Affiliation of authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
Correspondence to: Christopher I. Li, M.D., M.P.H., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., North, MP 381, P.O. Box 19024, Seattle, WA 981091024 (e-mail: cili{at}fhcrc.org).
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ABSTRACT |
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INTRODUCTION |
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Tamoxifen is thought to inhibit estrogen-induced breast cancer growth by competitively binding the ER and acting as a selective ER modulator (SERM). We, therefore, hypothesized that tamoxifen may simultaneously inhibit the development of ER-positive contralateral breast tumors while promoting the development of ER-negative contralateral tumors. Half of ER-positive breast tumors do not respond to tamoxifen; most of those that do eventually develop resistance to tamoxifen (3). The mechanisms through which both de novo and acquired resistance to tamoxifen occur are largely unknown. However, it has been proposed that prolonged hormonal therapy with SERMs, such as tamoxifen, may promote the growth of ER-negative tumor cells, since they simultaneously inhibit ER-positive tumor cells (4). Furthermore, it has been shown that tamoxifen can stimulate the growth of ER-negative tumors in animal models (5). A similar effect in women would be of concern, especially since ER-negative breast cancer is associated with a relatively poor prognosis (68).
We used data from a population-based tumor registry to assess the relationship between tamoxifen use for primary invasive breast cancer and the risk of contralateral breast cancer with respect to both ER status and progesterone receptor (PR) status.
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SUBJECTS AND METHODS |
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We conducted a retrospective cohort study in which subjects were identified through the Cancer Surveillance System (CSS), a population-based cancer registry that serves 13 contiguous counties in western Washington State. The CSS has been in operation since 1974 and is a participant in the Surveillance, Epidemiology, and End Results (SEER) Program1 of the National Cancer Institute. It is estimated that nearly 99% of all incident cancer cases in the population under CSS surveillance are ascertained (2000 SEER data quality profile: results of quality analyses of SEER data by region. Presented at the October 2000 SEER Managers Meeting).
Since 1990, the CSS has systematically collected information on the ER and PR status of breast tumors. The CSS also collects information on age at diagnosis, race/ethnicity, tumor stage, histology, and the first course of treatment received. The information on hormone receptor status and treatment received is based on hospital medical record abstraction. Treatment information focuses on the initial treatment regimen only, i.e. treatment within, or documented as planned within, 4 months after diagnosis (9). The CSS categorizes types of treatment as follows: surgery, radiation therapy, chemotherapy, and hormonal therapy. Follow-up information on survival is ascertained annually by the CSS through a variety of data sources that include hospital cancer registries and discharge datasets, the Washington State Department of Motor Vehicles registration files, regional records of the Health Care Financing Administration, Washington State death records, Washington State voters' registration records, and the Social Security death index. Further operational details and methods used by SEER are provided elsewhere (10).
A total of 9654 women were diagnosed with a first primary invasive breast cancer during the period from January 1990 through December 1998 and were eligible for our study. Of these women, 673 (7.0%) were excluded because information was missing on whether or not they had received hormonal therapy. Thus, our cohort consisted of 8981 women who were followed for a total of 36 012 person-years. Of these women, 4654 (contributing 18 032 person-years) were classified as tamoxifen users and 4327 (contributing 17 980 person-years) were classified as nonusers of tamoxifen. The length of follow-up time for cohort members was measured as the time from 6 months after the diagnosis of their first breast cancer to the date of diagnosis of a contralateral breast cancer, the last follow-up, death, or the end of the study period (December 1999), whichever occurred first. Women were considered to have developed contralateral breast cancer if their second breast tumor was diagnosed more than 6 months after their first breast cancer was diagnosed, if it occurred in the opposite breast, and if it was invasive.
To identify women who were most likely to have received adjuvant tamoxifen, we defined tamoxifen users as those women who were diagnosed with their first primary breast cancer at 50 years of age or older, who were diagnosed with early-stage disease (i.e., localized or regional), and who had received adjuvant hormonal therapy but not chemotherapy. These parameters are consistent with the definition of tamoxifen users applied in previous work using SEER data (11). We defined nonusers of tamoxifen as those women who were diagnosed with their first primary breast cancer at 50 years of age or older and who were diagnosed with early-stage disease (i.e., localized or regional) but who were not treated with either adjuvant hormonal therapy or chemotherapy. Women who received chemotherapy for their first primary breast cancer were excluded from our study because such patients often also receive corticosteroids, which SEER classifies as a form of hormonal therapy.
