Trudy L. Bush, PhD, MHS,† Maura Whiteman, andJodi A. Flaws, PhD.
From the Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland. This work was supported by grantsfrom the Department of Defense (# DAMD 17-00-0321 to Trudy Bush and Jodi Flaws) and Wyeth-Ayerst Laboratories (Trudy Bush). We thank Karen Mittleman, Laura Hirshfield, and Lynn Van Ruiten for their assistance.
† Dr. Bush is deceased (March 14, 2001).
Address reprint requests to:Jodi A. Flaws, PhD, Department of Epidemiology and Preventive Medicine, University of Maryland Medical School, Howard Hall, Room 133B, 660 West Redwood St., Baltimore, MD 21201-1596; E-mail: jflaws@epi.umaryland.edu.
Summary
OBJECTIVE: To assess whether recent epidemiologic evidence supports an association between use of estrogen replacement therapy or hormone replacement therapy and risk of breast cancer.
DATA SOURCES: The keywords “estrogen,” “estrogen replacement therapy,” or “hormone replacement therapy,” and “breast cancer” or “breast neoplasm,” were used to search for articles published from 1975-2000 in MEDLINE and Dialogweb. Only articles published in peer-reviewed journals and containing original data were included in this review.
METHODS: Unadjusted or age-adjusted risk estimates for breast cancer among ever users of estrogen therapy compared with never users were abstracted from published articles or calculated using the data provided in the published reports.
TABULATION, INTEGRATION, AND RESULTS: We found little consistency among studies that estimated the risk of breast cancer in hormone users compared with nonusers and in studies assessing the risk by duration of use. However, there was consistently a lower risk of death from breast cancer in hormone users compared with nonusers.
CONCLUSION: The evidence did not support the hypotheses that estrogen use increases the risk of breast cancer and that combined hormone therapy increases the risk more than estrogen only. Additional observational studies are unlikely to alter this conclusion. Although a small increase in breast cancer risk with hormone therapy or an increased risk with long duration of use (15 years or more) cannot be ruled out, the likelihood of this must be small, given the large number of studies conducted to date. (Obstet Gynecol 2001;98:498-508.
© 2001 by the American College of Obstetricians and Gynecologists.)
Introduction
Over 25 years ago, epidemiologic studies identified and subsequently confirmed that unopposed estrogen replacement therapy was associated with increased risk of endometrial carcinoma.[1-20] Despite the absence of data from clinical trials, this association has been acknowledged as causal by the medical community, in large part because it is consistent among studies, relatively strong, and more apparent at increased doses and longer durations of use. The association of menopausal estrogen therapy with breast cancer risk, however, remains controversial, despite the publication of over 50 epidemiologic studies and at least six meta-analyses during the past 25 years.[21-81]
This topic is of significant public health concern, given the fear of breast cancer and the relatively prevalent use of estrogen therapy. Currently, the prevailing opinion appears to be that estrogen replacement therapy (ERT, unopposed estrogen therapy) modestly increases the risk of breast cancer, and hormone replacement therapy (HRT, combined estrogen and progestin therapy) increases the risk more than ERT.[50,63,64] Recent publications that have garnered considerable media attention appear to support this opinion.[63,64]
A pooled reanalysis of over 90% of the world’s data on breast cancer and hormone replacement therapy published in 1997[80] likely had considerable influence on the formation of that opinion. Although some investigators reason that the summation of observational data, either by pooled reanalysis or traditional meta-analysis, produces precise and definitive answers, others have raised serious concerns about the integrity and validity of these summary risk estimates.[82,83] Furthermore, meta-analysis can distance the reader from the original data (Smith GD, Egger M. Meta-analyses of observational data should be done with due care. BMJ 1999;318:56 [letter]), thus potentially obscuring the overall pattern of results from the entire body of research.
Another appropriate approach is to assess qualitatively whether the body of observational epidemiologic evidence supports a causal association between use of hormone therapy (defined here as either ERT or HRT) and risk of breast cancer. If each study on hormone therapy and breast cancer samples the “ultimate” truth about the association, then the risk estimates for the association should have a distribution, with most estimates clustered around the “ultimate” truth and progressively fewer estimates at the extremes of the range. Among the criteria for inferring a causal association from observational studies are a consistency in the findings, a strong association, and biologic plausibility.[84] In this review, we examined the distribution of risk estimates obtained from studies of the association between hormone therapy and breast cancer, focusing on the overall pattern of results, the consistency of the results, and the strength of the associations. Specifically, we focused on the following key questions: (1) What is the risk of being diagnosed with breast cancer among postmenopausal women who ever received any form of ERT or HRT compared with those who never received such therapy? (2) What is the risk of death from disease among patients with breast cancer who have used ERT or HRT compared with patients who never used that therapy?
