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© 2002 American Society for Clinical Oncology
Why Do We Still Use Hormone Replacement Therapy? Why Don’t We Use It More?University of Pittsburgh Cancer Institute, Magee-Womens Hospital, Pittsburgh, PA THERE ARE MULTIPLE reasons why a woman and her physician may choose to initiate hormone replacement therapy (HRT). A large proportion of women begin therapy to alleviate menopausal symptoms, but it may have other effects as well. All selective estrogen receptor modulators (SERMs) that have undergone extensive clinical evaluation (most notably estrogen, tamoxifen, and raloxifene) lower serum cholesterol levels, but the effect of this lowering on preventing subsequent atherosclerotic coronary artery occlusive events is questionable. There is a belief that use of HRT may prevent heart disease, but recent studies suggest worsening of cardiovascular event rates among women who are at increased risk and use HRT.1,2 Patients and their physicians also believe that HRT may improve or maintain cognitive function as they age, and two cohort and 10 case-control studies suggest a 34% reduction in the risk of Alzheimer’s disease with the use of postmenopausal HRT.3 HRT does not seem to have a consistent effect, however, on visual recall, working memory, complex attention, mental tracking, mental status, or verbal function. Furthermore, published studies of HRT use do not show consistent improvement in cognition in older women. Although symptomatic women have improvement in memory, vigilance, reasoning, and motor speed with HRT, no benefits are reported in asymptomatic women; moreover, bias and confounding severely limit interpretation of the available studies. More definitive data may become available from prospective evaluations being performed as a part of the Women’s Health Initiative clinical trials. Elevated levels of endogenous estrogen are associated with increased risk of developing breast cancer, and the effect of circulating endogenous estrogen is physiologically apparent both in breast and bone: high circulating levels of estrogen are associated with radiographically dense bones and an increase in both breast parenchymal density and an increased risk of breast cancer. Conversely, the radiographically lucent bones of women with osteoporosis are associated with mammographically transparent breasts and a correspondingly lower risk of breast cancer.4 Published single-cohort observational studies,5 several meta-analyses,6-9 and the combined reanalysis of epidemiologic studies10 all indicate that increased risk of developing invasive breast cancer occurs among current users of HRT (especially those who have used HRT for 5 or more years), but among former users who had stopped taking hormones more than 5 years previously, the risk of breast cancer is no higher than the risk among never users. These observations suggest that the major effect of HRT on the breast may be through the promotion of cancer growth rather than through directly genotoxic effects.11 In this issue of the Journal of Clinical Oncology, Ursin et al12 report a large population-based, case-control analysis of the effect of estrogen replacement therapy (ERT), or of estrogen-progesterone replacement therapy (EPRT), collectively referred to as HRT, on the risk of development of invasive breast cancer. Importantly, they sought to investigate the possible interaction of hormonally determined breast cancer risk factors and HRT. Their analysis included cases of breast cancer from the Los Angeles County National Cancer Institute Surveillance, Epidemiology and End Results registry; both cases and matched control women were interviewed by telephone. Several features of the study design limit the certainty of their findings, however. Although adjustment for age at menopause is essential in performing this type of study, a large number of women were excluded from the analysis because their age at menopause could not be determined. The loss of these women may have biased their results. In addition, the investigators performed multiple comparisons when evaluating individual risk factors as well as performing a large total number of comparisons within the overall study. This may have led to individual results that were discovered by chance alone. They found, for example, that EPRT (but not ERT alone) increased the risk of breast cancer more in women who reported early age at menarche. Consequently, the effect of HRT on both this risk factor and others in the study should be evaluated with caution. It is certainly possible that women with early menarche may have, as the authors suggest, different hormone metabolism or higher hormone levels in response to postmenopausal HRT than women with later menarche, but this hypothesis must be evaluated in prospective studies before definitive conclusions can be made regarding either the safety of HRT in women with early menarche or the interaction of these two factors in the etiology of breast cancer. HRT is usually avoided in women with a history of breast cancer because of concerns that estrogen will stimulate tumor recurrence, although Ursin et al12 did not investigate this question. Recently reported data derived from a