Affiliations of authors: E. S. O'Meara, M. A. Rossing, J. R. Daling, N. S. Weiss, Fred Hutchinson Cancer Research Center and Department of Epidemiology, University of Washington, Seattle; J. G. Elmore, Departments of Epidemiology and General Internal Medicine, University of Washington, and Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle; W. E. Barlow, Department of Biostatistics, University of Washington, and Center for Health Studies, Group Health Cooperative of Puget Sound.
Correspondence to: Ellen S. O'Meara, Ph.D., Cardiovascular Health Study, University of Washington, 600 Stewart St., Suite 700, Seattle, WA 98101 (e-mail: eomeara{at}u.washington.edu).
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ABSTRACT |
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INTRODUCTION |
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Breast cancer treatment can induce menopause or its symptoms. Adjuvant chemotherapy causes ovarian failure in many premenopausal patients (5,6), and tamoxifen often promotes vasomotor and vaginal symptoms (7,8). Although nonhormonal alternatives to HRT are available (913), at this time, none are known to be as effective as HRT in the management of menopausal symptoms (12,13). Selective estrogen receptor modulators, such as raloxifene, have beneficial effects on bone and lipid profiles (11,14), but they can aggravate menopausal symptoms (14). Thus, despite the potential for harm, HRT is used by some women after a diagnosis of breast cancer. The present study was designed to explore the influence of such use on recurrence and mortality.
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SUBJECTS AND METHODS |
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This study was set within the Group Health Cooperative of Puget Sound, Seattle, WA, which is a health maintenance organization currently serving more than 400 000 residents of western Washington state. This record-based study was approved by the Institutional Review Board. Group Health Cooperative enrollees are representative of the surrounding population with respect to age, race/ethnicity, and marital status, although they have slightly higher levels of education on average (15). Female enrollees diagnosed with invasive carcinoma of the breast at ages 3574 years from 1977 through 1994 were identified retrospectively in the records of the Cancer Surveillance System, a population-based cancer registry operating as part of the Surveillance, Epidemiology, and End Results (SEER) Program1 of the National Cancer Institute. We excluded women with distant metastatic disease at diagnosis and women with a prior diagnosis of in situ or invasive breast cancer. The cohort comprised 2755 women who met these criteria.
Data Collection
The Cancer Surveillance System provided data on tumor characteristics at diagnosis, including the site, histology, and extent of disease (tumor size, extension, and lymph node status) and the first course of cancer treatment (surgery, radiation therapy, chemotherapy, and/or hormonal therapy). The Cancer Surveillance System was our primary source of vital status data, including date of death, cause of death from death certificates, or date of last physician contact. Cause-of-death information was available for 91% of women in the cohort who died by the end of 1996.
Group Health Cooperative pharmacy data were used to ascertain the use of HRT after a diagnosis of breast cancer. The pharmacy database contains records of all prescriptions filled at Group Health Cooperative outpatient pharmacies since 1977. Survey data show that 96% of female enrollees fill their prescriptions at these pharmacies (15). Pharmacy data were also obtained on tamoxifen and HRT use before diagnosis. The chronic disease score, a proxy measure of comorbidity based on 6 months of prescription data (16,17), was calculated as of 1 year before diagnosis.
Medical records at the Group Health Cooperative were reviewed to ascertain the following factors: parity, gravidity, and age at first full-term pregnancy; age at menarche; age at and reason for cessation of menses; menopausal symptoms; hysterectomy; oophorectomy; smoking history at diagnosis; family history of breast cancer; height and weight at diagnosis; and HRT use before diagnosis, including age started and duration of use. We ascertained whether the breast cancer was first suspected on mammographic screening. Results from estrogen and progesterone receptor assays were abstracted and classified as positive or negative as interpreted by the laboratory or physician. When a summary interpretation was not available, we classified the result as positive if the receptor was measured in concentrations of at least 10 fmol/mg or at least 3% of cells were positive. Treatments received for the initial breast cancer were ascertained.
Women who had a hysterectomy without bilateral oophorectomy or prior natural menopause were classified as postmenopausal if age 50 years or older. Age 50 years was chosen in accord with the median age of menstrual cessation among women in the cohort known to have had a natural menopause. Women who had menstruated within the previous 6 months were classified as premenopausal, unless they were also using HRT. Because HRT users may experience cycling due to the drug, their menopausal status is difficult to determine. Women with recent menstruation who were using HRT were classified as postmenopausal if 50 years old or older, as were women whose charts did not contain sufficient data to classify age at menopause.
