Breast cancer and post-menopausal hormone therapy

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 17, No. 1, pp. 123–137, 2003 doi:10.1053/ybeem.2003.239, available online at http://www.sciencedirect.com

8 Breast cancer and post-menopausal hormone therapy P. Kenemans*

MD, PhD

Professor and Chairman

A. Bosman

MD

Department of Obstetrics and Gynaecology, Free University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

From the introduction of post-menopausal hormone replacement therapy (HRT) there has been great concern that HRT could possibly increase the risk of breast cancer. Prolonged exposure to endogenous oestrogens undeniably increases the risk of breast cancer. Questions that are important and until now only partly answered, are the following. Are oestrogens tumour promoters, as they induce mitosis, lead to proliferation and, therefore, accelerated growth of clinically occult pre-existing tumours? In addition to this, are they genotoxic mutagenic carcinogens, or could they initiate tumours by way of accumulation of incessant DNA-replication damage mechanism? Opinions vary as to the effect of the addition of a progestogen. There is a multitude of different progestogens which could bind with differing affinity to progesterone receptor PR-A or PR-B, and which have different physiological functions via differential gene regulation. The action of a progestogen on the oestrogen-induced cellular mitotic activity could be synergistic or antagonistic (by different pathways: oestrogen receptor downregulation, activating of metabolic pathways within the breast or stimulation of apoptosis)? Over 60 observational studies and two randomized trials provide evidence that the small but significant increase in risk appears with long-term current post-menopausal hormone use. The addition of a progestogen does not decrease the risk as seen with oestrogens alone and might increase the risk further. It is not clear whether there is a difference in risk with sequentially combined versus continuously combined HRT. Many questions nevertheless still remain. Is the risk increase limited to lean women only? What about risk-modifying factors such as alcohol use and a positive family history for breast cancer? Are tumours detected under HRT less aggressive, is there a better prognosis and is the mortality not increased while morbidity is? And is HRT contraindicated for women with a positive family history for breast cancer or in those women who have been treated for breast cancer? And finally, are there alternative options for these women? Key words: breast; breast cancer; breast cancer risk; breast cancer incidence; breast cancer mortality; breast density; mammography; unopposed oestrogen therapy; combined hormone replacement therapy; continuously combined hormone replacement therapy; sequentially * Corresponding author. Tel.: þ 31-20-4444-813; Fax: þ 31-20-4444-811. E-mail address: [email protected] (P. Kenemans). 1521-690X/03/$ – see front matter

Q 2003 Elsevier Science Ltd. All rights reserved.

124 P. Kenemans and A. Bosman

combined hormone replacement therapy; oestrogens; progestogens; proliferation; apoptosis; incessant replication damage.

From the start, a possible relationship between post-menopausal hormone use and breast cancer has been a point of concern and until this moment, the issue remains controversial.1 – 3 Breast cancer is a major challenge to modern western medicine, with morbidity increasing steadily over the years.4 This ongoing increase in breast cancer incidence in western society has been related to the ongoing development of an unfavourable lifestyle, the risk for breast cancer being related to factors such as alcohol use and body mass index.5 However, in addition to lifestyle factors, the increased use of exogenous sex hormones in oral contraceptives6 and especially post-menopausal hormone replacement therapy7, have also been suggested as having an unfavourable influence on breast cancer risk. Hormone replacement therapy (HRT) can be defined as the peri- and post-menopausal use of sex hormones, mostly of oestrogens, alone or in combinations with progestogens. HRT is effective in reducing climacteric symptoms8 and a role has been suggested in the prevention of disease9 and the prolongation of life.10 Although observational studies show an overall reduction in age-specific mortality in HRT users11 – 15, some recent prospective clinical trials could neither find a role for the prevention of cardiovascular disease nor an overall benefit.16,17 Although a decrease in colorectal cancer risk in HRT users12,13,17 could fully explain the overall reduced mortality risk found in HRT users, in addition and surprisingly, a decreased mortality rate for breast cancer in HRT users has been reported in several studies.18 Breast cancer is generally considered to be a hormone-dependent disease. Therefore, medical inventions such as post-menopausal hormone therapy should ideally be instrumental in the hormonal prevention of a hormone-dependent tumour like breast cancer.19 – 21 However, there is great concern on the basis of both observational studies7 and controlled clinical trials16,17 that this is not the case. On the contrary, HRT might in fact, act as a promoter of breast cancer. In practice, HRT consists of a wide variety of both natural and synthetic substances, with many possible routes of administration. As to the various regimens, a distinction must be made between the unopposed oestrogen regimen (ERT) and the two combined HRT regimens in which the daily oestrogen dose is opposed by either a cyclical (sequentially; scHRT) or a continuous (ccHRT) daily addition of a progestogen. The risk for breast cancer might differ with the regimen used, the route of administration applied, and the type of oestrogen and of progestogen used. In addition to the classical oestrogens and progestogens, other HRT substances, such as tibolone, raloxifene and androgens, are increasingly being used in post-menopausal hormone therapy with a risk for breast cancer that will differ from that seen with the classical oestrogens and progestogens. In addition, possible risk-modifying factors exist—such as obesity, alcohol use and family history. Breast density on the mammogram has also been linked to HRT use and could influence the accuracy in diagnosing breast cancer. CELL BIOLOGY AND BREAST CANCER CARCINOGENESIS Oestrogens are substances that bind to the intranuclear oestrogen receptors alpha and