Validating the Operational Definition of Tamoxifen Use
The electronic files of the CSS do not list the specific agents used to treat patients. However, this information is recorded routinely in the abstracts from which the electronic files are derived. We, therefore, confirmed that the women whom we defined as tamoxifen users and nonusers were correctly classified by reviewing the CSS abstracts of all 189 women who were diagnosed with contralateral breast cancer, as well as those of 200 randomly selected women who did not develop contralateral breast cancer, to identify those women for whom tamoxifen use was documented. Half of the randomly selected women who did not develop contralateral breast cancer were operationally defined as tamoxifen users; the other half were defined as tamoxifen nonusers.
Of the 89 women diagnosed with contralateral breast cancer whom we classified as having received tamoxifen as a first course of treatment for their initial breast cancer, 82 (92%) actually received tamoxifen, six (7%) received hormonal therapy that was not specified (but could have been tamoxifen), and one (1%) received no adjuvant hormonal therapy (this woman's contralateral tumor was ER positive). Of the 100 women who did not develop contralateral breast cancer whom we classified as tamoxifen users, 93 actually received tamoxifen and seven received hormonal therapy that was not specified. Of the 100 women diagnosed with contralateral breast cancer whom we classified as nonusers of tamoxifen, 97 received no adjuvant hormonal therapy and three had no available information regarding the use of hormonal treatment. Of the 100 women who did not develop contralateral breast cancer and were believed not to have used tamoxifen, 94 received no hormonal therapy, one received hormonal therapy that was not specified, and five lacked information regarding the use of hormonal treatment. Therefore, given the criteria that we used to define tamoxifen use and nonuse, we estimate that we correctly classified at least 94% (366 of 389) of the study subjects with respect to their use of tamoxifen.
Statistical Methods
Associations between the use of adjuvant tamoxifen therapy and the development of contralateral breast cancer were estimated with the use of the Cox proportional hazards model (12). We used SPSS 9.0 for Windows (SPSS Inc., Chicago, IL) and STATA 6.0 for Windows (STATA Corporation, College Station, TX) statistical software programs to compute hazard ratios (HRs) and 95% confidence intervals (CIs) and to evaluate the effects of confounding and modifying factors. All statistical tests were two-sided. All analyses were adjusted for the patient's age and year of diagnosis of the first breast cancer. We performed a systematic evaluation for confounding and effect modification by other covariates, including race/ethnicity, tumor stage, histologic type, tumor size, number of positive lymph nodes, and whether treatment included radiation therapy. Of these covariates, only tumor stage appreciably altered (by >10%) the HRs associated with tamoxifen use; thus, only tumor stage was added to the final models as a confounding variable.
We also assessed the associations between tamoxifen treatment and contralateral breast tumors by the hormone receptor profiles of both the first breast tumors and the contralateral breast tumors. Among the 4654 women classified as tamoxifen users, 248 (5.3%) had no information of the ER status and 265 (5.7%) had no information on the PR status of their first primary breast cancers. Among the 4327 women classified as nonusers of tamoxifen, 832 (19.2%) had no information on the ER status and 861 (19.9%) had no information on the PR status of their first primary breast cancers. Of the 89 tamoxifen users who developed contralateral breast cancer, 12 (13.5%) had no information on both the ER and the PR status of their contralateral tumor. Among the 100 nonusers of tamoxifen who developed contralateral breast cancer, 17 (17.0%) lacked information on both ER and PR status, and one lacked information on PR status only. We reviewed the CSS abstracts of the 160 women who developed contralateral breast cancer with a known ER status to determine whether ligand-binding or immunohistochemical (IHC) assays were used to assess their tumor's hormone receptor status. Of the 83 nonusers of tamoxifen who developed contralateral breast cancer, 68 (81.9%) had the ER status of their tumor assessed with the use of an IHC assay, 10 (12.0%) had their tumors assessed with the use of a ligand-binding assay, and five (6.0%) lacked information on the type of assay used to assess the ER status of the tumors. Of the 77 tamoxifen users who developed contralateral breast cancer, 64 (83.1%) had the ER status of their tumor assessed with the use of an IHC assay, seven (9.1%) had their tumors assessed with the use of a ligand-binding assay, and six (7.8%) lacked information on the type of assay used to assess the ER status of their tumor. The sensitivity and specificity of the IHC assay are superior to those of the ligand-binding assay. Therefore, to reduce misclassification bias, we restricted our analyses of the risks of contralateral breast cancers with specific ER and/or PR profiles by tamoxifen treatment to those women whose tumors had been analyzed for hormone receptor status with the use of an IHC assay.
To test for heterogeneity of the association of tamoxifen with ER-positive versus ER-negative contralateral tumors, we first fit the models treating each of these two different failure types separately and recorded the log partial likelihood for each of these models. We then fit a model that treated both of them as a single failure type, recorded the log likelihood of this model, and then computed a test statistic with a chi-squared distribution with 1 df by taking twice the difference in the log-likelihoods to determine an exact P value for this test.
