Affiliations of authors: E. Tan-Chiu, Cancer Research Network, Plantation, FL; J. Wang, J. P. Costantino, C. Butch (Biostatistical Center), S. Paik (Division of Pathology), D. L. Wickerham, B. Fisher, N. Wolmark (Operations Center), National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA.
Correspondence to: Elizabeth Tan-Chiu, M.D., Cancer Research Network, 350 84th Ave., Suite 305, Plantation, FL 33324 (e-mail: tan-chiu{at}att.net).
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ABSTRACT |
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INTRODUCTION |
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In 1998, the National Surgical Adjuvant Breast and Bowel Project (NSABP) published results of its Breast Cancer Prevention Trial (BCPT; otherwise known as P-1), in which women at high risk for breast cancer were randomly assigned to receive tamoxifen or placebo (4). The BCPT demonstrated a statistically significant reduction in the incidence of invasive and noninvasive breast cancer by almost 50% in the tamoxifen-treated group compared with the placebo-treated group. Because the effects of tamoxifen on invasive and noninvasive breast cancers were observed early in the course of the BCPT, some investigators criticized the findings of the BCPT by positing that preclinical, invasive breast cancers were already existent and that tamoxifen had served as a treatment rather than a preventative agent. In the study described here, we have attempted to address this issue by examining the data on benign breast lesions found in the women who participated in the BCPT.
Several studies have reported that tamoxifen decreases the size of benign breast lesions. Cupceancu (5) reported that 48 women with benign breast disease who were treated with tamoxifen and the progestational agent, lynestrenol, had substantial reductions in the size of adenomas, fibroadenomas, cysts, and dysplasic lesions. Hurst et al. (6) reported on the spontaneous regression of a breast cyst in a premenopausal woman who was treated with tamoxifen for contralateral breast cancer. Because estrogen receptors are expressed in benign breast lesions (7,8), we hypothesized that women who took tamoxifen, a selective estrogen receptor modulator, would have a reduced incidence of diagnosed benign breast disease and a reduced number of breast biopsies compared with women who took placebo. In this study, we have concentrated on the most common diagnoses of benign breast disease that clinicians encounter in interpreting a pathology report.
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SUBJECTS AND METHODS |
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Women were eligible for participation in the BCPT if they were 60 years of age or older or if they were between the ages of 35 and 59 years and had either a 5-year predicted risk for breast cancer of at least 1.66% or a history of lobular carcinoma in situ (4). Accrual to the BCPT was from June 1992 through September 1997. Participants provided written informed consent before they were registered in the BCPT; the clinical trial was in compliance with federal and institutional guidelines. A total of 13 388 women were randomly assigned to receive tamoxifen or placebo in the BCPT. Among those women, 13 203 women who were at high risk for breast cancer and whose follow-up had occurred before the trial was unblinded were included in this analysis.
Diagnosis and Outcome Measures
The mean time on study for these high-risk women was 49.3 months. During the course of follow-up in the study, the participants received a clinical breast examination twice a year and a bilateral mammogram once a year. There were no differences between the two treatment groups in the number of clinical breast examinations or mammograms that were performed. On the basis of the average time of follow-up for the study population, we predicted that the women in our study should have received an average of eight clinical breast examinations and four mammograms. The actual average number of clinical breast examinations and mammograms that were performed was 7.2 and 3.6, respectively, for women in the placebo group and 7.1 and 3.7, respectively, for women in the tamoxifen group. Findings from all examinations and evaluations, as well as supporting documents (i.e., pathology reports, breast imaging reports, and progress notes), were submitted to the NSABP Biostatistical Center. Pathology reports that listed a diagnosis of benign breast disease that was rendered by a local pathologist were prospectively collected in the BCPT. All reports of benign breast biopsies were reviewed centrally by a medical oncologist along with a pathologist who served as a consultant. The following benign histologic breast tissue diagnoses were identified and evaluated as endpoints for this study: 1) cyst (gross or microscopic), 2) adenosis (sclerosing or nonsclerosing), 3) fibrosis, 4) duct ectasia, 5) hyperplasia (typical ductal or typical lobular versus atypical ductal or atypical lobular), 6) metaplasia (apocrine or squamous), 7) fibrocystic disease, 8) fibroadenoma (with or without complex features), and 9) papilloma. In addition to the biopsy reports, mammographic and ultrasound reports that confirmed the presence of a cyst were included in the analysis.