Breast cancer and post-menopausal hormone therapy 125

beta. Subsequent binding of the ligand receptor complex to oestrogen-response elements within the DNA could lead to activation of proto-oncogenic and growth factor pathways, resulting finally in mitotic activity and, therefore, proliferation and growth. During DNA replication at the time of mitosis, damage to the DNA is likely to occur. However, DNA replication damage is commonly corrected by intrinsic repair mechanisms such as mismatch repair mechanisms. Other mechanisms are also involved. For instance, abnormal cells that have escaped DNA repair mechanisms could go into programmed cell death. Several of these apoptotic pathways are modulated by sex hormones. Oestradiol is known to induce an anti-apoptotic pathway, via Bcl-222, while progestogens and anti-oestrogens are pro-apoptotic.22,23 Generally, carcinogenesis is seen as a multi-step process involving some five to seven mutations in important regulatory genes. Theoretically, continuous oestrogen stimulation would result in incessant mitotic cellular activity, with, consequently, a steadily growing accumulation of unrepaired replication DNA damage. Subsequent inactivation of important regular genes, such as tumour suppressor genes, would ultimately lead to impairment of the above-mentioned DNA repair and apoptotic destruction mechanisms. According to this ‘Incessant DNA Replication Hypothesis’19,20, oestrogens could induce new cancers while not necessarily being genotoxic mutagenic carcinogens. Thus, induction or initiation of tumours by oestrogens could be a possibility in addition to the generally accepted late stage promoters effects of oestrogens that lead to accelerated growth of clinically occult, pre-existing tumours. However, a direct DNA-damaging effect of oestrogens or their metabolites cannot be totally excluded.24 See also Figure 1. Opinions differ as to the effect that the addition of a progestogen could have. It is now known that a total of at least 94 genes are up- or downregulated via progesterone receptor PR-A or PR-B. The two progesterone receptors are isoforms transcribed from two promoters on a single gene and have different physiological functions via differential gene regulation. Four genes are uniquely regulated via PR-A, 65 genes uniquely by PR-B and only 25 by both receptors.25 Different progestogens might have a different affinity for these two progesterone receptors. The action of a progestogen on the oestrogen-induced cellular mitotic activity is claimed by some to be synergistic21,26, and by others to be antagonistic.27 – 29 An antagonistic action could be explained by downregulation of the oestrogen receptor, activation of certain metabolic pathways27,28 or stimulation of apoptosis.23,29 The action of progestogens in combination with oestrogens on mitotic epithelial activity is highly tissue-specific. In this respect, the endometrium differs from the breast. Proliferation in the endometrium is seen in the follicular phase (with over 80% of the endometrial cells proliferating), while proliferation in the breast is seen typically in the luteal phase (with, however, only 10% of the epithelial breast cells proliferating).28,30,31 Nevertheless, it should be noted that, in the breast, in the luteal phase, not only is mitotic rate at its height, but so too is the rate of apoptosis.22 It could well be that the ultimate effect of sex hormones on the breast should not be understood solely in terms of mitosis but rather in terms of the balance between mitotic and apoptotic rates. In conclusion, the influence of the addition of progestogen to oestrogens on breast proliferation in relation to breast cancer risk is not well understood. However, effects could vary substantially between the different HRT regimens common today.26,31 – 35

126 P. Kenemans and A. Bosman

A tumour initiation

E2 mutagens

direct DNA damage DNA

DNA*

normal cell

cancer cell

E2

tumour promotion

B

mitosis

DNA

proliferation DNA

*

* DNA

DNA

* DNA

occult tumour

*

*

clinical tumour

C tumour initiation

E2 mitosis

accumulation of replication damage DNA normal cell

DNA

*

cancer cell

Figure 1. Hormone-dependent carcinogenesis. This figure depicts in a cartoon-like fashion the three possible hypothetical roles that oestrogens could play in the carcinogenesis of breast tumours. (A) Oestrogen acts here as a genotoxic mutagenic carcinogen. The International Agency for Research on Cancer (IARC, Lyon), has classified oestradiol as a weak carcinogen because oestradiol, via its catechol metabolites, can cause freeradical-mediated DNA damage to epithelial breast cells24 (B) Oestrogen as a late-stage tumour promoter via oestrogen-receptor-mediated proto-oncogene activation and subsequent mitotic activity and proliferation, leading to accelerated growth of pre-existing occult tumours that are clinically less aggressive. (C) Oestrogen as a tumour initiator, resulting from incessant mitotic activity, leading to accumulation of unrepaired replication DNA damage with subsequent damage to the tumour suppressor genes and impairment of mismatch repair and apoptosis mechanisms.

Breast cancer and post-menopausal hormone therapy 127

OESTROGENS AND BREAST CANCER: THE EPIDEMIOLOGICAL EVIDENCE A variety of epidemiological studies suggest that prolonged exposure to endogenous oestrogens has an important role in relation to breast cancer risk. In this respect, wellknown established risk factors for breast cancer are early age at menarche, late onset of menopause and post-menopausal obesity.36 Post-menopausal women with a relatively high blood concentration of endogenous oestrogens have been shown to have a substantially increased risk for breast cancer, compared to those with low levels (Ref. 37 and Table 1). It should be noted, however, that, probably due to differences in local metabolism, tissue oestradiol concentrations in the breast and in breast cancer tissue, are not directly related to peripheral blood oestradiol concentrations.38 As to a possible relationship between post-menopausal hormone use and breast cancer, a large series of over 50 observational studies provides evidence that a small but frequently significant risk increase exists with post-menopausal, long-term (5 years and more) use. Predominantly, ERT were used in these studies.1 – 3 Data from 51 epidemiological studies, including 52 705 women with breast cancer and 108 411 controls, have been re-analysed by the Collaborative Group for hormonal effects on breast cancer.7 Eighty per cent of the users were on unopposed oestrogen replacement. For long-term users, the relative risk of developing breast cancer was calculated to be 1.35 (95% CI: 1.21 –1.49). However, the absolute increase in breast cancer cases attributable to post-menopausal hormone use is relatively low. After a period of 25 years, in a group of 1000 women, all having used HRT for 5 years, there would be only two extra cases of breast cancer (See Figure 2). The increased risk was present from the start of use and was roughly equivalent to the relative risk increase that was associated with each year the moment of menopause came later (beyond 50 years of age) in non-HRT users within the same population. Within 5 years after cessation of HRT, the effect on breast cancer risk had largely disappeared.7 Although very large, and comprising 90% of all studies available at that time, the Table 1. Endogenous sex hormones and breast cancer risk. Hormone E2 Free E2 Non-SHBG E2 Oestrone Oestrone sulphate Androstenedione DHEA DHEAS Testosterone SHBG a