Methods
We identified a list of publications of observational epidemiologic studies that included original data on ERT and breast cancer risk, HRT and breast cancer risk, and hormone therapy and breast cancer mortality.
Data sources
The keywords “estrogen,” “estrogen replacement therapy” or “hormone replacement therapy,” and “breast cancer” or “breast neoplasm,” were used to search for articles published from 1975-2000 in MEDLINE and Dialogweb. Each coauthor performed searches using several combination terms, such as “estrogen plus breast cancer and/or breast neoplasm,” “estrogen replacement therapy plus breast cancer and/or breast neoplasm,” “hormone replacement therapy plus breast cancer and/or breast neoplasm.” Additionally, reference lists from identified original articles, previous reviews, and meta-analyses were searched by each coauthor to enhance completeness. We then compared our searches to obtain a complete list of articles on ERT or HRT and breast cancer risk and mortality rates. All articles were included in this list if they contained original data and were published in peer-reviewed journals. There were no discrepancies between the coauthors regarding which papers should be included because we agreed to include all published papers with original data, regardless of study characteristics, reliability, or quality. We did not assess the reliability or quality of each study because the purpose of this review is to present the results from all published studies on the association between ERT or HRT and breast cancer risk. Thus, we did not make subjective judgments about the reliability or quality of individual studies and instead included all studies. The major characteristics of each included study are listed in Table 1.
Table 1. Design and Population of Published Studies on the Association Between Estrogen or Hormone Replacement Therapy and Breast Cancer Risk
Unadjusted or age-adjusted risk estimates for breast cancer incidence and mortality rate among ever users of estrogen compared with never users was abstracted from the published article or calculated by the authors from information provided in the publication. We elected to present unadjusted or age-adjusted risk estimates so that reasonable comparisons could be made across the studies that adjusted for a variety of different factors. For case-control studies, the risk estimate was the odds ratio (OR), and for cohort studies, the estimate was the relative risk (RR). These risk estimates and their 95% confidence intervals (CI) were plotted in chronological order on a logarithmic scale.
Additionally, all cohort studies were reviewed to assess whether the investigators had presented risk estimates for breast cancer by duration of hormone use. If so, the published results were extracted or calculated from information available in the publication and are presented graphically.
In situations where there are multiple publications from one study population, only one risk estimate is included (eg, there are three publications from the Iowa Women’s Health Study). This estimate was from the most recent publication from that population unless that article included only subgroup analyses.[85,86] In that case, the risk estimate from the most recent publication that assessed information on the entire population was used. Other than this exclusion criterion, all other publications were included in this review.
Results
We identified 45 publications that assessed the association between ERT and breast cancer risk (Figure 1).[21-65] Twenty studies assessed the association between HRT and breast cancer risk (Figure 2), [31,40,44,45,47,51,53-57,60,61,63-69] five assessed the risk of hormone therapy and death from breast cancer (Figure 3),[69,71-74] and six assessed the risk of hormone therapy and breast cancer survival (Figure 3),[70,75,88-91] The data presented in Figures 1 and 2 show an overall lack of consistency and only modest increases or decreases in risk of breast cancer for estrogen users. Of the studies in Figure 1, 20% reported risk estimates less than 0.9, [23,31,32,35,37,56,58,62,65] 33% reported risk estimates greater than 1.1, [21,22,25,27,29,30,39,42,44,46,49,50,52,57,60] and 47% reported risk estimates between 0.9 and 1.1 [24,26,28,33,34,36,38,40,41,43,45,47,48,51,53-55,59,61,63,64] None of those studies reported risk estimates greater than 2.0.
Figure 1. Risk estimates for incident breast cancer: ever users compared with never users of estrogen replacement therapy (unopposed estrogen). Bush. Estrogen and Breast Cancer. Obstet Gynecol 2001.
The studies on HRT use reported in Figure 2 also show inconsistent results. Only four of these observational studies reported statistically significant findings: two showed a significant higher risk of breast cancer with HRT use,[60,61] and two found a significant protective effect of HRT on breast cancer risk.[31,68] Additionally, one small clinical trial of HRT use found no increase in breast cancer among women taking combined therapy for up to 22 years.[87]
Figure 2. Risk estimates for incident breast cancer: ever users compared with never users of hormone replacement therapy (estrogen plus progestin). Bush. Estrogen and Breast Cancer. Obstet Gynecol 2001.
