An epidemiological overview of the relationship between hormone replacement therapy and breast cancer

Abstract

Large-scale randomized clinical trials and observational studies have consistently found that use of hormone replacement therapy (HRT) increases the risk of breast cancer. More recently, ecological studies have shown correlations between dramatic reductions in use of HRT in many countries, and declines in the rates of breast cancer in older women. Meta-analyses of data from the trials and observational studies show that the increase in breast cancer risk is greater for combined estrogen–progestin therapies compared with estrogen alone; that for both types of preparation, breast cancer risk increases with duration of use; and that the risks decrease relatively quickly after cessation of use. For both estrogen-only and combined therapies, the risk of breast cancer is higher if therapy is initiated close to the time of the menopause, relative to the risks in women starting HRT later. Most drug regulatory authorities currently recommend that HRT be prescribed only to fully informed women who have moderate-to-severe menopausal symptoms, for the shortest duration possible; and it is recommended that the need for therapy be reviewed at least every 6–12 months.

Keywords::

• combined estrogen–progestin therapy
• estrogen
• hormone replacement therapy
• medroxyprogesterone acetate
• progestins

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at www.medscape.org/journal/expertendo; (4) view/print certificate.

Release date: 16 May 2011; Expiration date: 16 May 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the risk for breast cancer associated with different types of HRT

• • Evaluate how the timing of HRT affects the risk for breast cancer

• • Distinguish other factors which contribute to HRT’s associated risk for breast cancer

• • Apply the results of the current review to prescribe postmenopausal hormone therapy effectively

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD,

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure:Charles P Vega has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Usha Salagame, MSc

Cancer Epidemiology Research Unit, Cancer Council NSW, School of Public Health, University of Sydney, Australia.

Disclosure: Usha Salagame has disclosed no relevant financial relationships.

Karen Canfell, DPhil

Senior Research Fellow, Cancer Epidemiology Research Unit, Cancer Council NSW, School of Public Health, University of Sydney, Australia.

Clinical Associate Professor, Sydney Medical School – Public Health, University of Sydney, 153 Dowling Street, Woolloomooloo, Sydney 2011, Australia.

Disclosure: Karen Canfell is funded by the Australian National Health and Medical Research Council.

Emily Banks, MBBS (Hons), PhD

National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT, 0200 Australia.

Disclosure: Emily Banks is funded by the Australian National Health and Medical Research Council.

Clinical practice and research must be based on the best possible evidence. Importantly, this includes quantitatively summarizing the cumulative worldwide findings from appropriate large-scale studies, rather than focusing on specific findings from individual studies. For breast cancer, where the disease event is unpredictable and other risk factors can be reasonably accounted for, data from observational studies are generally reliable [1] and should be considered together with the data from randomized controlled trials in quantitative summaries of the evidence.

Compelling evidence from over a century of research shows that the risk of breast cancer increases with increasing exposure to estrogen [2]. Direct evidence on the association between use of hormone replacement therapy (HRT) and risk of developing invasive cancer of the breast has been accumulating over several decades. Since the 1990s, several landmark studies and meta-analyses have progressively informed our current, detailed understanding of the epidemiological and clinical aspects of this relationship. The first large-scale attempt to formally synthesize the evidence on this topic was a 1997 pooled analysis of the worldwide data, which was performed by the Collaborative Group on Hormonal Factors in Breast Cancer [3]. The evidence base was subsequently informed by the findings of the Women’s Health Initiative (WHI) trials and observational studies, which were designed to assess the risks and benefits of HRT [4,5], the Million Women Study [6–8] and a number of other studies, which are represented in an updated 2007 independent synthesis of the evidence by the UK Medicines and Healthcare Products Regulatory Agency (UK MHRA) [101].

In the past 5 years, a number of ecological studies have documented declines in rates of breast cancer in various settings following large reductions in the use of HRT [9–15], which occurred after the initial findings of the WHI combined estrogen–progestin HRT trial were released in 2002 [4]. Most recently, longitudinal follow-up data from the WHI [16] and another major cohort study, the California Teachers Study [17,18], have consolidated the evidence by demonstrating similar reductions in breast cancer rates in study women who had ceased use of HRT compared with those that were observed in the population-based ecological studies.