RR quintile 5 versus 1 P for trend quintile 1 to 5 n cases/controls quintile 1 to 5 2.00 (1.47–2.71) 2.58 (1.76–3.78) 2.39 (1.62–3.54) 2.19 (1.48–3.22) 2.00 (1.26–3.16) 2.15 (1.44–3.21) 2.04 (1.21–3.45) 1.75 (1.26–2.43) 2.22 (1.59–3.10) 0.66 (0.43–1.00)

,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.05 ,0.01 ,0.001 ,0.05

656/1709 478/980 474/972 469/232 310/651 375/1000 231/423 578/1501 585/1574 373/1160

This table gives the result of a re-analysis of nine prospective studies on the relation between endogenous sex hormones and risk of breast cancer in post-menopausal women.37 The increase in risk for breast cancer was statistically significant with increasing concentrations of all sex hormones examined, quintile five being the quintile with the highest hormone level. DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulphate; SHBG: sex hormone binding globulin.

128 P. Kenemans and A. Bosman never use use for 5 years use for 10 years use for 15 years

90 80 70

89 83 79 77

60 50 40 30 20 10 0

45

50

55

60

65

70

75

Figure 2. Estimate of increase in cumulative number of breast cancers per 1000 post-menopausal women using hormone replacement therapy for 0, 5, 10 and 15 years, respectively, all having started at age 50. Reproduced from Collaborative Group on Hormonal Factors in Breast Cancer (1997, Lancet 350: 1047– 1059) with permission.

re-analysis7 could not report a significant difference in risk related to the various HRT regimens, after 5 years or more. The relative risk reported for combined HRT was 1.53. With oestrogens alone the RR was 1.34. Following the publication of the re-analysis7 in 1997, a dozen epidemiological studies from both the USA and Europe, have been published; the majority of these confirm the existence of a small but consistent increase with long-term use of unopposed oestrogen (Table 2).

COMBINED HRT REGIMENS: THE EPIDEMIOLOGICAL EVIDENCE In the mid 1970s it became evident that unopposed oestrogen use resulted in an increased risk for endometrial cancer. Consequently, a progestogen was added to the oestrogens, commonly for 10 – 14 days of each artificial cycle. A dramatic decline in the incidence of endometrial cancer followed.39,40 Currently, a number of studies are available that have looked specifically at the risk for breast cancer associated with the use of combined HRT as compared to that of ERT users in the same population.17,41 – 53 Generally, an increase in breast cancer risk was reported for combined HRT users compared to ERT users; however, this difference in risk increase never reached significance (See Table 2). When compared to non-users, a significantly increased risk for long-term combined HRT users was found in several recent studies.46 – 52 Continuous combined HRT has been developed to overcome the monthly bleeding episodes associated with sequentially combined HRT, and is becoming increasingly popular. Although it might be too early to draw definite conclusions, the optimistic view that continuous combined HRTwould be less stimulatory to the breast19,33 has thus far not been supported by epidemiological studies. A limited number of observational studies have been published comparing the impact of ccHRT and scHRT on breast cancer risk in the same population.47,49,51,52 Where some studies47,51 found a higher risk for continuous combined HRT users, others49 found a higher risk for sequentially combined HRT users or a highly similar effect.52 However, the differences found between these two regimens were not statistically significant. Within two recent prospective, placebo-controlled clinical trials16,17 continuous combined HRTwas found to induce a higher risk than that among women in the control group. In the HERS study16 long-term use of continuous

Table 2. HRT and breast cancer: studies published after the re-analysis by the Collaborative Group for Hormonal Factors in Breast Cancer in June 1997.7 Study (reference) Persson et al (1997)45 Sweden. Nested case–control, n ¼ 435 cases Persson et al (1999)46 Sweden. Cohort, n ¼ 11 231 Magnusson et al (1999)47 Sweden. Case–control n ¼ 3345 cases Schairer et al (2000)48 USA. Cohort, n ¼ 46 355

Newcomb et al (2002)52 USA. Population-based. Case–control, n ¼ 5298 cases Ursin et al (2002)53 USA. Population-based. Case–control, n ¼ 1897 cases Hulley et al (2002)16 USA. RCT, n ¼ 1380 on HRT WHI (2002)17 USA. RCT, n ¼ 8506 on HRT

HRT

1.3 (0.5 –3.7)

2.4 (0.7–8.6)

10 years of use HRT with NETA

1.1 (0.7 –1.7)

1.7 (1.1–2.6)

6 years of use 45% NETA, 55% MPA

2.18 (1.07 –4.45)

2.43 (1.72– 3.44)

1.5 (1.2 –2.0)

2.0 (1.3–3.0)

1.06 (0.97 –1.15)

1.24 (1.07– 1.45)

1.5 (0.5 –3.9)

2.6 (1.1–5.8)

1.84 (1.04 –3.27)

1.61 (1.03– 2.50)

1.62 (1.03–2.55)

1.85 (0.81–4.21)

1.36 (1.17 –1.58)

1.58 (1.16– 2.15)

1.57 (0.95–2.60)

1.54 (1.15–2.07)

0.77 (0.54 –1.11)

1.51 (0.97– 2.36)

Ongoing

scHRT

1.89 (0.88–4.09)

1.38 (1.13–1.68)

ccHRT

Remarks

2.89 (1.66–5.00)

5–10 years of use HRT with NETA

1.09 (0.88–1.35)