subset of 174 women who used HRT after a diagnosis of breast cancer suggest that this assumption may need to be re-examined. These women were identified from a group of 2,755 women between the ages of 35 and 74 years who were diagnosed with incident breast cancer while they were members of a large health maintenance organization between 1977 and 1994.13 In a matched case-control study, rates of recurrence of and death from breast cancer were calculated, and relative risks (RRs) were adjusted using Cox proportional hazards regression. Somewhat surprisingly, the rate of breast cancer mortality was 5 per 1,000 person-years in the HRT users compared with 15 per 1,000 person-years in the nonusers (RR = 0.34; 95% confidence interval [CI], 0.13 to 0.91). Breast cancer recurrence rates were 17 per 1,000 person-years in HRT users and 30 per 1,000 person-years in the nonusers (RR = 0.50; 95% CI, 0.30 to 0.85). Total mortality rates were 16 per 1,000 person-years in HRT users and 30 per 1,000 person-years in the nonusers (RR = 0.48; 95% CI, 0.29 to 0.78). Although it is possible that these results simply reflect either detection or length bias among women who were followed more carefully for breast cancer recurrence because they were taking HRT, the possibility of a true beneficial effect cannot be dismissed. The mechanism whereby HRT could paradoxically increase the likelihood that a woman using it will develop an incident invasive breast cancer, yet improve her survival, remains to be described. Equally contradictory of assumptions widely held among clinicians are older data reported by Schairer et al14 that demonstrate reduced mortality from breast cancer among women who were current users of ERT when they were diagnosed with node-negative breast cancer. The rate ratio of breast cancer mortality associated with current use of ERT compared with nonuse at diagnosis was 0.5 (95% CI, 0.3 to 0.8), an effect greater than the benefits reported with the use of tamoxifen in early breast cancer. Clinicians assist patients in considering the safety of HRT in the context of its combined risks and benefits based on known morbidity and mortality for multiple disease outcomes. Unlike the second breast cancers that develop among women using tamoxifen as adjuvant therapy, there is no evidence of increased risk of estrogen receptor (ER)–negative disease developing with greater frequency among women who use HRT. On the contrary, Ursin et al12 found that women who use HRT (and particularly those who use EPRT), are at increased risk of developing invasive breast cancer that expresses ER protein. Based on the observations, along with the older data that are available, we must distinguish for our patients the risk of developing breast cancer from the risk of dying from the disease when considering HRT. This difference in the phenotype of breast cancer that develops during exposure to hormones also needs to be explained mechanistically at a molecular level, but no experimental data yet address this question. This study used matched interview data, and it is subject to all the limitations of interview studies including recall bias, the representativeness and generalizability of the selected control population, and the accuracy of self-reported information. The study is based, nevertheless, on an important and fundamental underlying question: namely, is there an interaction between the type of HRT a woman takes after menopause and the presence of known breast cancer risk factors, especially those that may be influenced by hormonal events in a woman’s life? These breast cancer risk factors influenced by or related to hormonal events in a woman’s lifetime appear not to be differentially related to the development of either estrogen or progesterone receptor–positive breast cancer based on the data presented in this study. These risk factors include early age at menarche, nulliparity or late age at first birth, body mass index, alcohol intake, and dietary fat. It is also possible to construct arguments suggesting that chronic exposure to HRT should downregulate hormone receptor expression and select for clinically more aggressive and more difficult-to-treat breast cancer. It is, perhaps, counterintuitive that this was not observed, but it is consistent with other data reported in the literature suggesting an improved prognosis for women developing breast cancer while taking HRT, largely based on the increased proportion of ER-positive tumors. The lack of a demonstrable interaction between these hormonally linked risk factors and HRT implies a common, and not fully determined, pathway, through which both hormonally driven life events and HRT influence the development or progression of human breast cancer. Elucidation of this pathway is an urgent objective of translational research. We are learning that all SERMs may not be created equal. Among the SERMs, only estrogen reduces the frequency and severity of menopausal symptoms. The most certain and reproducible effect of SERM therapy is the increase in bone mineral density and the consequent reduction of fracture rates, but this benefit is also seen with bisphosphonate therapy, which provides an alternative management strategy. The frequency of