Therefore, the evidence base for assessing breast cancer risk in relation to the use of HRT is now substantial, with several key aspects of this relationship being consistently observed when the evidence is properly synthesized, including the following: the use of HRT increases the risk of breast cancer; the increased breast cancer risk is greater for combined estrogen–progestin therapies than for estrogen-only therapy; the current evidence does not support differential breast cancer risks for different chemical formulations, doses and routes of HRT administration; breast cancer risk increases with increasing duration of use; the increased breast cancer risk diminishes markedly over time after ceasing use of HRT; the relative risk (RR) of breast cancer is increased in women initiating HRT close to the menopause compared with those starting therapy later; and HRT-associated breast cancer risk is modulated by obesity: thinner women demonstrate greater RRs of breast cancer.

The use of HRT increases the risk of breast cancer

The most recent independent synthesis of the worldwide evidence by the UK MHRA included randomized trial and observational data and demonstrated that women who are currently using HRT have an increased risk of breast cancer compared with women who are not using HRT [101]. These findings updated and built upon the 1997 pooled analysis by the Collaborative Group on Hormonal Factors in Breast Cancer, which had involved the synthesis of data derived primarily from studies of the risks associated with estrogen-only HRT [3]. The Collaborative Group reported summary estimates of RR of 1.14 (standard error [SE] = 0.031) in ever-users (both current and past) compared with never-users, and an RR of 1.35 (95% CI: 1. 21–1.49) for current users of 5 years or more, compared with never-users.

The first major report of the Million Women Study in 2003 found an overall RR of 1.66 (95% CI: 1.58–1.75) in current users of any HRT type compared with never-users [6]. In a 2011 analysis with extended follow-up time and with updated exposure information, this finding was confirmed, with a summary RR of 1.68 (95% CI: 1.64–1.72) in current HRT users versus those who had never used HRT [8]. It should be noted that the Million Women Study population reflects a higher proportion of combined estrogen–progestin HRT users (50%) [6] compared with the Collaborative Group analysis, which is likely to partly explain the lower estimate of RR observed in the Collaborative Group analysis. The original reports of the findings of the WHI trials identified a significantly elevated risk of breast cancer in users of combined estrogen–progestin HRT (RR: 1.26; 95% CI: 1.00–1.59) [4], but not for women using estrogen-only HRT (RR: 0.77; 95% CI: 0.59–1.01) [19].

The increased breast cancer risk is greater for combined estrogen–progestin therapies than for estrogen-only therapies

Although the evidence to date shows that the use of either estrogen-only HRT or combined estrogen–progestin preparations is associated with an increased risk of breast cancer, this increase in risk has repeatedly been shown to be substantially greater in users of combined estrogen–progestin therapies. In 20 out of 21 large-scale studies (including the WHI trial and the Million Women Study) that separately reported on these results, risks of breast cancer were higher for combined therapy than for estrogen-only HRT. The MHRA quantitative summary of the evidence found that, among European women, RRs of breast cancer in current versus never-users of estrogen-only HRT were 1.2 (95% CI: 1.1–1.4) after 5 years of use and 1.3 (95% CI: 1.2–1.5) after 10 years of use. For estrogen–progestin HRT, the RRs of breast cancer were 1.6 (95% CI: 1.5–1.7) after 5 years of use and 2.2 (95% CI: 2.0–2.4) after 10 years of use. Risks were still significantly raised, but to a lesser extent, in North American studies; a fact chiefly attributed to the higher BMI in participants in North American compared with European studies (see later). In the case of the WHI trial, it has also been suggested that the lower RRs observed compared with the Million Women Study are also likely to be partly explained by the large proportion of the study population (90%) who were entered into the study at a relatively older age, when they were more than 5 years postmenopausal, thus attenuating HRT-associated risks (see later) [8].

The combined estrogen–progestin arm of the WHI trial was stopped early in 2002 (after a mean of 5.2 years of follow up in trial participants) because the risks for invasive breast cancer, as well as the global index for risk–benefit, exceeded the predetermined stopping boundaries for the trial [4,20]. In an intention-to-treat analysis, users of combined HRT had an elevated risk of breast cancer, with a hazard ratio (HR) of 1.24 (95% CI: 1.02–1.50) [21] compared with placebo, but no significant increase in risk was reported in the estrogen-only arm of the trial [19]. A twofold risk for current users of combined therapy versus never-users was reported from the Million Women Study in the 2011 updated analysis (RR: 1.96; 95% CI: 1.90–2.02); whereas an increase in RR of approximately 40% compared with never-users was observed in current users of estrogen-only therapy (RR: 1.38; 95% CI: 1.32–1.44) [8].