8–16 years of use for ERT, .4 years of use for HRT, BMI , 24.4 kg/m2 RR per 5 years of use HRT with MPA

.0.5 years of use RR for lobular carcinoma HRT with MPA 5 years of use for ERT, .3 years of use for HRT, .3 years of use for scHR, .1.5 years of use for ccHRT .5 years of use for ERT, .5 years of use for HRT 5–10 years of use BMI , 24.6 kg/m2

1.27 (0.84–1.94)

6.8 years of HRT

1.26 (1.00–1.59)

5.2 years of use HRT with MPA

Breast cancer and post-menopausal hormone therapy 129

Ross et al (2000)49 USA. Population-based. Case–control, n ¼ 1897 cases Li et al (2000)50 USA. Population-based. Case–control, n ¼ 537 cases Chen et al (2002)51 USA. Nested case –control, n ¼ 1995 cases

ERT

130 P. Kenemans and A. Bosman

combined HRT resulted in an RR of 1.27 (95% CI: 0.84 –1.94). In the WHI study17, continuous combined use led to an RR of 1.26 (95% CI: 1.00 – 1.59). In view of the large population of women on continuous combined HRT (n ¼ 8506) and the lack of overall benefit in this group, the continuous combined HRT arm of the WHI study was ended prematurely, but not so the oestrogen-only arm, indicating an increased risk with continuous combined HRT when compared to oestrogens only.

BREAST CANCER TUMOUR CHARACTERISTICS IN WOMEN ON HRT USE AND PROGNOSIS Breast cancer tumours found in women on HRTare more localized in nature7 and more often have characteristics that can be defined as less aggressive, such as being more often well differentiated and less often lymph-node-positive.54 – 71 This might explain why most studies that report on death from breast cancer found a lower diseasespecific mortality rate in HRT users compared to non-users.18 Breast cancers in HRT users are significantly smaller in size in some studies54 – 62, but not in others63 – 68, more well differentiated54,55,60,61,64,69,70, but not in all57 – 59,63 and they are less likely to spread to the axillary lymph nodes54,59,63,71; but not all studies found this.57,58,60 – 62,64 – 67,70 Also, results relating to oestrogen receptor positivity are conflicting. So, in conclusion, there is strong but not conclusive evidence to show that breast cancers arising in HRT users have better prognostic characteristics than those found in non-users. However, the possibility should be considered that HRTusers could develop an increased risk for relatively mild breast tumours, while probably not reducing their base-line risk for aggressive tumours, which have a poorer prognosis. Finally, there is the possibility that the phenomenon of a better prognosis of breast cancer in HRT users is due to confounding factors.12 This could be the case when HRT users have easier access to medical care, have more mammograms, have tumours diagnosed earlier and adhere more frequently to a healthier lifestyle, thereby favourably influencing their prognosis. A point that deserves further investigation is the suggestion that HRT only elevates the risk of lobular carcinoma.50 – 53

RISK-MODIFYING FACTORS Studies have investigated whether body mass index, alcohol use and a positive family history for breast cancer might modify the risk for breast cancer when using HRT. A large case – control study47 and a large cohort study48 both found a higher excess risk for breast cancer in lean women, confirming a finding in the re-analysis.7 However, a recent large case– control study did not find any difference.53 Relatively lean women have been shown to have lower concentrations of sex hormones compared to more obese women, when not using exogenous hormones.72 Obesity in post-menopausal non-HRT users has been related to a weakly increased risk of breast cancer, with relative risks calculated generally between 1.1 and 1.9.73 As to alcohol use, in a meta-analysis74 it was shown that post-menopausal alcohol intake (24 g daily—about two drinks) could be related with an increased risk of developing breast cancer. In cohort studies, a relative risk of 1.7 (95% CI: 1.4 –2.2) and in case – control studies a relative risk of 1.4 (95% CI: 1.0 – 1.8) had been calculated.

Breast cancer and post-menopausal hormone therapy 131

The mechanism behind this association is not fully elucidated. However, moderate alcohol consumption can result in a significantly raised serum concentration of oestrone sulphate and dehydroepiandrosterone sulphate.75 It has been shown in observational studies, that a moderate alcohol intake in women on HRT raises the oestradiol levels in the peripheral blood.76 In the Collaborative Group re-analysis7, breast cancer risk among long-term HRT users was also modified by alcohol intake. Surprisingly, women with a family history of breast cancer, using HRT after a natural or a surgical menopause, have not been shown to have an increased risk for breast cancer.77,78 This is especially important for women with a BRCA-1 or 2-gene mutation who are nowadays often being offered bilateral oophorectomy during the premenopause as a prophylactic measure against ovarian cancer. For these particular groups of women, HRT is very important, both in relation to climacteric complaints as well as for the protection against osteoporosis. In the re-analysis of the Collaborative Group7 the relative risk for long-term HRT users with a positive family history for breast cancer was calculated to be lower when compared to those HRTusers without a positive family history. This finding was confirmed in the more recent case – control study by Magnusson et al.47 However, it is important to realize that even a minor increase in relative risk for breast cancer due to HRTuse in women already at a high risk would result in a considerable increase in their absolute risk, as a priori risk for breast cancer in a healthy 50-year-old BRCA1 mutation carrier can be as high as 30% or more.79

