Hormone replacement therapy and breast cancer

European Journal of Obstetrics & Gynecology and ReproductiveBiology67 (1996) 1-4

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Guest editorial

Hormone replacement therapy and breast cancer P e t e r K e n e m a n s *a, M e i r S t a m p f e r b aDepartment of Obstetrics and Gynaecology, Free University Hospital, Amsterdam, The Netherlands bprofessor of gpidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA

Accepted 19 February 1996

Keywords: Hormone replacement therapy; Breast cancer; Oestrogen; Progestagen

1. InUroduetion

Breast cancer is the main concern with regard to the use of hormone replacement therapy (HRT); one that is equally shared by postmenopausal women and their physicians. Uncertainty persists as to whether long-term use of HRT adversely affects breast cancer incidence and mortality. While long-term use is necessary to obtain the claimed beneficial effects of H R T on bone (fractures) and heart (infarction), long-term compliance with HRT is rare, in part because of this worry about breast cancer. Although there is no uniformity in the results of observational studies reported, recent findings [1] indicate that in women using H R T for 5 years or more an increased risk for breast cancer is not as 'hypothetical' as suggested in a recent review article in this journal [2]. This is true not only for (hysterectomised) women who use 'oestrogens only' therapy (ERT), but also for women using a combined regimen of a progestagen (sequentially) added to an oestrogen (cHRT). 2. Breast cancer as a hormone-related disease

The evidence that endogenous and exogenous sex steroids profoundly influence normal and malignant breast tissue is overwhelming, and comes from both in vitro investigations and from animal and human studies. Classical risk factors for breast cancer, like early * Corresponding author.

menarche and late menopause, point to a prolonged endogenous hormonal stimulation, while breast cancer risk is reduced after a reduction in exposure to female sex hormones as it is after natural and surgical menopause. Moreover, postmenopausal women with increased endogenous oestrogen serum levels appear to have an increased short-term risk of breast cancer [3]. A similar endogenous stimulation has long been postulated for obese postmenopausal women, explaining their increased risk via increased peripheral aromatisation of adrenal steroids. HRT, in a dosage adequate for symptom relief and fracture prevention, has been reported to give serum oestradiol levels many times higher than those present in untreated postmenopausal women, although it is not easy to measure these serum levels of exogenous oestrogens reliably [4]. Sex steroids are not carcinogens. The role that estrogen plays in the pathogenesis of breast cancer relates to its receptor mediated activation of proto-oncogenes, like c-fos and c-myc, codifying for nuclear proteins that, in turn, can activate other genes [5]. On theoretical grounds, both the influence of oestrogen alone as well as the synergistic action of oestrogen and a progestagen have been postulated to be of prime importance in the development of breast cancer. A protective effect of progestagen as seen for endometrial neoplasia, is not present with regard to breast neoplasia. Observational studies as to the risk of breast cancer incurred with long-term ERT provide extensive, but partly inconsistent evidence; studies on long-term use of combined HRT are limited in size and number.

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3. ERT and breast cancer risk

The relationship between breast cancer risk and replacement therapy with unopposed conjugated equine oestrogens has been investigated in over 30 observational studies. Meta-analyses, that give risk estimates based on the extensive, but partly inconsistent material, all point in the same direction [6-10]. They estimated that women who have used oestrogen for 5 years or less have no increased risk, but also that long-term users incur a significant increase in risk, of approximately 20%-30%, compared to women who never have used oestrogens. It would seem that oral 17/3-oestradiol produces a similar, if not greater, risk than the equine conjugated oestrogens. Data on transdermal oestradiol are totally lacking. 4. Combined oestrogen/progestagen HRT and breast cancer risk

The (cyclic) addition of a progestagen to postmenopausal HRT as a common practice to prevent endometrial pathology [111 dates from around 1980, and therefore the evidence is limited. During the time that combined HRT became the standard regimen for nonhysterectomised women in many countries, a substantial annual increase in breast cancer incidence was also noted, thus increasing the concern as to a possible association. The results of several case-control studies reported until now are not fully compatible. In some of these studies, an increased risk was found for use at any time ('ever use'), when compared to 'never use' [12,13], while no relationship was proven in various other studies [14,151. It should be noted that a risk increase for longterm use (up to 30%), is compatible with the data reported in the Seattle study [15] and therefore cannot be excluded on basis of this study. Several cohort studies of the association between combined HRT and breast cancer risk are now available. The results of these relative large prospective, but non-randomised studies are also not uniform as some find with long-term use an increased risk for invasive breast cancer [1], or only for in situ but not for invasive cancer [16], while others do not find any risk increase at all [17]. One explanation for this could be methodological in nature (confounders, selection bias, surveillance bias, prevalence bias). However, it could also be that the real risk increase, if any, is relatively small. Full concordance exists between these cohort studies in that they agree that there is no statistical difference in breast cancer risks for women on H R T during at least the first 5 years of use. This is also found by the two recent case-control studies, an American one [15] and a European one [18]. The anxiety relating to the long-term HRT use is