Current evidence indicates similar breast cancer risks for different formulations, doses & routes of HRT administration

The estrogens, progestins and other constituents used in HRT are available in a variety of formulations and doses, and they may be delivered either orally, transdermally or via implant. However, current evidence does not support the view that there are any differences in the HRT-associated risks of breast cancer related to the specific HRT formulation (other than the differences associated with the broad type of HRT – estrogen-only vs combined HRT), dosage or route of administration. Where quantitative evidence is available, it shows similar increases in breast cancer risk with the various estrogens (i.e., equine estrogen and estradiol) and progestins (i.e., medroxyprogesterone acetate, norgestrel and norethisterone) [6]. The elevated risk of breast cancer has not been shown to vary significantly according to whether HRT is delivered orally, transdermally or via implant, or according to dose [6,22]. Therefore, at present, all chemical formulations, including so-called ‘bio-identical hormones’, must be considered to confer a similar increased risk of breast cancer, and it is not possible, from the perspective of breast cancer risk, to recommend the usage of one chemical constituent or one route of administration over another. In addition, the overall evidence does not currently support the idea that lower-dose regimes are associated with a lower risk of breast cancer [6].

Breast cancer risk increases with increasing duration of HRT use

Evidence from randomized and observational studies is consistent in finding that the RR of breast cancer is greater the longer a woman uses HRT [101]. Among current users of combined therapy in the initial analysis of the Million Women Study cohort, RRs increased from 1.45 (95% CI: 1.19–1.78) for those with less than 1 year of use at baseline to 2.31 (95% CI: 2.08–2.56) in women using HRT for 10 years or longer. For users of estrogen-only therapy, the comparable RRs were 0.81 (95% CI: 0.55–1.20) and 1.37 (95% CI: 1.22–1.54) [6].

Risks increasing with duration of use were observed in both the WHI randomized trial and the observational arm of the study [23]. A statistically significant linear trend of increasing risk of breast cancer events by year of follow-up was reported in the WHI trial [24]. Using combined data from the WHI randomized trial and observational study, the estimated RR was 1.85 (95% CI: 1.03–3.34) for 2–5 years of use and 2.75 (95% CI: 1.73–4.39) for more than 5 years of use of estrogen–progestin HRT, compared with never-users, in women initiating use within 5 years of menopause [23].

In terms of the absolute impact of HRT, based on a meta-analysis of trial and observational studies, in women 50–59 years of age, 5 years of combined therapy has been projected to result in six extra breast cancers per 1000 HRT users, while 10 years of use is expected to result in 24 extra cancers [101]. A total of 5 years of estrogen-only therapy was estimated to result in two extra cases of breast cancer per 1000 HRT users, while six cancers per 1000 HRT users would be expected with 10 years of use [101]. To put these risks into context, in the European setting, ten in 1000 women 50–59 years of age and 15 women 60–69 years of age would be expected to develop breast cancer over a 5-year period [101]. One additional unit of alcohol per day increases breast cancer risk by 7% [25] and an extra unit of BMI (equivalent to a weight gain of ∼2.6 kg for a woman of average height) is associated with a 4% increase in postmenopausal breast cancer risk [26]. Hence, 5 years of estrogen-only use is equivalent to around two-to-three additional alcoholic drinks per day or a 13 kg weight gain for a woman of average height. Estrogen–progestin HRT over 5 years is the equivalent of approximately eight extra drinks per day or a 39 kg weight gain. Having a mother or a sister with breast cancer is associated with a 65% increase in breast cancer risk for women aged 50 and over, equivalent to 5 years of estrogen–progestin therapy [27].

Because the evidence is consistent with the RR of breast cancer continually increasing after initiation of HRT use, and relatively short durations of use are associated with an elevation in the risk of breast cancer, it is not possible to define a completely safe period of use. In the Million Women Study, for both estrogen-only and combined estrogen–progestin HRT, a significant elevation in breast cancer risk was observed among current users with less than 5 years of use (RR [estrogen only]: 1.24; 95% CI: 1.14–1.35; RR [estrogen–progestin]: 1.62; 95% CI: 1.54–1.71) [8]. The finding of increased breast cancer risk in relatively short duration users, as well as increases in stroke and venous thromboembolism risk soon after use commences, means that it is not possible to define a period where use of HRT is without appreciable risk. Hence, current drug regulatory guidelines state that hormone therapy should be used for the shortest duration required, in women who are fully informed about its risks and benefits [28,101–105].