HRT AFTER BREAST CANCER In healthy post-menopausal women, HRT is an accepted treatment for relief of acute symptoms, such as flushes and vaginal dryness.8 In women with a history of breast cancer, however, the use of oestrogen-containing replacement regimens is highly controversial and HRT has generally been considered to be contraindicated in these women.2,3 This is quite understandable as many animal studies and in vitro cell line studies have shown breast cancer cells to be oestrogen-dependent.80 Clinically it is well known that ovarian ablation in pre-menopausal women with breast cancer leads to a significantly longer disease-free survival and a reduced mortality.81 This suggests that so-called dormant residual breast cancer cells are present and can be activated by oestrogens, and, therefore, might precipitate the recurrence of clinical breast cancer. Also, oestrogens could induce a new tumour in the contralateral breast in these women. However, there is an increasing number of women in whom subclinical earlystage breast cancer has been detected in screening programmes. It has been argued that quality of life is an important issue in these breast cancer patients, especially in young pre-menopausal women who enter menopause prematurely and artificially, due to surgery, chemotherapy or treatment with gonadotrophin-releasing hormone analogues. After treatment, a substantial portion of these women survive their tumour but suffer from hot flushes and vaginal dryness, and an impaired quality of life. Most probably osteoporosis and cardiovascular disease are long-term health concerns in women with an induced, premature menopause. Questions have been raised as to whether it is correct to regard a history of breast cancer as an absolute contraindication for oestrogen-containing HRT in view of this quality of life issue in breast cancer survivors.3,35 It is important to realize that all clinical data on the effect of HRT on breast cancer recurrence rates come from observational studies that are susceptible to considerable

132 P. Kenemans and A. Bosman

selection bias and publication bias. Recently, Col et al reviewed 11 studies on this matter, including 669 breast cancer cases.82 Four of these studies (including 214 cases) had control groups. RRs calculated for breast cancer recurrence in HRT users compared with non-users were 0.64 (95% CI: 0.36 – 1.15) for the four controlled studies and (using estimated control groups for the other seven studies) 0.82 (95% CI: 0.58 – 1.15) for all 11 studies.82 A more recent study, in 174 breast cancer survivors using HRT, found no adverse impact on recurrence and mortality.83 Again, although these data are reassuring they might be confounded to a significant extent. We look forward to the results of three large, ongoing trials, all on the recurrence rate for women randomized for 2 years of HRT or not, after a diagnosis of breast cancer.84,85

ALTERNATIVES TO OESTROGEN-CONTAINING HORMONE REPLACEMENT THERAPY Tibolone86 as well as raloxifene87 have been suggested as possible options for women seeking alternatives to oestrogen-containing HRT. Both substances are useful in the protection of osteoporosis88,89, with a minimum or absence of breast stimulation.90,91 Interestingly, raloxifene has been shown to reduce breast cancer risk in women with osteoporosis, by about 70%91, while also probably reducing cardiovascular risk.92 Another difference between tibolone and raloxifene is that tibolone is effective in reducing hot flushes and other climacteric complaints, while raloxifene is not. Phyto-oestrogens are a complex group of plant-derived substances of which soy foods and black cohosh are the most well known, and have been claimed to reduce the number of hot flushes, and also LDL cholesterol, but the effect on the breast is not well documented and the effects on the nervous system are controversial.93 Women with climacteric complaints in the perimenopause, or directly thereafter, should be advised not to smoke, to eat a healthy diet, to get adequate exercise, reduce stress and to attain or keep to a healthy weight. Women with hot flushes should reduce drinking alcohol and hot beverages and limit the consumption of spicy foods. So-called paced respiration (deep breathing) might be effective in some patients. Progestogens such as megesterol acetate, when given continuously, diminish flushes in most patients.94 In severe cases, a specific serotonin re-uptake inhibitor such as fluoxetine95 or a cardiovascular drug, for example clonidine96, can be considered. For vaginal dryness and dyspareunia a limited intravaginal dose of oestradiol or oestriol could be considered.97 A non-hormonal vaginal lubricant may offer an acceptable alternative. To reduce the risk of osteoporosis, daily exercise and an adequate dose of calcium and vitamin D are advised. In women with osteopenia or osteoporosis, bisphosphonates have been proven to be very effective. To reduce the risk for cardiovascular disease, control of blood pressure and cholesterol level is important. Appropriate preventive treatment options are nowadays available (aspirin, statins).

SUMMARY The majority of women who use post-menopausal hormones are on one of the following regimens: oestrogens only (ERT), sequentially combined HRTor continuously

Breast cancer and post-menopausal hormone therapy 133

Practice points † long-term, current oral HRT increases breast cancer risk slightly † in a cohort of 1000 women, when all have used HRT from 50 to 55 years of age, there will be two more breast cancers at age 75 that are attributable to HRT (79 women instead of 77 women with breast cancers.) † the excess breast cancers found are more localized and less aggressive † three glasses of wine, daily, produce an increase in breast cancer risk similar to that of HRT † lean women have a higher relative risk for breast cancer with HRT use than do obese women † family history for breast cancer does not increase the HRT-induced risk further † in women with a history of breast cancer, HRT for climacteric symptoms, vaginal dryness and feelings of well being is highly controversial † the effect of the addition of a progestogen to unopposed oestrogens is not exactly known, but probably adverse † our knowledge of other routes of administration than the oral route is very limited † in addition to HRT, effective alternative options exist to treat flushes, vaginal dryness, or to prevent osteoporosis

Research agenda † basic research is needed to definite the role of oestrogens in the process of carcinogenesis more precisely: tumour promoters or genotoxic mutagenic carcinogens? The ability of progestogens to modulate enzymatic and apoptotic pathways needs more study † the role of specific ER-a and ER-b receptor ligands needs to be investigated † the role of specific PR-A and PR-B receptor ligands needs to be studied † the route of administration of oestrogens and progestogens needs to be studied in relation to breast cancer risk

combined HRT. These three regimens have distinctly different effects on the endometrium, resulting in different vaginal bleeding patterns and a differing risk for endometrial cancer. However, the effect on the breast is less well known, and knowledge is lacking about whether they differ in effect on breast cancer risk. In post-menopausal women, oestrogen levels in breast tissue are only weakly correlated to peripheral 17-b-oestradiol serum levels. Locally, oestradiol is produced from oestrone (via oestrone sulphate, or via androstenedione). Many metabolic enzymatic pathways (sulphotransferase, sulphatase, 17-b-OH-steroid-dehydrogenase) are modified by progestogens. Different progestogens could differ in their effect. Oestrones are only very weak mutagenic carcinogens, if at all. Oestrogen induction and oestrogen promotion of breast cancer tumours is a result of ER-a and -b receptor-mediated upregulation of oncogenes (e.g. c-myc and other growth factors) resulting in incessant mitotic activity with subsequent accumulation of resulting replication DNA damage. Receptor expression, mitotic activity and cancer preventing apoptosis are all progestogen-dependent.

