1 Maturitas 51 (2005) Breast cancer risk in the WHI study: The problem of obesity Herbert Kuhl Department of Gynecology and Obstetrics, J. W. Goethe University of Frankfurt, Theodor-Stern-Kai 7, D Frankfurt am Main, Germany Abstract In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy Elsevier Ireland Ltd. All rights reserved. Keywords: Breast cancer risk; Postmenopause; Obesity; Hyperinsulinemia; Hormone replacement therapy Tel.: ; fax: address: /$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved. doi: /j.maturitas
2 84 H. Kuhl / Maturitas 51 (2005) Introduction Breast cancer is the most frequent malignant disease in Western countries and seems to be dependent on lifestyle and nutrition. The development of breast cancer is usually regarded as a multifactorial process which means that the etiology is unknown. There are many theories that are based on experimental investigation and relatively inconsistent epidemiological data. There is, however, no doubt that reproductive factors play an important role. Concerning the impact of sex steroids, the cumulative exposure to endogenous and exogenous estrogens and progestins seems to determine the life-time risk of breast cancer. 2. Risk factors for the development of breast cancer Certain risk factors for the development of breast cancer like age and gene mutation (e.g., BRCA1 Table 1 Risk factors for the development of breast cancer Risk factor Relative risk Reference no. Sex male:female 1:100  Age 25 years:45 years 1:20  Body weight normal 1:2.5  weight:obesity Age at menopause 42 years:52 1:2.0  years Age at menarche 14 years:11 1:1.3  years Parity multiparous:nulliparous 1:1.3 [7,8] Age at first birth 20 years:35 1:1.4 [7,8] years Total duration of lactation 5 1:1.2  years:never Benign breast disease no:yes 1:1.57  Oral contraceptives never 1:1.1 [10,11] user:ever user Hormone replacement never:5 1:1.3 [4,12] or more years Alcohol consumption 1:1.3  none: 20 g daily Serum lipids normal:raised 1:1.6  Physical activity active:inactive 1:1.2  Shift work never:shift 1:1.36  work > 30 years Antibiotic use never:50 days in total 1:1.5  and BRCA2) must be accepted as an unchangeable predisposition. Many other risk factors, e.g., obesity or hormone replacement therapy (HRT) can, however, be avoided or changed. Early menarche and late menopause indicate a prolonged exposition to estrogens and progesterone that increase the risk of breast cancer, whereas long-term lactation decreases the risk (Table 1) [1,2]. The latter may be due to the suppression of ovulation during breastfeeding. Moreover, the Nurses Health Study showed that irregular cycles in young women are associated with a reduced life-time breast cancer risk . As in anovulatory cycles there is generally no estrogen deficiency, it may be assumed that the protective effect of anovulation is associated with the lack of progesterone. Obesity, insulin resistance, disorders of lipid metabolism and elevated alcohol consumption seem to increase breast cancer risk. The impact of long-term shift work is possibly related to the prolonged light exposure at night resulting in a suppression of melatonin levels, while the cumulative association of use of antibiotics with the risk of breast cancer might reflect a weakened immune function (Table 1) [1 17]. 3. Breast cancer risk and HRT: epidemiological data 3.1. Observational studies Many observational studies on the influence of HRT on breast cancer risk revealed contradictory results, and every new case-control study or cohort study will enlarge this long row of inconsistent outcomes. The collaborative reanalysis from 1997 was an attempt to bring together and re-examine the individual data of all relevant studies published so far. It revealed that each year of delayed menopause increases the risk by 2.8% which was in the range of 2.3% for each year of HRT . The relative risk of breast cancer increased by 35% in postmenopausal women who had used HRT for 11 years on average. The cumulative excess of breast cancers diagnosed between the ages of 50 and 70 years per 1000 women who began HRT at age 50 and used it for 5, 10, and 15 years, were estimated to be 2, 6, and 12 cases. Within 5 years after discontinuation of treatment, the elevated risk has returned to baseline .