The increased breast cancer risk diminishes rapidly after ceasing use of HRT

Randomized and observational study data are consistent in showing that the effect of HRT on breast cancer risk returns to baseline (i.e., to that of never HRT users) relatively rapidly after women stop using HRT. Initial findings from the 1997 Collaborative Group analysis identified an increased risk of breast cancer in current users of HRT (RR: 1.21; SE: 0.05; 2p = 0.00002), but no significant increase in risk among women who had used HRT in the past (RR: 1.07; SE: 0.04; p = 0.10) [3]. Since then, findings from the WHI, Million Women Study and other studies have confirmed this result. In particular, in the follow-up of the WHI observational cohort and of the trial participants, the incidence of breast cancer was found to decrease year by year, in parallel to the post-2002 decrease in the use of HRT in these women [29]. In the WHI observational cohort, breast cancer incidence declined by 43% between 2002 and 2003 in women who had ceased use of HRT [29]. Within the Million Women Study cohort, a slightly increased risk of breast cancer remained apparent among women ceasing HRT within the previous 2 years, compared with never-users (RR: 1.16; 95% CI: 1.08–1.24) but by 3 or more years after ceasing use (and with information available for up to 14 years), the risks were similar to those in women who had never used HRT (RR: 0.99; 95% CI: 0.93–1.05) [8].

At a population level, temporal trends in breast cancer rates have shown an increase in incidence parallel to the increased uptake of HRT. A steep decline in breast cancer rates in women over 50 years of age following the decline in HRT use after the findings of the WHI trial were released in 2002 has now been observed in a number of countries (see later) [30].

Current evidence suggests greater increases in breast cancer risk among women initiating HRT use closer to menopause

An area of recent speculation relates to the ‘estrogen timing hypothesis’ [31], where some commentators have suggested favorable effects for coronary heart disease [32] when HRT is commenced soon after menopause [33]. However, dedicated re-analyses of the WHI data, the data from which the ‘timing hypothesis’ originated, do not support this hypothesis for coronary heart disease [5]. On the whole, the risks outweighed benefits for combined hormone therapy, while there was a lack of net benefit from the use of estrogen-only therapy [5,23,34,35].

More importantly, the timing hypothesis was never considered to relate to breast cancer. In fact, for breast cancer, the evidence from WHI demonstrated, if anything, significantly higher RRs of breast cancer for women starting HRT close to the menopause, compared with those starting later [5,16,35].

Recent findings from the Million Women Study have confirmed and strengthened the finding that women starting HRT close to the time of the menopause have a greater elevation in their risk of breast cancer compared with those initiating therapy later [8]. This pattern is observed for both estrogen-only and combined HRT; among women who had used HRT for either short or long durations (<5 years vs ≥5 years); and also in both lean and obese women. For current users of estrogen-only HRT, there was little or no increase in risk compared with never-users if use was initiated 5 years or more after the menopause (RR: 1.05; 95% CI: 0.89–1.24), but a significant elevation in risk if initiated within 5 years of the menopause (RR: 1.43; 95% CI: 1.35–1.51). A similar pattern was seen with use of estrogen–progestin HRT; for current versus never-users of combined estrogen–progestin HRT, the RR of breast cancer in women initiating HRT after 5 years was 1.53 (95% CI: 1.38–1.70) and 2.04 (95% CI: 1.95–2.14) in those starting HRT earlier [8].

Extrapolating the WHI trial results directly to clinical practice has been met with some reservations [36,37]. The average age of the women in the trials and high rates of nonadherence (∼40%) have been cited as drawbacks of the trial. The new findings from the Million Women Study help to clarify the potential underlying reasons for differences in the magnitude of the estimated RR between the Million Women Study and the WHI. In addition to differences in duration of use and BMI profile of the populations involved, differences in the timing of initiation of HRT use in each study are an important variable that must be taken into consideration. In the WHI trials, most of the participants (90% in the estrogen-only trial and 83% in the combined therapy trial) were randomized when they were more than 5 years postmenopausal, although it should be noted that a substantial proportion of these had initiated therapy before the trial commenced [5,35]. The authors of the recent Million Women Study publication propose that this later timing of HRT initiation, in addition to the high average BMI of participants and poor adherence to therapy, is likely to have influenced the WHI breast cancer findings [8]. In particular, these differences between the WHI trials and other studies may explain the lack of a significant increase in the risk of breast cancer in the estrogen-only arm of the trial and the lower RRs of breast cancer in the combined HRT arm, compared with other studies [101].

HRT-associated breast cancer risk is modulated by obesity: RRs are greater in thinner women

A large body of evidence exists to suggest that the RRs for breast cancer associated with use of HRT are attenuated in overweight and obese women [3,7,38]. Updated analyses from the Million Women Study have found that, compared with those who had never used HRT, the RR of breast cancer for users of estrogen-only HRT was 1.65 (95% CI: 1.54–1.76) in women with a BMI <25 kg/m², but 1.22 (95% CI: 1.15–1.30) in women with a BMI of 25 kg/m² or more. Similarly, for users of combined HRT, the corresponding RRs were 2.20 (95% CI: 2.11–2.30) and 1.81 (95% CI: 1.73–1.90), respectively [8].