134 P. Kenemans and A. Bosman

Mammographic breast density and breast tenderness differ between regimens. It is not clear whether breast density and breast pain can be considered to be biomarkers for breast cancer risk. In 1997, a re-analysis of the observational studies done so far found a slightly increased risk for breast cancer, but no significant difference between regimens. Four later studies, which reported cancer risk in relation to each of the three regimens, produced conflicting results. A recent randomized controlled trial found continuous combined HRT to increase the relative risk for breast cancer, when compared to placebo as well as to ERT. In summary, it appears that the picture is far from clear, but HRT regimens probably differ significantly with respect to breast stimulation and breast cancer risk. The choice of the progestogen in combined HRT regimens is probably also of great importance. Data on non-oral routes (patches, nasal sprays) are very limited. Alternative options for treatment of climacteric complaints are available as well as drugs that protect against osteoporosis and cardiovascular disease.

REFERENCES 1. Kenemans P & Stampfer M. Hormone replacement therapy and breast cancer. European Journal of Obstetrics, Gynecology,and Reproductive Biology 1996; 67: 1 –4. 2. Kenemans P, Scheele F & Burger CW. Hormone replacement therapy and breast cancer morbidity, mortality and recurrence. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1997; 71: 199–203. * 3. Marsden J. Hormone-replacement therapy and breast cancer. Lancet Oncology 2002; 3: 303 –311. Review. 4. Lacey JV Jr, Devesa SS & Brinton LA. Recent trends in breast cancer incidence and mortality. Environmental and Molecular Mutagenesis 2002; 39: 82 –88. 5. Key TJ, Verkasalo PK & Banks E. Epidemiology of breast cancer. Lancet Oncology 2001; 2: 133–140. 6. Collaborative group on Hormonal Factors in Breast Cancer, Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347: 1713–1727. * 7. Collaborative Group on Hormonal Factors in Breast Cancer, Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047–1059. 8. Kenemans P. Menopause, HRT and menopausal symptoms. Journal of Epidemiology and Biostatistics 1999; 4: 141–153. 9. Crosignani PG, Kenemans P, Paoletti R et al. Hormone replacement and the menopause: a European position paper. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1997; 74: 67–72. 10. Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Annals of Internal Medicine 1992; 117: 1016–1037. 11. Ettinger B, Friedman GD, Bush T et al. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstetrics and Gynecology 1996; 87: 6– 12. 12. Sturgeon SR, Schairer C, Brinton LA et al. Evidence of a healthy estrogen user survivor effect. Epidemology 1995; 6: 227 –231. 13. Schairer C, Adami H-O, Hoover R & Persson I. Cause-specific mortality in women receiving hormone replacement therapy. Epidemiology 1997; 8: 75–79. 14. Grodstein F, Stampfer M, Colditz GA et al. Postmenopausal hormone replacement therapy and mortality. New England Journal of Medicine 1997; 336: 1769–1775. 15. Persson I, Yuen J & Bergkvist L. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy—long-term follow-up of a Swedish cohort. International Journal of Cancer 1996; 67: 327– 332. * 16. Hulley S, Furberg C, Barret-Connor E et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy. Journal of the American Medical Association 2002; 288: 58–66. * 17. Writing Group for the Women’s Health Initiative Investigators, Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Journal of the American Medical Association 2002; 288: 321 –333.