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RESULTS |
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DISCUSSION |
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Other studies (2,16) have reported that women who take tamoxifen for 5 years have a 47% reduction in the risk of developing contralateral breast cancer. In contrast, in our study, we found that the tamoxifen users had a 10% overall reduction in the risk of developing contralateral breast cancer and that tamoxifen users whose first tumor was ER positive had a 20% reduction in risk. It is difficult to directly compare the results of these randomized controlled trials with those of our study because we do not know the duration of tamoxifen use for the women in our study. However, the previous studies also reported that women who took tamoxifen for 1 year or 2 years had only 13% and 26% reductions in risk of contralateral breast cancer, respectively. Given that a certain proportion of the tamoxifen users in our study probably took tamoxifen for less than 3.9 years (the mean follow-up time for this group), the magnitude of the reductions in risk that we observed may, in fact, be consistent with that observed in the randomized controlled trials.
One of the potential limitations of this study was our use of the hormone treatment classification recorded by SEER as a surrogate to identify women who took adjuvant tamoxifen as a first course of treatment for their first primary invasive breast carcinoma. A previous study (17) found that the hormonal therapy variable recorded in SEER has a 99% specificity and a 59% sensitivity as a surrogate in identifying tamoxifen use when the analysis was restricted to women who were 50 years of age or older, had early-stage disease, and had not received chemotherapy. However, it has been estimated (18) that, if these same restrictions are applied to the CSS registry, 90% of the women coded as hormone users will be classified correctly as tamoxifen users, and 90% of the women coded as nonusers of hormones will be classified correctly as nonusers of tamoxifen. We confirmed these estimates in our own validation study of selected CSS records and found that approximately 94% of our subjects had been classified correctly with respect to tamoxifen use. However, we could not reliably identify women who took tamoxifen beyond the first course of therapy, which prevented us from evaluating how the duration of tamoxifen therapy affects the risk of contralateral breast cancer. In addition, we were unable to investigate the effect that tamoxifen in combination with chemotherapy has on the risk of contralateral breast tumors because women who received chemotherapy for their first breast cancer were excluded.
Another potential limitation of this study arises from the possible misclassification of tumors by hormone receptor status. During the early 1990s, some laboratories in western Washington State used ligand-binding assays to determine the ER status of breast tumors. Because tamoxifen can bind the ER, such ligand-binding assays often lead to false-negative results when they are used to determine the ER status of breast tumors of women receiving tamoxifen therapy (19). The IHC assay, which is more sensitive than ligand-binding assays and not affected by a patient's tamoxifen use (2022), has been used in recent years to determine the hormone receptor status of tumors (23). We predicted and demonstrated that the misclassification of tumors by hormone receptor status would bias our results toward an increased association between tamoxifen use and ER-negative contralateral tumors. We eliminated this potential source of bias by restricting our analyses that stratify the risk of contralateral breast cancer by hormone receptor status to women for whom an IHC assay was used to determine the hormone receptor status of their contralateral tumors.
An understanding of the molecular actions of tamoxifen and its effects on the ER may provide a mechanistic explanation for our finding of an association between tamoxifen use and the incidence of ER-negative contralateral breast cancer. ER expression appears to be heterogeneous within most breast tumors (24), and prolonged tamoxifen therapy can lead to the selective emergence of recurrent tumors that are ER negative. Specifically, it has been shown that recurrent tumors in tamoxifen users express less ER than the originally excised tumor and recurrent tumors in nonusers of tamoxifen express ER at a level comparable to that of the originally excised tumor (4). One explanation for this observation is that tamoxifen may promote the preferential growth of residual ER-negative cells after surgery. Because women who develop breast cancer have an increased risk of developing a second cancer, our results may suggest that tamoxifen selectively promotes the growth of ER-negative cancer cells in the contralateral breast, since it inhibits ER-positive cancer cells that are not tamoxifen resistant.
Our findings are of potential clinical and public health importance, given the poorer prognosisan 8%35% lower 5-year survival depending on the assay used to measure ER statusthat women with ER-negative and ER-negative/PR-negative breast tumors have compared with women with ER-positive tumors (68). However, further studies are required to confirm these findings and to evaluate the survival of women who develop contralateral breast cancer according to their prior use of tamoxifen and the ER status of their tumors. It will also be important to explore the influence of other SERMs, such as raloxifene, on the incidence of contralateral breast tumors.
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NOTES |
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Supported by Life Possibilities and by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Public Health Service contract N01CN67009 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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Manuscript received November 22, 2001; revised April 19, 2001; accepted May 8, 2001.
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