3 H. Kuhl / Maturitas 51 (2005) Randomised controlled trials Randomised placebo-controlled trials are regarded as the non-plus-ultra for the investigation of the impact of drugs on disease risk. Therefore, the results of the HER study and both arms of the WHI study were highly estimated [12,18,19]. The question arises, however, whether the group of women investigated in these studies, reflects those women who normally receive HRT. In the WHI study and the HER study the participating women were selected as to suffer not from climacteric symptoms. Consequently, their mean age was very high (about 63 years) and a high proportion of the women was obese (35 45% had a BMI 30 kg/m 2 ). As obesity is associated not only with an elevated risk for developing a metabolic syndrome and coronary heart disease, but also with an increased risk of breast cancer, the results may be rather questionable. The HER study on the secondary prevention of coronary heart disease by continuous treatment with mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate (CEE/MPA), observed a non-significant 27% increase in the relative risk of breast cancer after 6.8 years . In the WHI study 5.2 years of treatment with CEE/MPA increased the relative risk of breast cancer by 24%, but only in those women who were pretreated with hormones prior to the start of the WHI study . Moreover, that arm of the WHI study which investigated the effect of CEE alone in hysterectomized women, revealed a highly surprising result: after 6.8 years of treatment the relative risk of breast cancer was 0.77 . Even though the result narrowly missed statistical significance, the consistent time course of the Kaplan Meier estimates suggests that the estrogen therapy had a protective effect  Effect of different regimens of hormone therapy In the collaborative reanalysis the type of HRT was known for about 40% of the users: 80% of them were treated with conjugated estrogens and only 12% with estrogen/progestin combinations. The relative risk of breast cancer was found to be 1.34 in women treated for 5 years with estrogens alone and 1.53 in women treated for 5 years with estrogen/progestin combinations. There was no difference in risk between the dose of mg and 1.85 mg conjugated estrogens . The Million Women Study (MWS) reported on an increase in breast cancer risk by 30% using estrogens Table 2 Relative risk (RR) of breast cancer during replacement therapy with estrogens only (ERT) or estrogen/progestin combinations (HRT) Study Treatment ERT (RR; 95% CI) HRT (RR; 95% CI) HERS I + II  Current 6.8 years 1.27 ( ) a WHI [19,23] Current 6.8/5.2 years 0.77 ( ) 1.24 ( ) a MWS  Current 2.6 years 1.30 ( ) 2.00 ( ) b Magnusson et al.  Ever 1.94 ( ) 1.63 ( ) b Ross et al.  Ever 5 years 1.06 ( ) 1.24 ( ) b Colditz and Rosner  Ever 10 years 1.23 ( ) 1.67 ( ) b Schairer et al.  Current 1.10 ( ) 1.40 ( ) b Kirsh and Kreiger  Ever 10 years 1.74 ( ) 3.48 ( ) b Porch et al.  Current 5 years 0.99 ( ) 1.82 ( ) b Daling et al.  Ever 5 years lobular 1.30 ( ) 2.50 ( ) a Daling et al.  Ever 5 years, ductal 0.70 ( ) 1.20 ( ) a Weiss et al.  Current 5 years 0.81 ( ) 1.54 ( ) a Chen et al.  Current lobular 1.98 ( ) 3.91 ( ) b Chen et al.  Current non-lobular 1.08 ( ) 1.25 ( ) b Jernström et al.  Ever 1.50 ( ) 3.30 ( ) a Li et al.  Current lobular 1.30 ( ) 3.10 ( ) b Li et al.  Current ductal 1.00 ( ) 1.70 ( ) b Bakken et al.  Current 1.80 ( ) 2.50 ( ) b Stahlberg et al.  Current 1.96 ( ) 2.70 ( ) b Stahlberg et al.  Current ductal 2.03 ( ) 4.10 ( ) a a Continuous combined estrogen/progestin therapy. b Sequential or continuous combined estrogen/progestin therapy.