Breast cancer and post-menopausal hormone therapy 135 * 18. Nanda K, Bastian LA & Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review. American Journal of Obstetrics and Gynecology 2002; 186: 325–334. * 19. Hesch R-D & Kenemans P. Hormonal prevention of breast cancer: proposal for a change in paradigm. British Journal of Obstetrics and Gynaecology 1999; 106: 1006–1018. 20. Kenemans P, Burger CW & Scheele F. Postmenopausal hormone replacement therapy and gynecological malignancies. In Paoletti R et al (eds) Women’s Health and Menopause, Risk Reduction Strategies—Improved Quality of Health. pp 225–231, Hingham, MA: Kluwer Academic Publishers, 1999. 21. Spicer DV & Pike MC. The prevention of breast cancer through reduced ovarian steroid exposure. Acta Oncologica 1992; 31: 167– 174. 22. Gompel A, Somai S, Chaouat M et al. Hormonal regulation of apoptosis in breast cells and tissues. Steroids 2000; 65: 593– 598. 23. Ellis PA, Saccani-Jotti G, Clarke R et al. Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer. International Journal of Cancer 1997; 72: 608–613. 24. Liehr JG. Is estradiol a genotoxic mutagenic carcinogen? Endocrine Reviews 2000; 21: 40–54. 25. Richer JK, Jacobsen BM, Manning NG et al. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. Journal of Biological Chemistry 2002; 277: 5209–5218. 26. Pike MC, Spicer DV, Dahmoush L & Press MF. Estrogens, progestogens, normal breast proliferation and breast cancer risk. Epidemiologic Reviews 1993; 15: 17–35. 27. Pasqualini JR, Paris J, Sitruk-Ware R et al. Progestins and breast cancer. Journal of Steroid Biochemistry and Molecular Biology 1998; 65: 225 –235. 28. So¨derqvist G, Olsson H, Wilking N et al. Metabolism of estrone sulfate by normal breast tissue: influence of menopausal status and oral contraceptives. Journal of Steroid Biochemistry and Molecular Biology 1994; 48: 221–224. 29. Kandouz M, Lombet A, Perrot JY et al. Proapoptotic effects of antiestrogens, progestins and androgen in breast cancer cells. Journal of Steroid Biochemistry and Molecular Biology 1999; 69: 463–471. 30. So´derqvist G, von Schoultz B, Tani E & Skoog L. Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. American Journal of Obstetrics and Gynecology 1993; 168: 874 –879. 31. Thijssen JH. Oestrogens, progestins and breast proliferation. Zentralblatt fu¨r Gynakologie 1997; 119: 43–47. 32. Cline JM, So¨derqvist G, von Schoultz E et al. Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques. American Journal of Obstetrics and Gynecology 1996; 174: 93–100. 33. Wren BG & Eden JA. Do progestogens reduce the risk of breast cancer? A review of the evidence. Menopause 1996; 3: 4–12. 34. Burger CW & Kenemans P. Postmenopausal hormone replacement therapy and cancer of the female genital tract and breast. Current Opinion in Obstetrics and Gynecology 1998; 10: 41– 45. 35. Verheul HA, Coelingh-Bennink HJ & Kenemans P. Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies. Maturitas 2000; 36: 1–17. 36. Kelsey JL, Gammon MD & John EM. Reproductive factors and breast cancer. Epidemiologic Reviews 1993; 15: 36–47. 37. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. Journal of the National Cancer Institute 2002; 94: 606–616. 38. Blankenstein MA, van de Ven J, Maitimu-Smeele I et al. Intratumoral levels of estrogens in breast cancer. Journal of Steroid Biochemistry and Molecular Biology 1999; 69: 293 –297. 39. Ziel HK & Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. New England Journal of Medicine 1975; 293: 1167–1170. 40. Ziel HK, Finkle WD & Greenland S. Decline in incidence of endometrial cancer following increase in prescriptions for opposed conjugated estrogens in a prepaid health plan. Gynecologic Oncology 1998; 68: 253–255. 41. Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. International Journal of Cancer 1988; 42: 832–888. 42. Bergkvist L, Adami HO, Persson I et al. The risk of breast cancer after estrogen and estrogen–progestin replacement. New England Journal of Medicine 1989; 321: 293–297. 43. Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New England Journal of Medicine 1995; 332: 1589–1593. 44. Newcomb PA, Longnecker MP, Storer BE et al. Long-term hormone replacement therapy and the risk of breast cancer in postmenopausal women. American Journal of Epidemiology 1995; 142: 788 –795. 45. Persson I, Thurfjell E, Bergstrom R & Holmberg L. Hormone replacement therapy and the risk of breast cancer. Nested case –control study in a cohort of Swedish women attending mammography screening. International Journal of Cancer 1997; 72: 758–761.

136 P. Kenemans and A. Bosman 46. Persson I, Weiderpass E, Bergkvist L et al. Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement. Cancer Causes Control 1999; 10: 253–260. * 47. Magnusson C, Baron JA, Correia N et al. Breast-cancer risk following long-term oestrogen- and oestrogen–progestin-replacement therapy. International Journal of Cancer 1999; 81: 339–344. 48. Schairer C, Lubin J, Troisi R et al. Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. Journal of the American Medical Association 2000; 283: 485–491. * 49. Ross RK, Paganini-Hill A, Wan PC & Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. Journal of the National Cancer Institute 2000; 92: 328–332. 50. Li CI, Weiss NS, Stanford JL & Daling JR. Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. Cancer 2000; 88: 2570–2577. 51. Chen C, Weiss N, Newcomb P et al. Hormone replacement therapy in relation to breast cancer. Journal of the American Medical Association 2002; 287: 734– 741. * 52. Newcomb PA, Titus-Ernstoff L, Egan KM et al. Postmenopausal estrogen and progestin use in relation to break cancer risk. Cancer Epidemiology, Biomarkers and Prevention 2002; 11: 593–600. * 53. Ursin G, Tseng C, Paganini-Hill A et al. Does menopausal hormone replacement therapy interact with known factors to increase risk of breast cancer? Journal of Clinical Oncology 2002; 20: 699 –706. 54. Sacchini V, Zurrida S, Andreoni G et al. Pathologic and biological prognostic factors of breast cancers in short- and long-term hormone replacement therapy users. Annals of Surgical Oncology 2002; 9: 266–271. 55. Bonnier P, Sakr R, Bessenay F et al. Effets des traitements hormonaux substitutifs de la me´nopause sur les facteurs pronostiques des cancers du sein. Gyne´cologie, Obste´trique and Fertilite´ 2000; 28: 745–753. 56. Fowble B, Hanlon A, Freedman G et al. Postmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation. Journal of Clinical Oncology 1999; 17: 1680–1688. 57. Salmon RJ, Ansquer Y, Asselain B et al. Clinical and biological characteristics of breast cancers in post-menopausal women receiving hormone replacement therapy for menopause. Oncology Reports 1999; 6: 699 –703. 58. Magnusson C, Holmberg L, Norden T et al. Prognostic characteristics in breast cancers after hormone replacement therapy. Breast Cancer Research and Treatment 1996; 38: 325 –334. 59. Bonnier P, Bessenay F, Sasco AJ et al. Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer. International Journal of Cancer 1998; 79: 278–282. 60. O’Connor IF, Shembekar MV & Shousha S. Breast carcinoma developing in patients on hormone replacement therapy: a histological and immunohistological study. Journal of Clinical Pathology 1998; 51: 935–938. 61. Holli K, Isola J & Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. Journal of Clinical Oncology 1998; 16: 3115–3120. 62. Delgado RC & Lubain Lopez DM. Prognosis of breast cancers detected in women receiving hormone replacement therapy. Maturitas 2001; 38: 147–156. 63. Jones C, Ingram D, Mattes E & Hahnel R. The effect of hormone replacement therapy on prognostic indices in women with breast cancer. Medical Journal of Australia 1994; 161: 106– 110. 64. Harding C, Knox WF, Faragher EB et al. Hormone replacement therapy and tumour grade in breast cancer: prospective study in screening unit. British Medical Journal 1996; 312: 1646–1647. 65. Strickland DM, Gambrell RD Jr. et al. The relationship between breast cancer survival and prior postmenopausal estrogen use. Obstetrics and Gynecology 1992; 80: 400–404. 66. LeBlanc ES, Viscoli CM & Henrich JB. Postmenopausal estrogen replacement therapy is associated with adverse breast cancer prognostic indices. Journal of Women’s Health and Gender-based Medicine 1999; 8: 815–823. 67. Cobleigh MA, Norlock FE, Oleske DM & Starr A. Hormone replacement therapy and high S phase in breast cancer. Journal of the American Medical Association 1999; 28: 1528–1530. 68. Bonnier P, Romain S, Giacalone PL et al. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstetrics and Gynecology 1995; 85: 11–17. 69. Manjer J, Malina J, Berglund G et al. Increased incidence of small and well-differentiated breast tumours in post-menopausal women following hormone-replacement therapy. International Journal of Cancer 2001; 92: 919–922. 70. Bilimoria MM, Winchester DJ, Sener SF et al. Estrogen replacement therapy and breast cancer: analysis of age of onset and tumor characteristics. Annals of Surgical Oncology 1999; 6: 200–207. 71. Squitieri R, Tartter PI, Ahmed S et al. Carcinoma of the breast in postmenopausal hormone user and nonuser control groups. Journal of the American College of Surgeons 1994; 178: 167 –170. 72. Verkasalo PK, Thomas HV, Appleby PN et al. Circulating levels of sex hormones and their relation to risk factors for breast cancer: a cross-sectional study in 1092 pre- and postmenopausal women (UK). Cancer Causes Control 2001; 12: 47–59.