Medical charts were our primary source of data on breast cancer recurrence. Recurrence was defined as invasive disease confined to the ipsilateral breast (22% of diagnosed recurrences) or metastasis. New primary contralateral breast cancers were not included in this definition.
Use of HRT After Breast Cancer
We assessed the impact of HRT use in women with a history of breast cancer who appeared to be free of disease. Women who used HRT during the period from diagnosis to the first medical recognition of invasive recurrent breast cancer, or the end of 1996, were included. To be considered a user, the woman was required to have filled at least two prescriptions for an HRT medication containing estrogen within a 6-month interval, any time after her initial diagnosis and before diagnosed recurrence. HRT initiation was defined to occur on the date that the second prescription was filled. The presence of a second fill within 6 months increases our confidence that the drug was actually taken. According to pharmacy data, 206 women (7.5% of the cohort) met this definition of HRT use; 32 of these women were ineligible for the following reasons found on chart review: 18 had recurrent breast cancer diagnosed before HRT initiation, four took HRT as part of an experimental treatment for locally advanced breast cancer, six had prior breast cancer not already identified, three had charts that were missing, and the source of the primary tumor was undetermined for one. Thus, we identified 174 eligible HRT users.
The cumulative use of HRT since diagnosis was estimated. A run-out time for each oral HRT prescription was determined on the basis of the number of pills dispensed and the prescribing instructions. Run-out times were summed to yield total months of use. Because entry into observation occurred at the second of two prescriptions, users entered with the duration accrued since the first prescription. Adherence to the prescribed regimen was assumed. The cumulative dose of oral HRT was estimated in a similar manner. Prescription doses were converted to conjugated-estrogen dose equivalents. [Equivalence to 0.625 mg of conjugated estrogens has been determined at 0.625 mg for esterified estrogens and 0.05 mg for ethinyl estradiol (18).] Cumulative use of vaginal HRT was measured by summing the number of tubes of estrogen cream dispensed from the pharmacy.
Nonusers
A comparison group of nonusers of HRT was randomly selected from the cohort. Because users were required to be enrolled in the Group Health Cooperative and to be free of diagnosed recurrence when they initiated HRT, we required that nonusers meet the same conditions at the equivalent time since diagnosis. To do this, we matched a set of four nonusers to each user at a defined reference date marking the start of observation. For users, the reference date was the date of HRT initiation. For nonusers, the reference date was based on the interval between diagnosis and HRT initiation in the matched user. Thus, nonusers were restricted to those with a recurrence-free interval at least as long as the interval from diagnosis to HRT initiation in the matched user. With this approach, we sought to maintain comparability between users and nonusers with respect to lack of disease progression at the start of follow-up. Users and nonusers were also matched on age at diagnosis (3544 years, 4554 years, 5564 years, or 6574 years), year of diagnosis (19771982, 19831988, or 19891994), and stage at diagnosis (I, II, or III) (19). Of 793 potential nonusers selected at random (within matching criteria), the following 98 were excluded for reasons found on medical chart review: 55 had recurrent breast cancer diagnosed before reference, 27 had prior breast cancer not already identified, 12 had charts that were missing, three were found to have breast cancers that were not carcinomas, and one chart noted the patient's refusal to participate in research. This left 695 matched nonusers for analysis.
Statistical Analysis
We compared users and nonusers of HRT after breast cancer with respect to breast cancer recurrence, breast cancer mortality, and total mortality. Follow-up began at the reference date. For the analysis of recurrence, observations were censored at the time of death, disenrollment from the Group Health Cooperative, or the end of 1996. For mortality analyses, observations were censored at the end of 1996 or, for breast cancer mortality analyses, at the time of death from another cause. Women were followed for a median of 3.7 years for recurrence and 4.6 years for mortality.