4 86 H. Kuhl / Maturitas 51 (2005) alone and by 100% using estrogen/progestin combinations . The results may, however, be impaired by detection bias, as, e.g., within 1 year after the first mammographic screening the number of breast cancer diagnoses (interval cancers) had increased three-fold in postmenopausal women treated continuously with estrogen/progestin combinations since several years. The MWS did not find any difference in the risk of breast cancer regarding type and dose of estrogens, route of administration, type of progestins, or sequential or continuous treatment . During the last years evidence has accumulated that the increase in breast cancer risk is relatively low during use of unopposed estrogens, and is considerably enhanced by the addition of progestins (Table 2) [9,18 36]. The only exception was a Swedish casecontrol study which found the highest risk with estrogen only . A qualitative review showed the inconsistency of results of observational studies, and most of the cohort studies were not associated with a significant increase in risk . Recent studies confirmed the elevated breast cancer risk using estrogen/progestin combinations. According to the data of the Nurses Health Study, the use of unopposed estrogens increases the risk of breast cancer by 23% and of estrogen/progestin combinations by 67% . The randomised, double-blind, placebo-controlled Womens s Health Study revealed no increase in risk using estrogens alone or sequential estrogen/progestin combinations, but a significant 82% increase in women treated with continuous combined estrogen/progestin preparations . Three Scandinavian cohort studies revealed a considerably higher relative risk in women treated with estrogen/progestin combinations than with estrogen alone (Table 2) [32,34,35] Histological types and receptor status of breast tumors In most studies continuous combined HRT was associated with the highest relative risk of breast cancer, particularly of hormone receptor-positive carcinoma. While the use of estrogens alone was associated with no or a slightly elevated risk, estrogen/progestin combinations increased the incidence of lobular cancers to a much greater extent than that of ductal carcinoma [29,31,33,37]. Treatment with estrogen/progestin combinations increased the frequency of estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) invasive breast cancers 2- to 2.5-fold, whereas the effect on receptor-negative carcinoma was less pronounced [33,36,37]. Current use of hormones was associated with a higher incidence of tumors with the low malignancy grade1 . The analysis of data from the Nurses Health Study revealed that postmenopausal women who used HRT had a higher probability of developing ER+ and PR+ tumors, and a higher body mass index (BMI) was associated with ER+/PR+ tumors . 4. The role of sex steroids in the development of breast cancer 4.1. Effect of sex steroids on the proliferation of normal and malignant breast tissue Although estrogens may be involved in the initiation of breast cancer, a carcinogenic/mutagenic role of sex steroids is rather improbable. The available experimental, clinical and epidemiological data suggest that the development of breast cancer is closely related to an accelerated hormone-induced growth of preexisting occult tumors. In an autopsy study, small occult breast cancers were found in 39% of women aged years . Epidemiological studies revealed that the impact of estrogens on the relative risk of breast cancer is modest, but considerably enhanced by the addition of progestins. This corresponds to the proliferative effects both on normal mammary epithelium and breast cancers of estrogens which is enhanced by the presence of MPA or progesterone. The mitosis rate of both ER+/PR+ and ER /PR carcinoma was higher in the luteal phase than in the follicular phase . Similarly, the mitosis rate of healthy breast epithelium was highest in the luteal phase, and higher during treatment of postmenopausal women with CEE/MPA as compared to CEE alone [41,42]. Similar effects of CEE and CEE/MPA were observed in the monkey model . In contrast, neither ethinylestradiol plus norethisterone nor tibolone had a significant effect on the proliferation of normal breast epithelium [44,45], even though both tibolone and all types of estrogen/progestin combinations were found to be associated with an increased risk of breast cancer [21,32,34,35,37]. Therefore, it is ques-