These recent findings from the Million Women Study have also clarified that the attenuation of the RR with increasing BMI is likely to be driven by the underlying adiposity-related increasing breast cancer incidence among never-users of HRT (the usual reference group for RR calculations of HRT-associated risk) [8].

Body mass index varies by population [106] and is therefore a major factor in determining the HRT-associated risk in a population. European studies have generally identified a higher relative risk of breast cancer with the use of HRT than North American studies [101]. It is plausible that these overall regional differences are driven by the differences in BMI profiles between the two regions [38,39].

HRT use lowers the sensitivity & specificity of mammographic screening for breast cancer

Randomized and observational study data show that women taking HRT are more likely than non-users to have breast cancers missed at mammographic screening (reduced sensitivity) and are more likely to have additional investigations, without a subsequent diagnosis of breast cancer (i.e., a false-positive screen and reduced specificity) [21,40–45]. Hence, as well as increasing the risk of breast cancer occurring, HRT reduces the ability of breast cancer screening to both detect breast cancer and to efficiently exclude its presence.

The HRT-associated breast cancer risk is higher for certain tumor types

Lobular and ductal tumors account for 5–10% and 70–80% of invasive breast cancer cases, respectively [46]. A considerable body of evidence now exists suggesting that the HRT-associated risk of breast cancer is higher for lobular compared with ductal tumors [7,47–50]. Table 1 summarizes the results of the relevant studies. The higher RRs observed overall in users of combined estrogen–progestin versus estrogen alone HRT is present within the major histological subtypes of breast cancer examined. The evidence for differences in breast cancer risk for the other, less common, histological subtypes is more limited because most studies are not sufficiently powered to allow for precise estimates in these types. However, data from the Million Women Study and a related meta-analysis of the wider literature [7] did assess specific risks in several tumor types, finding that the highest RR estimates were obtained for tubular cancers, followed by lobular, mixed ductal-lobular and ductal tumors.

Use of HRT is associated with a greater risk of estrogen receptor-positive breast cancer

According to Surveillance, Epidemiology and End Results (SEER) program data, in the USA, in women 50–64 years of age, estrogen receptor-positive (ER+ve) tumors comprised 60% of all of invasive breast cancers between the years 1990–2001, prior to the publications of the findings from the WHI study [107]. A large body of evidence from observational studies exists to support a greater HRT-associated risk of ER+ve tumors than for ER-negative (ER-ve) breast tumors. The most recent updated analysis of Million Women Study data found that for estrogen-only HRT, the RR of ER+ve breast cancer compared with never-users was 1.76 (95% CI: 1.59–1.94) but it was 1.29 (95% CI: 1.06–1.56) for ER-ve tumors; the equivalent RRs for combined HRT were 3.10 (95% CI: 2.86–3.36) for ER+ve tumors and 1.37 (95% CI: 1.15–1.64) for ER-ve tumors [8].

The ecological studies of declining breast cancer risk with declining HRT use have provided confirmatory evidence of the relationship between HRT and ER status. In the USA, declines in breast cancer incidence in women over 50 years of age were observed in ER+ve, but not in ER-ve tumors [15]; supporting results have been documented in other US-based studies [51–53].

Ecological trends in breast cancer incidence reflect population-level utilization of hormone therapy

After the WHI trial was stopped early in 2002, a dramatic fall in HRT prescribing occurred in many countries [9–15,54–57]. In some, but not all, of these countries, parallel trends in decreasing rates of breast cancer in women over 50 years of age were observed.

The first major report of a trend for declining breast cancer incidence that was attributed to declining rates of HRT emerged from the USA in 2007. The analysis found a decline of approximately 11% in breast cancer incidence after 2001 (to 2004) among women aged 50 years and over, but not in younger women, and this was mainly attributed to a drop in HRT use [15]. A subsequent analysis for Australia reported similar findings: a substantial reduction in HRT prescriptions after 2001 was accompanied by a statistically significant 6.7% fall in breast cancer incidence among women aged 50 years and over, but not by any significant change in incidence among younger women [9]. Subsequent updated analyses for both the USA and Australia were published, and in both cases these showed a sustained decrease in breast cancer incidence until 2005; strikingly similar patterns in breast cancer trends in the two countries were observed over the period of interest [10,58]. Similar findings of declining rates of HRT use and declining breast cancer incidence in older women were also reported in studies from several other countries [30] including France [55], Germany [13,14] and, more recently, Canada [12].