clotting events increases with all SERMs: conjugated equine estrogen, tamoxifen, and raloxifene each approximately triple the baseline rate of thromboembolic events when compared with placebo-matched controls. These complications make current SERMs less than ideal therapy, especially for older postmenopausal women in the risk-reduction setting. Unlike tamoxifen, neither toremifene nor raloxifene seem to increase the risk of endometrial cancer, but few women-years of observation make this conclusion very uncertain. Raloxifene does not seem to promote the growth of ER-negative breast cancer, but again, few events make this conclusion equally tentative. Tamoxifen therapy reduces both the risk of first15 and second16 primary breast cancers by approximately 50%. Some concern has been expressed, however, that tamoxifen may select for clinically aggressive, ER-negative invasive breast cancer. Li et al17 identified 8,981 women diagnosed with invasive breast cancer in western Washington state between 1990 and 1998. Restricting their analysis to women who were at least 50 years of age, had localized or regional breast cancer, and who did not receive chemotherapy, they identified 4,654 women who were users of tamoxifen therapy. Of the 89 tamoxifen users and 100 nonusers of tamoxifen who developed second contralateral breast cancers, 112 had ER-positive breast cancer, 20 had ER-negative tumors, and in 57 women the ER status was unknown or undetermined. The risk of developing an ER-negative contralateral tumor among tamoxifen users was 4.9 (95% CI, 1.4 to 17.4). One explanation for this observation is that tamoxifen may promote the preferential growth of residual ER-negative cells after surgery. This interpretation has been criticized, however, because of the retrospective design of the study that assessed a treatment that was not randomly assigned.18 The study was also a subset analysis that excluded a substantial number of cases, with a small number of events from which to draw conclusions. Although the data might raise cautions for a clinician who is considering recommending tamoxifen to reduce breast cancer risk to a patient who herself wants HRT, the data are inconsistent with overview data in the literature, with randomized comparisons, and with a population-based case-control study showing no increase in ER-negative breast cancers among women taking tamoxifen. It is more likely that, rather than tamoxifen’s promoting emergence of ER-negative breast cancer, it instead decreases the proliferation of ER-positive cells, allowing the ER-negative cells to grow by selective pressure.18
Because adipose tissue is the major source of endogenous estrogen in postmenopausal women, it is not surprising that many epidemiologic studies have reported increased risk of breast cancer among obese, postmenopausal women. Other studies, however, have suggested an increased risk of breast cancer among lean (but not obese) women who use postmenopausal HRT. In this study, HRT had no apparently greater impact among women of lower body mass index (body mass index It is equally instructive that the apparent effect of HRT in this study on the histologic subtype of breast cancer did not differ substantially when comparing ductal to lobular subtypes. It is possible to hypothesize that the lobular portion of the terminal ductal-lobular unit may be more susceptible to hormonal influences, but the data of Ursin et al12 do not support that conclusion. Both medical oncologists and primary care physicians are now faced with the challenging situation of what to recommend to women who inquire about taking HRT after menopause. Although the paradox of improved survival from breast cancer seen in cohort and case-control studies of women using HRT is intriguing, these observations need to be confirmed in randomized, prospective studies such as the Women’s Health Initiative. It is clear that there are some benefits from taking HRT, including relief of symptoms and treatment of osteoporosis. The benefit on dementia and cognitive function remains uncertain, and women may not be willing to trade an increased risk of developing invasive malignancy with a hope for improved survival should it occur. These data beg the question of whether the combination of tamoxifen and HRT may be the ideal SERM. What also needs to be determined is why HRT should lead to the development of breast cancer with a favorable prognosis. An understanding of the molecular mechanisms of this process would shed great light on the overall relationship of hormones to human breast carcinogenesis. Answering these fundamental biologic questions will lead to both improved treatment and prevention of breast cancer. REFERENCES
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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the self-reported median of 24.56 kg/m2) than among women who were larger than the median body mass index. The molecular explanation for this seeming inconsistency may lie in the fact that intratumoral or stromal production of estrogen through aromatization of androgens is more important in the etiology of invasive breast cancer than is peripheral production of estrogen or circulating concentrations of estrogenic steroids.