Figure 3 presents the data from studies of breast cancer mortality rates (top half of figure) and survival after diagnosis of breast cancer (bottom half of figure). Although there is a lack of consistency regarding the risk of breast cancer with hormone therapy, there is consistency regarding hormone use and both mortality rates from breast cancer[69,71-74] and breast cancer survival.[70,75,88-91] The risk estimates for death from breast cancer in hormone users compared with nonusers in all five studies are less than 1.0, and several of those estimates are statistically significant.[69,73] Similarly, all of the risk estimates for breast cancer survival in hormone users versus nonusers are less than 1.0; two are statistically significant.[70,91]
Figure 3. Risk estimates for death from breast cancer and breast cancer survival: ever users compared with never users of hormone replacement therapy (estrogen plus progestin). Bush. Estrogen and Breast Cancer. Obstet Gynecol 2001.
Figure 4 presents the risk estimates for breast cancer by duration of hormone use for all cohort studies which evaluated the risk by duration.[42,43,50,59,61,62,92,93] Most studies included in Figure 4 presented estimates for any hormone use or all hormone use, while three[43,61,92] provided separate estimates for estrogen only (ERT) and estrogen combined with progestin (HRT). Each study reported risk estimates based on different durations of use, making direct comparisons for specific durations between studies somewhat difficult. However, we can generally assess the consistency of risk estimates between studies for those women using hormone therapy for the longest durations, which ranged from over 5 years[59,93] to over 20 years.[92] Again, there is a lack of consistency in the results between studies. Women using hormone therapy for the longest durations compared with nonusers had: 1) a significantly elevated risk of breast cancer in three studies (in one for ERT[43], one for any hormone therapy,[50] and one for HRT61), 2) a nonsignificantly elevated risk of breast cancer in five studies (three for any hormone therapy,[42,92,93] one for HRT,[43] and one for ERT[61]), and 3) no increase in risk in two studies for any hormone therapy.[59,62]
Figure 4. Relative risk estimates (95% CI) for incident breast cancer: ever users compared with never users of hormone replacement therapy by duration of use reported in cohort studies. ERT = unopposed estrogen replacement therapy. HRT = estrogen plus progestin. Bush. Estrogen and Breast Cancer. Obstet Gynecol 2001.
There is also a lack of consistency in the results for a duration effect within studies. For example, in three studies[43,50,61] and in Schairer et al’s[92] ERT cohort, there was a generally consistent increasing risk with longer durations of use. However, three other studies[59,62,93] found no evidence of an increase in risk with longer durations of use, while Mills et al[42] and Schairer et al for HRT92 found inconsistent results by duration of use.
Conclusion
Over 25 years ago, epidemiologic studies showed that ERT was associated with an increased risk of endometrial cancer, and that association was consistent among studies, relatively strong, and increased with increasing duration of use. In contrast, the relatively large body of literature on the association between estrogen and breast cancer is inconsistent, and the distribution of risk estimates is what would be expected if there were no association. That is, most of the estimates of risk converge around 1.0, and the range of the estimates is limited. Therefore, we conclude that the body of literature does not support an association between ERT or HRT use and breast cancer. In light of the overall pattern seen during the past 25 years, additional observational studies are unlikely to alter this conclusion. Conversely, consistent data suggest that estrogen users are less likely to die from breast cancer than nonusers, a finding that has received relatively little attention.
An association between estrogen and risk of breast cancer is thought to be biologically plausible for several reasons, including the finding that many risk factors for breast cancer (eg, early age at menarche, late age at first birth, nulliparity, late age at menopause) are thought to be related to estrogen; the discovery that removal of the ovaries can induce tumor regression in breast cancer patients[94]; and the finding that early oophorectomy protects against breast cancer.[95] However, risk factors such as those are not direct measures of estrogen but reflect ovarian functioning. The ovary produces many compounds in addition to estrogens, including progesterone, inhibin A, inhibin B, dehydroepiandrosterone (DHEA), and androgens. In light of the lack of direct evidence supporting an estrogen-breast cancer association and that these risk factors reflect ovarian functioning, an ovarian product other than estrogen might be associated with breast cancer pathogenesis.
The observation that breast cancer can be treated successfully with anti-estrogens (tamoxifen)[96] has also been used as an argument to support a biologically plausible association between hormone therapy and breast cancer. Tamoxifen was designated as an antiestrogen because it was shown to bind to the estrogen receptor and therefore was thought to block the action of estrogen in the breast. We now know that tamoxifen not only binds to the estrogen receptor, but also configures the receptor in a way similar (but not identical) to that of estrogen. Thus, it could be argued that tamoxifen is not an anti-estrogen but a partial estrogen that turns on some (but not all) of the genes that estrogen does, and probably turns on others that estrogen does not.