The most important potentially competing factor in such ecological analyses is screening behavior. In the USA and Australian studies, the observed changes in screening behavior over the period of the analysis were too small to account for the observed breast cancer incidence declines. However, in some settings (e.g., England), changes in screening practice occurred simultaneously with the changes in HRT use, making the effects difficult to disentangle [9,30].

Another factor important in the interpretation of the ecological data is the background prevalence of HRT use (prior to 2002); in some settings, a low initial prevalence of use or examination of the effects in small populations limited the statistical power to allow detection of the effects of any changes [56,57,59]. Other potentially competing effects, which can be considered and excluded, include the possibility of substantial increases in tamoxifen and/or raloxifene [9].

Recently, the substantial reductions in breast cancer rates that were observed in the ecological studies have been echoed in the findings of longitudinal follow-up results from large-scale cohort studies. These include the WHI trial and observational cohort [29] and the California Teachers Cohort studies [17]. These cohorts were established prior to 2002 and large numbers of participating women ceased use of HRT after 2002 (as did women in the general population). Hence, the follow-up data from these cohorts allow direct examination of the effects in populations for which data on HRT use, screening behavior and breast cancer incidence are available for individual women [17,18]. The results of the longitudinal analyses demonstrated that drops in breast cancer rates similar to the magnitude observed in the ecological studies were observed; and confirmed that the declines in breast cancer incidence were concentrated in women who had ceased use of HRT [18].

Use of HRT is associated with a higher risk of dying from breast cancer

The current evidence suggests that the RR of dying from breast cancer is higher in users of HRT. In the Million Women Study, a RR of 1.22 (95% CI: 1.00–1.48) for breast cancer mortality was estimated for women who were current versus never-users of HRT at cohort entry [6].

When the WHI combined estrogen–progestin HRT trial was stopped in 2002, women had been followed for an average of approximately 6 years. A recent analysis of 11-year follow-up from this trial found that the RR of dying from breast cancer was 1.96 (95%CI: 1.00–4.04) in women who had been originally randomized to combined HRT compared with those randomized to placebo; this study also found an increased risk of dying from all causes after a breast cancer diagnosis in women randomized to combined HRT (RR: 1.57; 95% CI: 1.01–2.48) [16].

In both the Million Women Study and WHI follow-up study, the finding of increased breast cancer mortality is reinforced by the finding that breast cancers in HRT users are more likely to be node positive than those in nonusers [8,16].

Mechanistic studies support the plausibility of the epidemiologic & trial findings

The biological mechanisms underlying the relationship between breast cancer risk and hormone exposure are complex, and a synthesis of this evidence is beyond the scope of this article. However, the data from epidemiological studies and clinical trials are important in informing and providing real-world tests of findings from basic biology. At the same time, what is known about the biology of estrogen reinforces the plausibility of the observed relationship between HRT and breast cancer.

Multiple pathways involving numerous molecular components have been proposed to explain the association between estrogen exposure and increase in breast cancer risk. It is well established that estrogen stimulates proliferation of mammary cells, which can lead to neoplastic transformation, possibly through accumulation of mutations [60]. Studies involving use of mammary epithelial cell lines [61], normal breast tissue explants [62] and animal models [63] have demonstrated the proliferative effects of estrogen. Many of the effects of estrogen are likely to be mediated through the ER, which has been shown to have a variety of functions. In addition to being a ligand-activated transcription factor, the ER also participates in extranuclear, as well as signal transduction, events.

Although there is mixed evidence on the mitogenic activity of progesterone [64], studies involving use of breast cancer cell lines and animal models [65] suggest that progestins can promote cellular proliferation. Progenitor cells in the breast have been suggested as targets for the growth-promoting effects of progesterone, acting both independently [66] and in concert with estrogen in animal models [67,68]. It would appear that some of the early transcriptional effects of estrogen and progestin involve establishing a balance between proliferation and surveillance [69].

Apart from the additionally increased RR of breast cancer in thinner women using HRT, no other subgroup of women has been identified that experiences differential HRT-associated RRs (i.e., risks above those seen in users of HRT in general). Although studies of gene–environment interactions between use of HRT and genetic factors in relation to breast cancer are limited, the studies carried out to date do not show any important modification of the effect of HRT on breast cancer in women with a range of genetic polymorphisms [70]. Furthermore, use of HRT results in a similar increase in the RR of breast cancer among women with, and without, a family history of breast cancer [3,6]. However, it should be borne in mind that women with a higher background risk of breast cancer (e.g., those who are older, have a family history of breast cancer or drink high levels of alcohol) will experience higher absolute increases in their risk of breast cancer from the use of HRT than women at lower background risk. The notable exception to this is postmenopausal women who are obese or overweight, as outlined previously.