Breast cancer and post-menopausal hormone therapy 137 73. Pujol P, Galtier-Dereure F & Bringer J. Obesity and breast cancer risk. Human Reproduction 1997; 12: 116–125. 74. Longnecker MP, Berlin JA, Orza MJ & Chalmers TC. A meta-analysis of alcohol consumption in relation to risk of breast cancer. Journal of the American Medical Association 1988; 260: 652 –656. 75. Dorgan JF, Baer DJ, Albert PS et al. Serum hormones and the alcohol-breast cancer association in postmenopausal women. Journal of the National Cancer Institute 2001; 93: 710 –715. 76. Zumoff B. Does postmenopausal estrogen administration increase the risk of breast cancer? Contributions of animal, biochemical and clinical investigative studies to a resolution of the controversy. Proceedings of the Society for Experimental Biology and Medicine 1998; 217: 30–37. 77. Kenemans P & Scheele F. Hormone replacement therapy in patients at high risk of developing breast cancer: the use of a combined risk model. Gynecological Endocrinology 1997; 11: 17–22. 78. Scheele F, Burger CW & Kenemans P. Postmenopausal hormone replacement in the woman with a reproductive risk factor for breast cancer. Maturitas 1999; 33: 191–196. 79. Ford D & Easton DF. The genetics of breast and ovarian cancer. British Journal of Cancer 1995; 72: 805–812. 80. Fishman J, Osborne MP & Telang NT. The role of estrogen in mammary carcinogenesis. Annals of the New York Academy of Sciences 1995; 768: 91 –100. 81. Early Breast Cancer Trialist’s Collaborative Group, Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189–1196. 82. Col NF, Hirota LK, Orr RK et al. Hormone replacement therapy after breast cancer; a systematic review and quantitative assessment of risk. Journal of Clinical Oncology 2001; 19: 2357–2363. 83. O’Meara ES, Rossing MA, Daling JR et al. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. Journal of the National Cancer Institute 2001; 93: 754–762. 84. Pritchard KI. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer and a review of possible alternatives. Annals of Oncology 2001; 12: 301–310. 85. Pritchard KJ. Hormone replacement in women with a history of breast cancer. Oncologist 2001; 6: 353–362. 86. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. Journal of Steroid Biochemistry and Molecular Biology 2001; 76: 231–238. 87. Barrett-Connor E. Raloxifene: risks and benefits. Annals of the New York Academy of Sciences 2001; 949: 295–303. 88. Delmas PD, Bjarnason NH, Mitlak BH et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. New England Journal of Medicine 1997; 337: 1641–1647. 89. Berning B, Bennink HJ & Fauser BC. Tibolone and its effect on bone: a review. Climacteric 2001; 4: 120– 136. 90. Gompel A, Chaouat M, Jacob D et al. In vitro studies of tibolone in breast cells. Fertility and Sterility 2002; 78: 351–359. 91. Cauley JA, Norton L, Lippman ME. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Research and Treatment 2001; 65: 125–134. 92. Barrett-Connor E, Grady D & Sashegyl A. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. Journal of the American Medical Association 2002; 287: 847 –857. 93. Albertazzi P & Purdie DW. The nature and utility of the phytoestrogens; a review of the evidence. Maturitas 2002; 42: 173 –185. 94. Loprinzi CL, Michalak JC, Quella SK et al. Megestrol acetate for the prevention hot flushes. New England Journal of Medicine 1994; 331: 347–352. 95. Freedman RR. Physiology of hot flashes. American Journal of Human Biology 2001; 13: 453 –464. 96. Loprinzi CL, Sloan JA, Perez EA et al. Phase III evaluation of fluxetine for treatment of hot flashes. Journal of Clinical Oncology 2002; 20: 1578–1583. 97. Nilsson K & Heimer G. Low-dose oestradiol in the treatment of urogenital oestrogen deficiency—a pharmacodynamic study. Maturitas 1992; 13: 121–127.