A major question this analysis presents is “Why do the findings presented here differ from the current opinion that ERT modestly increases the risk of breast cancer and that HRT increases the risk more than ERT?” One reason is because the data are inconsistent, and that inconsistency in the overall pattern of results means that alternative hypotheses can be supported readily with some data. In other words, causality can be in the eye of the beholder, particularly when results are ambiguous. Our findings might differ because the data presented here are from the entire study populations, whereas other investigators might report an association only in selected subgroups, hypothesizing that certain women might be more vulnerable to estrogen’s adverse effects (eg, current compared with past users, thin women compared with heavy women, or women with a family history of cancer).[63,85,86] Although subgroup analysis might be used to identify particularly susceptible groups of individuals, it is inherently problematic. If 40 different subgroups were investigated, the findings from two (5%) of those subgroups would be expected to be statistically significant by chance alone. Investigators rarely inform their readers of the number of subgroups considered, so the likelihood of a spurious association cannot be assessed. Therefore, a statistically significant finding found only in a subgroup and not in the entire study population should be viewed with caution.
The current belief that women using HRT have a higher risk of breast cancer than women using ERT could be a function of the recency of several publications[60,61,63,64] as well as failure of those studies to take ovarian status of the participants into account. In other words, women using HRT are much more likely to have their uterus and ovaries than women using ERT or no therapy. Because oophorectomy is protective against breast cancer and women taking ERT are more likely to have had an oophorectomy than women taking HRT, one can hypothesize that women taking ERT would have a lower risk of breast cancer than women taking HRT. Thus, a higher rate of breast cancer in HRT users would be expected because the other groups (ERT users, nonusers) are at lower risk because they include oophorectomized (lower-risk) women.
Two findings in this review were consistent across studies. One is that hormone users are less likely to die from breast cancer than nonusers. This finding makes the body of literature appear even more inconsistent; ie, the data suggest no effect on the incidence of breast cancer but suggest protection from death from breast cancer. It is difficult, but not impossible, to explain these two different findings. It would be difficult to explain an increase in breast cancer incidence together with a reduction in breast cancer mortality with hormone use. In other words, it is difficult to argue that hormone use causes breast cancer in women but then prevents them from dying from it, unless all previous studies suffer from both healthy estrogen user bias and surveillance bias.
Biologically, there are at least two reasons that hormone therapy could be associated with a real reduction in breast cancer mortality. First, it is possible that women taking hormone therapy are more likely to be screened for cancer than nonusers and thus are more likely to have their breast tumors diagnosed at an earlier and more curable stage. Many (but not all) studies found that women taking HRT were more likely to have smaller, lower grade tumors at diagnosis, and this is thought to occur because the breast cancers are more likely to be detected by screening mammography.[88,97] Thus, a survival benefit might be seen in users because of increased screening in that group. However, it is also possible that breast tumors growing in the presence of estrogen are biologically better tumors, ie, lower grade, well differentiated, and slower to proliferate. Some studies that control for screening modality report that breast tumors in hormone users are more likely to be ER+, grade 1, well differentiated, low S-phase, and node-negative than those in nonusers.[98-100] This situation could be analogous to that seen in estrogen-associated endometrial tumors, which are less aggressive and invasive than endometrial tumors occurring spontaneously.
The second consistent finding is that the lack of agreement between studies persisted throughout the entire 25-year period. We believe that results of additional observational studies are unlikely to vary from this pattern and therefore also unlikely to provide additional support for any hypothesis regarding the estrogen-breast cancer association. It is possible that randomized clinical trials could clarify the association between ERT or HRT and breast cancer. Currently, the Women’s Health Initiative is assessing the association between ERT or HRT and breast cancer risk, and we hope that this large randomized trial will shed some new light on the association.
Although the data presented here do not support an association between ERT or HRT and breast cancer risk, this review has some potential limitations. Although we made every attempt to find all published articles on the association between ERT or HRT and breast cancer, it is possible that we failed to include some studies. Although publication bias seems unlikely because other studies indicate that studies reporting a positive association (ie, studies that reported an association between HRT or ERT and breast cancer) are more likely to be published than those reporting a null association (ie, those that reported no association between HRT or ERT and breast cancer), we can not rule out that possibility. Finally, we chose to include all published studies without evaluating their quality and reliability. Thus, it is possible that some of the studies analyzed in this review are limited by confounders such as oophorectomy status, menopausal status, race or ethnicity, and socioeconomic factors.
Nonetheless, the evidence from the body of literature over the past 25 years does not support the hypothesis that estrogen use increases the risk of breast cancer or that combined hormone therapy increases the risk more than estrogen only. Although a small increase in breast cancer risk with hormone therapy or an increased risk with long duration of use (>15 years) cannot be ruled out, the likelihood of this must be small, given the many studies conducted to date.
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