Overall, the risks associated with the use of HRT outweigh its benefits, in terms of the risk of serious disease

The weighing up of the overall risks and benefits of HRT is a detailed quantitative exercise, involving the derivation of summary estimates of RR from the world evidence and applying these to estimates of background risk for each condition under consideration, for an appropriate population. This has been carried out most recently by the UK MHRA, as part of a public assessment report on the safety of HRT [101]. The MHRA considered the effects of HRT on a range of potentially life-threatening conditions relevant to women of the target age range for HRT use, namely stroke, venous thromboembolism, fractured neck of femur, coronary artery disease and breast, ovarian, endometrial and colon cancer [101]. The findings of this report were that the risks of HRT outweighed the benefits, in terms of these serious diseases. They found that, in a European population, 5 years use of estrogen-only HRT resulted in a net excess of potentially life-threatening events affecting five per 1000 users aged 50–59 years (number-needed-to-harm = 200), among women without a uterus; 10 years use led to an excess of 12 per 1000 users (number-needed-to-harm = 83) [101]. Use of estrogen–progestin HRT for 5 years led to a net excess of potentially life-threatening events affecting 14 per 1000 users aged 50–59 years (number-needed-to-harm = 71) among women with a uterus, and 10 years of use led to an excess of 40 per 1000 users (number-needed-to-harm = 25).

Another way of considering the overall risks and benefits of HRT is using a ‘global index’ of different conditions as a trial outcome. The WHI trials were stopped prematurely because the global index for the risks versus benefit for women treated with combined hormone therapy exceeded stopping boundaries [4]. This unfavorable risk–benefit ratio was maintained 3 years postintervention [20], and in fact, was shown to result in more deaths from all causes after breast cancer diagnosis on long-term follow-up [16]. The evidence regarding estrogen-only HRT in the WHI trials indicates a lack of net benefit [5,19].

Regulatory authorities recommend that HRT be used by symptomatic women only, for the shortest time possible

It is now clear that, overall, HRT does not prevent long-term serious disease in women [71]. However, HRT remains the most effective treatment for specific menopausal symptoms, such as hot flushes, night sweats and vaginal dryness. The difficult task for women and their health professionals is weighing up the benefits of HRT, in terms of symptom relief, against the risk of serious disease.

The guidance provided by drug regulatory bodies internationally is that HRT should be used for the shortest time possible among women with moderate-to-severe menopausal symptoms, and only by women who have been informed of the risks and benefits [101–105]. It should not be used for the long-term prevention of disease, particularly cardiovascular disease or dementia. It has also been recommended that the need for use of HRT be reviewed every 6–12 months. In Europe, Australia and the UK, HRT is not recommended as the first-line option for the prevention and treatment of osteoporosis. HRT has never been approved for the prevention or treatment of cardiovascular diseases by the US FDA in the USA or in the aforementioned countries.

Expert commentary

The evidence regarding most aspects of the increased breast cancer risk following the use of postmenopausal HRT is now well established and consistent. Given this knowledge, it is no longer appropriate to conduct large-scale randomized trials of HRT; this means that new relevant trial data are unlikely to be forthcoming. Due consideration should therefore be given to carefully conducted independent meta-analyses of the existing studies and deriving further insights from observational studies. Population-level declines in breast cancer incidence are very encouraging, but vigilance is required to ensure that the worldwide decline in hormone therapy use is preserved. Although the optimal level of HRT use in the population is not known, prevalence of use is still well above what it was in the late 1980s. Hence, there remains a considerable number of HRT users, and there is a potential for further reduction in the incidence of breast cancer and its related morbidity and mortality, through further reductions in use.

Five-year view

Evidence on the risks associated with HRT continues to grow. Survey data indicate that there are still pockets of long-term users in the population who are exposed to the risks associated with long-term hormone therapy use. Therapies for menopause-associated conditions such as osteoporosis have improved significantly in recent years, with a number of nonhormonal options now available. In the absence of other alternatives, HRT remains the most effective option for menopausal symptoms. Drug regulatory authorities continue to recommend that HRT be used for the shortest duration required and that use be reviewed every 6–12 months. In the absence of new studies and fresh evidence, this guidance from drug regulatory bodies is unlikely to change substantially in the next few years.

Table 1. Estimated relative risks in current versus never-users of hormone replacement therapy, by histological type of breast cancer.