Statistical Analysis
Average annual event rates for the study endpoints were calculated for each treatment group by dividing the number of observed events by the number of observed event-specific person-years of follow-up. P values (two-sided) for tests of differences between the treatment groups for the rates of each of the endpoints analyzed were determined by the exact method, conditional on the total number of events and person-years at risk, assuming that the events came from a Poisson distribution. Average annual event rates in the two treatment groups were also compared by using RRs and 95% confidence intervals (CIs), in which the rate in the tamoxifen group was contrasted to the rate in the placebo group. CIs for RRs were determined by assuming that the events followed a Poisson distribution. CIs for RRs were conditional on the total number of events and person-years at risk. Cumulative incidence of benign breast disease through 69 months of follow-up was estimated. All analyses were based on the assigned treatment at the time of randomization, regardless of treatment status at the time of analysis. All randomly assigned participants with follow-up were included in this analysis. The analysis was restricted to those endpoints that were diagnosed before the results of the BCPT were announced, when the therapies were still being evaluated in a double-blinded fashion.
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RESULTS |
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A total of 3960 occurrences of benign breast disease were identified in 1764 of the women (1014 women in the placebo group and 750 women in the tamoxifen group); of these, 2372 occurred in women receiving placebo and 1588 in women receiving tamoxifen. The number of events, the rates of disease, and the RR for each type of benign breast disease are shown in Table 1 for each treatment group. Tamoxifen therapy resulted in a statistically significant reduction in the annual rate of adenosis, cyst, duct ectasia, fibrocystic disease, hyperplasia, and metaplasia. The risk reduction was 41% for adenosis (RR = 0.59, 95% CI = 0.47 to 0.73), 34% for cyst (RR = 0.66, 95% CI = 0.58 to 0.75), 28% for duct ectasia (RR = 0.72, 95% CI = 0.53 to 0.97), 33% for fibrocystic disease (RR = 0.67, 95% CI = 0.58 to 0.77), 40% for hyperplasia (RR = 0.60, 95% CI = 0.50 to 0.71), and 49% for metaplasia (RR = 0.51, 95% CI = 0.41 to 0.62). Tamoxifen therapy also reduced the rates of fibroadenoma (RR = 0.77, 95% CI = 0.56 to 1.04) and fibrosis (RR = 0.86, 95% CI = 0.72 to 1.03), but those reductions were not statistically significant at the P = .05 level. Overall, tamoxifen decreased the annual rate of benign breast disease by 28% (RR = 0.72, 95% CI = 0.65 to 0.79).
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We also examined the effect of tamoxifen therapy on the number of biopsies BCPT participants underwent while they were being followed, excluding those biopsies that occurred at or subsequent to the diagnosis of in situ or invasive breast cancer. There were 1830 women who underwent a breast biopsy for benign breast disease while in the trial; the remaining 11 373 women did not. The distribution of women by number of biopsies and by treatment group is shown in Table 4. Women in the placebo group underwent statistically significantly more biopsies than did women in the tamoxifen group (P<.001). There were 1469 biopsies performed in 1019 women in the placebo arm, and 1048 biopsies were performed in 819 women in the tamoxifen arm. There were 29% fewer biopsies among the tamoxifen-treated group than in the placebo group (1048 versus 1469), and 19% fewer women in the tamoxifen group than in the placebo group underwent a biopsy (819 versus 1019). The reduction in the number of biopsies occurred predominantly among women who were 49 years of age or younger at the time of entry into the study (Table 5
). Among that age group, the rate of biopsy per 1000 person-years of follow-up was 52.3 for women who received tamoxifen and 89.0 for women who received placebo (RR = 0.59, 95% CI = 0.53 to 0.65). There was no statistically significant difference between the treatment groups in the rate of biopsy for women who were 50 years of age or older (RR = 0.94, 95% CI = 0.83 to 1.07).
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DISCUSSION |
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Benign breast lesions, like invasive breast cancer, express hormone receptors. Roger et al. (17) studied the two estrogen receptors ER- and ER-
in benign breast disease. They noted that the ratio between the two was high in normal breast tissue and decreased significantly in proliferative breast lesions (17). ER-
functions as a potent and dominant inhibitor of ER-
transcriptional activity and decreases the mitogenic sensitivity of a cell to estradiol (1820). The effect of tamoxifen on the ER-
and ER-
receptors of benign breast lesions remains a field of active investigation (21). Tamoxifen may act as both agonist and antagonist through ER-
or ER-
. Other agents that co-activate or co-repress the estrogen receptors are likely to influence the proliferation rate of the cell in addition to modifying estrogen-mediated proliferation of benign breast disease.
In our study, the effect of tamoxifen on benign breast disease was seen predominantly in women younger than 50 years, although the effect of the drug was also evident in women who were 50 years old and older (see Fig. 1). This difference is interesting, because it is possible that tamoxifen was able to affect more benign pathologic entities in younger women than in older women because of the higher incidence of benign breast disease in women younger than 50 years. The number of biopsies among women 49 years of age and younger was almost twofold higher than that among women 50 years of age and older. One possible explanation for this finding is that younger women tend to have denser breasts upon imaging, making suspicious masses or microcalcification harder to biopsy with as much accuracy. Another explanation for younger women having more biopsies is that the levels of hormonal fluctuation, which affect breast tissue proliferation rates, are higher in younger women than in older women, making the magnitude of estrogen blockage with tamoxifen treatment appear more prominent in younger women. Findings from NSABP Protocol B-14, a trial on the use of tamoxifen in women with lymph node-negative, hormone receptor-positive breast cancer, also showed a greater magnitude of benefit from tamoxifen in terms of disease-free survival and overall survival in premenopausal women than in postmenopausal women (22,23).