5 H. Kuhl / Maturitas 51 (2005) tionable whether the effects of different HRT preparations on healthy mammary epithelium reflect those on breast carcinoma Regulation of growth in benign and malignant breast tissue There are profound differences between healthy and malignant breast tissue concerning the hormonedependent regulation of mitoses. In the resting normal mammary tissue ER and PR are expressed in very few epithelial cells, while ER is present in 70% of the cells. Those 2% of epithelial cells which are proliferating, do not contain ER . The mitoses are probably controlled by paracrine interactions of adjacent epithelial cells containing ER and PR, while ER was suggested to inhibit ER -induced effects. The effect of progesterone on proliferation and differentiation of the mammary epithelium is primarily dependent on the PRB, whereas PRA has a negative effect on PRB, and overexpression of PRA may reflect a more aggressive state . While in healthy tissue ER is expressed only in resting cells, the transition of benign to malignant mammary tissue is characterized by a switch from paracrine to autocrine regulation of epithelial cell proliferation by sex steroids, i.e., in breast tumors ER and PRs are expressed also in proliferating cells [47 49]. The development of breast cancer is closely related to the function of the normal, slow dividing, long living, undifferentiated stem cells which have both a highly proliferative potential and the ability to differentiate . Long-term exposure to genotoxic agents may cause mutations resulting in the formation of breast cancer stem cells/progenitor cells. They can either lose their steroid receptors and become rapidly proliferating ER cells or they become ER+ progenitor cells which proliferate and in addition stimulate growth of ER cells by producing paracrine factors . The better prognosis of ER+ breast tumors and the more aggressive behaviour of ER tumors as well as the effect of HRT on these subtypes are associated with their origin. ER and ER are expressed in 60 75% of breast cancers [48,49]. ER tumors which arise from the most primitive ER stem/early progenitor cells, are poorly differentiated, more aggressive, and have a poor prognosis. Their growth is neither influenced by HRT nor by SERMs . Early mutations of ER stem cells may cause the differentiation of a subset of cells into ER+ cells. These tumors contain ER+ and ER cells and may transitorily respond to HRT and antiestrogens, but would not have lasting effects, because proliferation of ER cells continues. Therefore, HRT should not increase significantly the risk of this subtype of breast cancer . A third subtype may arise through transformation of ER+ progenitor cells and consists of more differentiated cells. Their growth may be slowed down by treatment with antiestrogens and accelerated during HRT, and in both cases this subtype has the best prognosis . 5. Interference of overweight with HRT concerning breast cancer risk 5.1. Relation between breast cancer risk and body mass index Obesity is associated not only with an elevated risk of developing coronary heart disease, but also with an increase in risk of various cancers [51,52]. Moreover, there is a highly significant association between the risk of breast cancer and BMI, % body fat and weight gain in postmenopausal women (Table 3) [52 55]. Epidemiological data suggest that a high BMI may attenuate the effect of estrogens on breast cancer risk. The collaborative reanalysis from 1997 found an association between body mass index (BMI) and the relative risk of breast cancer, increasing by 3.1% per kg/m 2 . Moreover, the relative breast cancer risk associated with HRT decreased progressively with increasing weight or BMI. It was 1.73 in postmenopausal women with a BMI below 22.5 kg/m 2 and 1.02 for BMI of 25.0 kg/m 2 (Table 3) . Estrogen therapy was found to increase the risk of breast cancer only in women with a BMI of less than 24.5 kg/m 2 . In the Nurses Health Study, the risk of breast cancer correlated with the BMI in postmenopausal women without HRT, but less in premenopausal women . It is well known that an increase in caloric uptake and energy expenditure leads to a stimulation of adrenal androgen secretion, a decrease in SHBG and an elevated aromatisation of androgens in the excessive fat tissue. A significant correlation between the serum levels of total and free estradiol and the
6 88 H. Kuhl / Maturitas 51 (2005) Table 3 Association between risk of breast cancer and obesity-related factors in postmenopausal women Breast cancer risk is elevated in obese postmenopausal women At very low serum concentrations breast cancer risk correlates with serum estradiol levels HRT does not increase risk of breast cancer in obese postmenopausal women Breast cancer risk correlates with body mass index Breast cancer risk correlates with % body fat Breast cancer risk correlates with weight gain Prevalence of metabolic syndrome is elevated in obese women Insulin resistance and hyperinsulinemia increase breast cancer risk in postmenopausal women Serum level of C-peptide correlates with risk of mammary epithelial hyperplasia and breast cancer Serum level of adiponectin correlates with insulin sensitivity Serum level of adiponectin correlates negatively with body mass index Serum level of adiponectin correlates negatively with insulin resistance and hyperinsulinemia Serum level of adiponectin correlates negatively with breast cancer risk Estrogen replacement therapy reduces fasting insulin and increases