especially based on the recent update on the large Nurses' Health Study [1]. The Nurses' Health Study finds that the risk with combined HRT is highly similar to that with ERT, and that this increased risk exists both for breast cancer incidence and for death due to breast cancer. These results, although not in full agreement with those of the other cohort studies, must be taken very seriously in view of the large number of cases present in this cohort. Also of importance is that this study again confirms that the risk of breast cancer is not significantly increased in the first 5 years. Moreover, there is no further increase with long-term use of ___ 10 years and after stopping HRT, also after long-term use, the risk for breast cancer returns to normal within 2 years. Years before the recent paper of Colditz et al. [1] a smaller European study, using a different regimen, mainly 17/3-oestradiol in combination with a non-MPA progestagen, had already suggested that the addition of a progestagen does not reduce the increased risk caused by long-term ERT. In 1989, this Swedish prospective study reported a non-significant four-fold increase in the risk of breast cancer in women who had used sequentially combined HRT for more than 6 years [19]. An update of this study indicated a significantly increased risk in women who had at any time used combined cHRT [20]. A new update of this Uppsala study is awaited shortly. Thus, with cyclically combined HRT-use, both with equine oestrogens and with synthetic oestrogens, an increased breast cancer risk cannot be excluded at the moment. Moreover, and contrary to earlier reports, the recent update of the Nurses' Health Study finds that the risk of death due to breast cancer parallels that of breast cancer incidence, suggesting that these breast cancers were not of a less aggressive type as had been suggested before [21]. 5. Clinical advice to the individual woman

The net health effect of ERT in hysterectomised women and of cHRT in women with an intact uterus should provide the basis for the counselling of peri- and postmenopausal women considering HRT, and also of those already on HRT for some years and considering whether to stop HRT. The use of HRT should possibly be both long-term and current to render its greatest degree of cardioprotection and its largest reduction of osteoporotic fractures [22], but it is precisely with long-term and current use that the increased risk for breast cancer morbidity and mortality also emerges. The effect of stopping HRT on the breast cancer risk is also not very clear: while the Nurses' Health Study [1] finds that the risk returns to normal within 2 years, a recent Italian case-control study claims that an increased risk persists up to 10 years after cessation of HRT [18].

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5. I. Advice for apparently healthy women Combined H R T and ERT can be prescribed (in an adequate dosage with a view to preventing cardiovascular disease and osteoporosis) for a period of 5 years or shorter, without an increase in breast cancer risk. With longer duration of use, the risk of breast cancer must, from an epidemiological point of view, be regarded as somewhat increased. On average, the beneficial effects of H R T probably outweigh the potential adverse effects [91. However, it should be realised that there are no data available as to many modern forms of HRT, such as the transdermal route and the continuous combined regimen. Annual breast examination and a mammography every other year is urgently advised in long-term HRT.

[3]

[4]

[5]

[6] [7]

[8]

5.2. Advice for women at increased risk of breast cancer [9]

A history of breast cancer or a family history of breast cancer have generally been considered relative contraindications for HRT. At present H R T in patients with a 'past' history of breast cancer is controversial [23-27], as oestrogens might or might not activate occult metastases, which can lie dormant over a very long timespan in breast cancer. Before prescribing H R T in women with prior diagnosis of breast cancer, it should be remembered that breast cancer patients without H R T run a two- to five-fold increased risk of breast cancer in the other breast [28]. Women with a mother or a sister diagnosed with breast cancer, have a two-fold increased risk of breast cancer without H R T [29], and patients with a family history of breast cancer, in whom an atypical proliferative breast lesion has also been found, incur an eight- to nine-fold risk for breast cancer [30]. Although the relative risks of breast cancer with H R T are similar in women with or without a family history, the absolute risks are of course higher. Women that belong to a risk group for breast cancer should be counselled very thoroughly before they make, together with their doctor, a decision regarding the use of HRT. A careful consideration of the range of risks and benefits of postmenopausal hormone therapy should lead to a risk-profile based decision for each individual woman. Risk scoring systems, like the European Menopause Journal risks score for long-term H R T [31] could assist in reaching a balanced conclusion. Alternative treatment modalities for climacteric complaints (e.g. clonidine, paced-respiration) or for preventive H R T (e.g. tamoxifen) should also be discussed [32].

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