We found that tamoxifen decreased the risk of biopsies among women 49 years and younger by 41% but did not statistically significantly change the total number of biopsies among women 50 years and older. The occurrence of fibrocystic disease and fibroadenoma, conditions that frequently result in biopsies, is highest among women younger than 50 years and then drops off in older women (24). It is not surprising that tamoxifen therapy was associated with a decrease in the biopsy rate among women 49 years and younger because the breast parenchyma in younger women is under the strong influence of hormone-modulated proliferation and resolution. When there is a reduction in estrogen-induced stimulation of normal breast tissue, a reduction in breast symptomatology is likely to be associated with fewer complaints of pain and swelling, which may lead to fewer breast biopsies. As a woman becomes postmenopausal, the breast is subjected to less hormone cycling and, therefore, less symptomatology and fewer biopsies, independent of the effect of tamoxifen on benign breast disease.
We also found that both the number of women who required biopsies and the total number of biopsies required over the study period were lower for the tamoxifen group than for the placebo group. These reductions were most notable among women who required two or more biopsies (Table 4). The psychosocial and economic implications of decreasing the biopsy rate in women at high risk for breast cancer are not trivial. In an era in which optimum care is countered by the reality of shrinking resources, a decrease in biopsy rate is also likely to translate into decreased imaging and test requirements, to say nothing of lower levels of anxiety for women who are at high risk for breast cancer.
One of the limitations of our study is that we did not use a central pathology review of individual benign breast biopsies that were reported because there was no provision for the collection of tissue blocks of noninvasive tumors in the P-1 trial. However, acceptance of the diagnoses rendered by the submitting pathologists from multiple institutions reflects clinical practice in the real world. Moreover, most of the biopsy samples were small, and the biopsies were performed on the basis of mammographic abnormalities. We realize that benign breast lesions are usually the result of a combination of one or more of the studied histologic diagnoses. We did not provide RR estimates for the different combinations of these histologies (e.g., combination of cyst with adenosis, hyperplasia with fibroadenoma, or a third combination) because the number of possible combinations was too large to enumerate and such estimates were also likely to demonstrate a tamoxifen effect. The fact that tamoxifen therapy had an effect on benign breast disease, regardless of individual histology, supports the theory that tamoxifen affects tumorigenesis at an even earlier stage than previously thought.
Our results raise several additional questions that must be answered in future studies. First, what effects might other selective estrogen receptor modulators or aromatase inhibitors have on the pathology of benign breast disease? Because the effect of tamoxifen on benign breast disease was seen predominantly in women younger than 50 years, we think that it is unlikely that any of the aromatase inhibitors, which are currently being studied only in postmenopausal women, will achieve the same success that tamoxifen has in the field of breast cancer prevention. Second, what is the relationship between molecular markers of benign breast disease and the risk of invasive breast cancer? Third, can a diagnosis of benign breast disease serve as an intermediate marker of treatment efficacy in future breast cancer prevention trials? One way to answer these questions may be to establish a registry of women who have had a breast biopsy that was diagnosed as benign and then use that registry to determine whether findings from the biopsy are associated with any subsequent development of breast cancer.
Although we have now shown that tamoxifen therapy affects benign breast disease as well as invasive breast cancer, we do not advocate the indiscriminate use of tamoxifen for the treatment of benign breast disease. Tamoxifen use is associated with adverse events such as deep vein thrombosis, pulmonary embolism, stroke, and endometrial cancer (4). Increases in these side effects were evident only among the postmenopausal women in the BCPT (4).
In summary, we found that tamoxifen decreased the risk of benign breast disease, particularly hyperplasia and metaplasia, in both premenopausal and postmenopausal women and reduced the risk of biopsies required among premenopausal women by 41%. Thus, in the BCPT, tamoxifen not only reduced the risk of invasive and noninvasive breast cancer but also reduced the risk of benign breast disease and the morbidity and costs of repeated diagnosis and treatment that are associated with it.
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NOTES |
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Supported by Public Health Service grants U10CA37377 and U10CA69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank Barbara C. Good, Ph.D., for editorial assistance, Lynne Anderson for data management, and Nova Smith for preparation of the manuscript.
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Manuscript received May 10, 2002; revised November 26, 2002; accepted January 6, 2003.
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