insulin sensitivity Estrogen/progestin reduces incidence of diabetes mellitus in postmenopausal women Estrogen replacement therapy reduces risk of breast cancer in obese postmenopausal women risk of breast cancer in postmenopausal women has been reported. At estradiol levels of above 8 pg/ml the risk was three times higher than that at levels below 5 pg/ml, and at levels of above 11 pg/ml it was five times higher than that at levels below 8 pg/ml [56 58]. Correlations do not imply causality, and it seems rather improbable that such large differences in breast cancer risk are due to such small differences in the estradiol levels. There must be an additional risk factor associated with obesity, e.g., insulin resistance and hyperinsulinemia, which is influenced by sex steroids and might be involved in the development of breast cancer (Table 3)  Hyperinsulinemia and breast cancer risk The prevalence of insulin resistance and hyperinsulinemia increases with age, BMI and estrogen deficiency . Obese postmenopausal women are at a high risk to develop a metabolic syndrome that is characterized by hypertension, coronary heart disease, dyslipidemia, insulin resistance and hyperinsulinemia . Recent investigations suggest that it is in all probability the elevated insulin level in obese postmenopausal women which is responsible for the increased risk of breast cancer. A specific protein secreted by adipocytes, adiponectin, correlates with insulin sensitivity. Low levels of adiponectin which precede a decrease in insulin sensitivity, are closely and inversely associated with insulin resistance and hyperinsulinemia . In postmenopausal women a significant inverse relation between serum adiponectin and breast cancer risk was observed, whereas in premenopausal women no such association was found [63 65]. IGF-1 has been suggested to be associated with breast cancer risk in premenopausal women, but in postmenopausal women no relation between breast cancer risk and the levels of IGF-1 was found [63 65]. The significant correlation of the levels of C-peptide with the occurrence of epithelial hyperplasia of the breast or breast cancer suggests a key role of elevated insulin levels in the growth of breast cancer in postmenopausal women . Postmenopausal patients, but not premenopausal women with type 2 diabetes had a 16% higher breast cancer risk than women without diabetes (Table 3) . The lack of an association between breast cancer risk and hyperinsulinemia in premenopausal women suggests a modulatory role of sex steroids. Low doses of estrogens have been demonstrated to improve insulin sensitivity in postmenopausal women and to reduce elevated fasting insulin levels, while higher estrogen levels or the use of more potent estrogens may decrease insulin sensitivity. The addition of progestins may decrease insulin sensitivity, possibly by reducing insulin binding to the insulin receptor and glucose transport. Treatment of non-obese postmenopausal women with mg CEE improved insulin sensitivity by 25%, whereas 1.25 mg CEE caused a decrease by 25%. The sequential addition of 10 mg MPA antagonized the beneficial effect of mg CEE and caused an 18% decrease in insulin sensitivity . Treatment of postmenopausal women with estrogen-only reduced fasting insulin by 35%, while estrogen/progestin combinations were less effective . The PEPI study revealed that treatment of postmenopausal women with mg CEE with or without additional progestins led to a reduction in fasting insulin and glucose levels .
7 H. Kuhl / Maturitas 51 (2005) In postmenopausal women with impaired glucose tolerance continuous combined treatment with mg CEE and 2.5 mg MPA reduced insulin resistance and fasting glucose levels, while in women with normal glucose tolerance the levels of fasting insulin and glucose were decreased . The increase in the postchallenge glucose concentrations during OGTT that was observed in postmenopausal women under HRT, might be caused by a delayed insulin response to glucose and an increased insulin clearance in the liver [67,68,70]. It was observed in the WHI study that treatment of postmenopausal women with CEE/MPA for 5.6 years on average caused a significant decrease in the incidence of diabetes mellitus by 21%. This was probably mediated by a decrease in insulin resistance, as already after 1 year of treatment fasting glucose and insulin had significantly decreased . 