Rates of recurrence and death were calculated among users and nonusers by dividing the number of events by the total person-time at risk. Because time at risk began at the reference date, rates were calculated among women who had remained free of recurrence as of that date. Unadjusted relative risks (rate ratios) were obtained by dividing the event rate in users by that in nonusers. Multivariate associations were estimated by using the Cox regression model (20). Relative risks (hazard ratios) and 95% confidence intervals (CIs) were calculated, adjusting for influential factors. To assess confounding, we added a factor to the model and examined its effect on the relative risk associated with HRT use. Potentially confounding or modifying factors examined included the following: age, year, and disease stage at diagnosis; age at reference; time from diagnosis to reference; characteristics of the initial tumor including lymph node involvement, size, histology (ductal or other), and estrogen and progesterone receptor status; whether the cancer was first identified by screening; treatments received for the initial cancer, including surgery, radiation therapy, chemotherapy, and hormonal therapy; height; weight; body mass index; smoking status; marital status; family history of breast cancer; race/ethnicity; age at menarche; number of prior pregnancies and full-term pregnancies; age at first full-term pregnancy; hysterectomy; oophorectomy; menopausal status, age at menopause, and time since menopause; prior HRT use, its duration, and age at first use; and the chronic disease score. We adjusted for matching by using risk set stratification, which allows baseline hazards to vary freely between matched sets. A global test of the proportional hazards assumption that the relative risks are constant over time was performed (21).
Because oral HRT and vaginal HRT may represent different exposures, we analyzed the data comparing nonusers with users of any HRT, users of any oral HRT, and users of vaginal HRT only. For analyses of dose and duration, HRT was modeled as a time-dependent covariate for which cumulative use was updated at each prescription date. Categories of cumulative use for analysis were chosen on the basis of approximate equivalence of person-years between categories.
Nonusers were sampled without regard to HRT use after the reference date; we required only that a nonuser had not used HRT after diagnosis and before her assigned reference date. Thirty-two women randomly selected as nonusers went on to use HRT. At HRT initiation, each of these women was censored from her original, nonusing matched set. She then re-entered the analysis as a user and was matched to her own set of nonusers. Thus, her contribution to the analysis as a nonuser stops at the time that she initiated HRT. Her subsequent follow-up experience reflects her new status as a user. By not omitting subsequent users from the pool of nonusers for comparison, we avoided exaggerating any underlying differences between exposure groups. A selected nonuser also remained in the pool of potential matches for other HRT users. Random sampling resulted in 120 women serving as matched nonusers for more than one user. Analyses included these women in each matched set for which they were selected. In Cox models, variances for the estimated parameters were adjusted to account for data clustering from this source (21). Stata (21) and SAS (22) data management and statistical software were used. All statistical tests were two-sided.
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RESULTS |
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Among women with estrogen receptor-positive tumors, the unadjusted relative risks associated with use of HRT after diagnosis were 0.31 for recurrence (95% CI = 0.10 to 0.98), 0.16 for breast cancer mortality (95% CI = 0.02 to 1.19), and 0.30 for total mortality (95% CI = 0.11 to 0.82). The respective relative risks in estrogen receptor-negative women were 0.81 (95% CI = 0.30 to 2.17), 0.56 (95% CI = 0.12 to 2.53), and 0.59 (95% CI = 0.20 to 1.71).
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DISCUSSION |
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The potential for confounding is of crucial concern in observational studies of HRT use after breast cancer. The reasons women seek HRT or other correlates of use may favor improved prognosis apart from any effect of HRT itself. In this study, HRT users and nonusers are known to have differed in several ways. The low relative risks of recurrence and death associated with HRT persisted after adjustment for those factors in the analysis. An important strength of this study is that both HRT users and nonusers were free of diagnosed recurrence at reference (HRT initiation or the equivalent time since diagnosis), when survival comparisons began. Without this feature, nonusers of HRT with recurrent breast cancer would have been compared with users who, by definition, were free of recurrence at the start of follow-up, and relative risks would have been falsely low. Confounding by indication for the use of HRT may nonetheless exist in our data. Most of the users sought HRT after breast cancer to treat symptoms of menopause. Menopausal symptoms are associated with low circulating levels of endogenous estrogens (25). If estrogens contribute to breast cancer progression, then the users may have been at lower underlying risk than the nonusers because of lower underlying estrogen levels. To explore this issue, we analyzed our data restricted to the 122 users who reported starting HRT to treat menopausal symptoms and their matched nonusers. With this restriction, the relative risk of recurrence dropped only slightly (from 0.54 to 0.45), in the expected direction if this form of confounding were present. The relative risks of breast cancer mortality and total mortality were essentially unchanged. Although confounding by indication may be present, it is unlikely that its magnitude is large enough to conceal a true adverse effect of HRT on recurrence and mortality.
The users of HRT after breast cancer were more likely than the nonusers to have used HRT before diagnosis. HRT users may be screened more aggressively for breast cancer than nonusers. Screen-detected cancers are identified at an earlier stage and are more amenable to treatment than are symptom-detected cancers. In this study, users and nonusers of HRT were matched on stage at diagnosis, and similar proportions had that diagnosis prompted by a screening mammogram. Relative risks held after adjustment for prior use of HRT and its duration, as well as for mode of detection of the initial breast cancer.
