occurred during treatment and one stroke occurred after treatment (17). Evaluation of an association between stroke and chemotherapy in these trials was limited by the inclusion of stroke in the same category as other thromboembolic diseases, unconfirmed individual physician diagnoses, follow-up periods limited to the time of active treatment and shortly thereafter, and the absence of information on known stroke risk factors.
There are several possible explanations for the observed association between stroke and chemotherapy. Although our results did not change when case patients were stratified by stage, women who receive chemotherapy may have more aggressive breast cancer, which in turn may be associated with harboring occult malignancies. Such occult malignancies could be associated with activated thrombogenesis, which increases risk of stroke (1820). It is also conceivable that some women may experience lingering cardiotoxic effects from chemotherapy (21), increasing their risk of a cardioembolic stroke. However, cardioembolic strokes were no more common in our case patients than would be expected in the general population, making this explanation unlikely. Chemotherapy agents may accelerate development of atherosclerotic disease as a result of altered coagulation, vasospasm, and endothelial damage (20,2224). Furthermore, agents used in conjunction with chemotherapy, such as erythropoietin, might somehow increase stroke risk (25). Because our study was not designed to examine an association between chemotherapy and stroke, we are unable to fully explain this finding.
Risk factors for stroke include hypertension, diabetes, hypercholesterolemia, and smoking (26). One study suggests that, relative to men, women are older at stroke and that cardioembolic disease and hypertension play a stronger role in stroke risk (27). The Atherosclerosis Risk in Communities (ARIC) study found that stroke was two to three times more common in black women than in white women (28). Our study demonstrated that hypertension and diabetes are independently associated with stroke after breast cancer but did not identify any association of stroke with race/ethnicity, body mass index, smoking, hypercholesterolemia, or exogenous hormones. Among strokes of known type, the distribution of stroke types in our case patients was similar to that expected in the general population (29).
Although our study was retrospective, by matching on age, year of diagnosis, and length of follow-up, we replicated several key features of randomized trials. In addition, our population-based study avoids volunteer bias that can occur in randomized trials. By conducting our study within an integrated health care system, we were able to identify, confirm, and classify strokes systematically as well as to gather detailed information on treatments for breast cancer and known stroke risk factors. Because KPSC has a safe and effective system for returning members hospitalized at non-KPSC facilities to KPSC facilities, we likely missed few strokes (30). Moreover, we were able to accurately classify tamoxifen use for the majority of study subjects, with only a small proportion of study subjects having insufficient medical record information regarding tamoxifen use. For the remaining subjects, we gathered detailed information on tamoxifen use from medical records an information source that is not affected by the bias of self-reporting. It is possible that tamoxifen was prescribed preferentially to women at lower risk of stroke, which could bias our results toward a finding of no association between tamoxifen use and stroke risk. Nevertheless, we observed that a greater percentage of women with a history of stroke were prescribed tamoxifen than women with no stroke history.
To date, randomized trials have not resolved conclusively the question of whether tamoxifen use is associated with stroke. In our casecontrol study of first incident stroke after first breast cancer diagnosis nested among female residents of Los Angeles County enrolled in a large health maintenance organization, we found no association of stroke and adjuvant tamoxifen use, including no effect by cumulative dose, duration, or recency of use. Our study suggests that women and their clinicians considering tamoxifen use for breast cancer treatment can do so without concern for stroke. Our results may also have implications for, but do not directly apply to, women with breast cancer who have a history of stroke or other thromboembolic disease before breast cancer, nor do they apply to women considering tamoxifen for preventive use. In addition to examining tamoxifen, we identified an association of stroke and chemotherapy, although we were unable to attribute the association to a specific chemotherapy regimen. The risk of a relatively rare but life-altering condition such as stroke must be balanced with the well-known life-extending benefits of chemotherapy. Although this study cannot generate specific recommendations, it seems logical that women with a history of chemotherapy may benefit from approaches to reduce stroke risk, such as appropriate management of hypertension and diabetes.
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NOTES |
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REFERENCES |
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Manuscript received June 4, 2004; revised July 29, 2004; accepted August 18, 2004.
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