Study (year)	Study type	Preparation type	Histological subtype studied	Relative risk estimates (95% CI)	Ref.
Collins et al. (2005)	Meta-analysis	Combined Estrogen only	Lobular Ductal Lobular Ductal	2.82 (1.95–4.07) 1.15 (0.86–1.54) 1.44 (0.97–2.13) 0.90 (0.69–1.18)	[48]
Million Women Study and meta-analysis – Reeves et al. (2006)	Cohort study Meta-analysis of Million Women Study and other available data	Combined Estrogen only Combined Estrogen only	Lobular Ductal Tubular Lobular Ductal Tubular Lobular Ductal Tubular Lobular Ductal Tubular	2.80 (2.46–3.18) 2.00 (1.89–2.12) 3.51 (2.80–4.41) 1.68 (1.43–1.96) 1.22 (1.13–1.31) 1.81 (1.36–2.42) 2.51 (2.27–2.77) 1.76 (1.68–1.85) 3.57 (2.93–4.36) 1.42 (1.27–1.57) 1.10 (1.05–1.15) 1.77 (1.34–2.33)	[7]
Calle et al. (2009)	Cohort study	Combined Estrogen only	Lobular Ductal Lobular Ductal	2.12 (1.62–2.77) 1.75 (1.53–2.01) 1.30 (0.94–1.78) 0.99 (0.84–1.17)	[50]
Phipps et al. (2010)	Cohort study – Breast Cancer Surveillance Consortium	Mostly combined Estrogen only	Lobular Ductal Lobular Ductal	1.46 (1.25–1.70) 1.17 (1.11–1.23) 1.26 (1.03–1.54) 0.98 (0.91–1.05)	[49]

Key issues

• • The use of hormone replacement therapy (HRT) increases the risk of breast cancer.

• • The increased breast cancer risk is greater for combined estrogen–progestin therapies than for estrogen-only therapies.

• • Current evidence indicates similar breast cancer risks for different formulations, doses and routes of HRT administration.

• • Breast cancer risk increases with increasing duration of HRT use.

• • The increased breast cancer risk diminishes rapidly after ceasing use of HRT.

• • Current evidence suggests greater increases in breast cancer risk among women initiating HRT use closer to menopause.

• • HRT-associated breast cancer risk is modulated by obesity: thinner women demonstrate higher relative risks.

• • Use of HRT is associated with a higher risk of dying from breast cancer.

• • Overall, the risks associated with the use of HRT outweigh its benefits, in terms of the risk of serious disease.

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An epidemiological overview of the relationship between hormone replacement therapy and breast cancer

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Your patient is a 51-year-old woman who has developed significant symptoms associated with menopause. However, she is highly reticent to initiate hormone therapy, because she is very nervous about the possibility of developing breast cancer. Her overall breast cancer risk is normal for a woman of her age, and she has no history of gynecologic surgery. What can you tell her about specific types of hormone replacement therapy (HRT) and their associated risks for breast cancer?

• □ A Transdermal HRT is associated with a lower risk for breast cancer compared with oral HRT

• □ B Low-dose HRT is associated with a lower risk for breast cancer compared with moderate-dose HRT

• □ C Estrogen-only HRT is associated with a lower risk for breast cancer compared with combined estrogen-progestin HRT

• □ D Synthetic HRT is associated with a lower risk for breast cancer compared with conjugated equine estrogen HRT

2. What can you tell this patient about the timing of HRT and the risk for breast cancer?

• □ A Longer duration of HRT increases the risk for breast cancer

• □ B Taking HRT for less than 6 months does not change the risk for breast cancer

• □ C HRT initiated at this patient’s stage of menopause is associated with a lower risk for breast cancer compared with initiation later in menopause

• □ D The increased risk for breast cancer will persist for years after discontinuation of HRT

3. What other factor should you consider when contemplating HRT for this patient?

• □ A The risk for breast cancer associated with HRT is greater among obese vs normal-weight women

• □ B HRT particularly increases the risk for ductal breast tumors

• □ C HRT particularly increases the risk for estrogen receptor-negative breast cancer

• □ D Combined HRT is associated with a higher risk for breast cancer mortality

4. On the basis of the results of the current review, what is the best recommendation for this patient with significant menopausal symptoms?

• □ A Do not start HRT given that there is little clinical benefit for symptoms and an attendant high risk for breast cancer

• □ B Initiate low-dose HRT to reduce the risk for breast cancer

• □ C Take HRT for the shortest duration possible to reduce the risk for breast cancer

• □ D HRT should be used at a high dose for 1 year and then the dose may be tapered