Matching on a recurrence-free interval since diagnosis and adjusting for other factors do not assure complete comparability between users and nonusers of HRT. Women with a history of breast cancer who seek HRT are likely to be thoroughly evaluated for recurrence. Nonusers are unlikely to undergo a similar evaluation at the equivalent time before an arbitrary reference date. A nonuser may enter the study with an undiagnosed recurrence, leaving her at higher risk than her matched user for a period of time. Differential screening of this sort may account for some of the reduced risk seen in users, especially early in follow-up (26).
Published case series report low rates of recurrence and death in users of HRT after breast cancer (2732). Four (3336) of five (37) cohort studies identified found no increased risk of recurrent breast cancer among users of HRT after diagnosis compared with nonusers. However, these studies tended to be small, relatively brief, and limited in their ability to control confounding. Of the two cohort studies that clearly matched on disease-free interval before HRT initiation, one (37) included only 21 users of estradiol (not commonly used in the United States) and found a relative risk of recurrence of 1.7 (95% CI = 0.3 to 8.9). The other study (33) included 90 users of various estrogens and reported a relative risk of recurrence of 0.4 (95% CI = 0.2 to 0.9).
The use of HRT at or shortly before a diagnosis of breast cancer represents exposure in the presence of the developing tumor. Such use may, therefore, be relevant to the question of HRT use after diagnosis. Most studies of HRT use before diagnosis find better prognosis in users than in nonusers (38), although it is not clear why. Confounding may account for some of the difference. Another possibility is that HRT users develop breast tumors with favorable biologic features (3841).
Certain results of this study argue against a causal influence of HRT after breast cancer on recurrence and mortality. We found no evidence of improved disease-free or overall survival with greater cumulative use of HRT. The total duration of oral HRT use was relatively short on average. Also, we found that the relative risks associated with oral HRT and vaginal HRT were similar, within the limits of chance. While systemic absorption of estrogens delivered transvaginally can be substantial, serum estrogen levels following administration of conjugated estrogens by vaginal cream average only about one-fourth that of the same oral dose (42). Consensus is lacking on the degree to which vaginal HRT has systemic effects (43,44).
The risk of a second primary breast cancer is also of concern when considering the use of HRT after an initial diagnosis. Although this study was not designed to address that question, we collected data that may be relevant. Women who were diagnosed with contralateral breast cancer or who had a contralateral mastectomy before the reference date were excluded from this analysis. A new primary contralateral breast cancer was diagnosed after the reference date in 10 (6%) of 167 users and in 26 (4%) of 642 nonusers at risk. The rate of contralateral cancer was 12 per 1000 person-years in users (95% CI = 6 to 22) and eight per 1000 person-years in nonusers (95% CI = 6 to 12). The relative risk of contralateral breast cancer associated with ever use of HRT after the initial diagnosis was 1.42 (95% CI = 0.69 to 2.95) when unadjusted and 1.33 (95% CI = 0.66 to 2.68) when adjusted for bilateral oophorectomy, hysterectomy, positive lymph nodes at diagnosis, and the matching variables. Other adjustments had little effect. This result reinforces the need for caution in assessing the overall impact of HRT after breast cancer.
Additional evidence against a true benefit of the use of HRT is found in related breast cancer research. Tamoxifen has antiestrogenic effects on the breast and reduces risks of recurrence and death (5,6). Ovarian ablation by bilateral oophorectomy, pelvic irradiation, or drugs improves survival in young women with breast cancer (5,6). Postmenopausal patients with breast cancer who are obese experience worse survival than those who are lean (45), possibly because of higher estrogen levels in the obese women (46).
Our findings suggest that women who seek and use HRT after breast cancer do not have elevated risks of recurrence and death. Given the limitations of this study and uncertainty about noncausal explanations, these results should be interpreted with caution. Additional observational studies are needed, especially those that are able to address potential biases with strategies similar to those used in this study and that are large enough to examine in detail issues of dose, duration, and regimen. We believe it would also be desirable to conduct randomized trials of HRT in women in remission after breast cancer who have symptoms of estrogen loss.
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NOTES |
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Supported in part by Public Health Service grants N01CN67009 and 5T32CA09168 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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Manuscript received November 15, 2000; revised March 5, 2001; accepted March 13, 2001.
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