6. The WHI study unsuitable for the investigation of breast cancer risk 6.1. Characteristics of the women participating in the WHI study Concerning the assessment of breast cancer risk, the high age of the women enrolled in the WHI study could be regarded as an advantage, because the incidence of invasive breast cancer rises with increasing age. The annual number of breast cancer diagnoses increases from 18/1000 women at age 50 years up to 45/1000 women at age 63 years and to 63/1000 women at age 70 . In both arms of the WHI study the mean age was about 63 years on average and two third of the women were older than 60 years at screening (Table 4). On the other hand, the extremely high mean body mass index (30.1 and 28.5 kg/m 2 ) and the high percentage of overweight (34.8 and 35.3%) and adipose women (44.6 and 34.1%) in the CEE arm and the CEE/MPA arm of the WHI study suggests a high prevalence of the metabolic syndrome (Table 4) [12,19]. The incidence of the metabolic syndrome increases with menopause, and is associated not only with an elevated risk of cardiovascular disease, but also with an increased risk of breast cancer owing to insulin resistance and hyperinsulinemia [51,52,59,65]. Consequently, the women participating in the WHI study had both an elevated risk of coronary heart disease, and a high breast Table 4 Baseline characteristics of the volunteers participating in the WHI study Characteristics CEE CEE/MPA Number of participants Age at screening 63.6 ± ± 7.1 (mean ± S.D., years) Age group years (%) Age group years (%) Age group years (%) Body mass index 30.1 ± ± 5.8 (mean ± S.D., kg/m 2 ) Body mass index 25 kg/m 2 (%) Body mass index kg/m 2 (%) Body mass index 30 kg/m 2 (%) Current or past smoking (%) Treated for diabetes mellitus (%) Treated for hypertension (%) Treated for hypercholesterolemia (%) Use of statins (%) Use of aspirin (%) Past or current hormone use at screening In the estrogen-only study the women were randomly assigned to be treated with either placebo or mg conjugated equine estrogens (CEE) , and in the estrogen/progestin study either with placebo or mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (CEE/MPA) . cancer risk. As it was shown that HRT does not influence breast cancer risk in postmenopausal women with a BMI above 25 kg/m 2 [4,9,26], the WHI study was not suitable for the investigation of the influence of HRT on breast cancer risk. This was even confirmed by the WHI Observational Study with about 86,000 women  The WHI study: effect of CEE/MPA or placebo The randomised placebo-controlled WHI study was planned for an average time of 8.5 years of exposure to either CEE/MPA or placebo . The premature discontinuation of treatment with CEE/MPA after 5.2 years was justified with an increased risk of cardiovascular disease and a pretendedly elevated risk of breast cancer . The estimated hazard ratio (HR) for inva-
8 90 H. Kuhl / Maturitas 51 (2005) Fig. 1. Number of breast cancer diagnoses per 1000 women per year during the course of treatment with placebo or CEE/MPA in the WHI study (data from Table 2, subanalysis of the WHI study published by Chlebowski et al. ). The left part of the graph refers to women who were not treated with hormones prior to the WHI study, the right part of the graph refers to women who have received hormone replacement therapy prior to the WHI study (reproduced from Kuhl 2004 ). sive breast cancer was calculated as 1.26 which was, however, not significant. A subsequent updated subanalysis based on a mean follow-up of 5.6 years revealed a significantly elevated HR of breast cancer of 1.24 which just surpassed the border of statistical significance . The analysis revealed, however, that in those women who had never used hormones before initiation of the WHI study, treatment with CEE/MPA did not increase the risk of breast cancer. It was elevated during treatment with CEE/MPA only in those patients who reported HRT prior to WHI study . A graph showing the annual number of breast cancers per 1000 women during the course of the study (Fig. 1) which was based on the data depicted in the paper of Chlebowski et al. , arouses suspicion that the elevated risk calculated in this group is an artifact due to a pretreatmentassociated selection bias . In the group of women without prior HRT, both the 6277 women treated with CEE/MPA and the 6020 women on placebo showed a similar age-dependent rise in the rate of breast cancer which corresponded to a hazard ratio (HR) of In the group of women with prior HRT before the WHI study, treatment of 2225 women with CEE/MPA also caused an age-dependent increase which after smoothing for fluctuations was similar to that of the 6020 never users. In this group, the calculated HR of 1.7 for women with <5 years of prior use and of 2.27 for 5 years of prior use of HRT was due to the extremely low risk in the 2079 women on placebo which did not show an age-dependent increase in risk. This can be interpreted as a hangover effect of pretreatment. In the Nurses Health Study, the HRT-induced elevation in breast cancer risk decreased within 2 years after cessation of treatment and remained lowered during the first 5 years without hormones . The lacking effect of CEE/MPA on breast cancer risk in the WHI study corresponds to the results of other studies which showed that HRT does not increase breast cancer risk in overweight postmenopausal women with a BMI of 25 kg/m 2 or more. This has been observed in the collaborative study in 1997 , in cohort studies [26,54], but also in the large WHI Observational Study  The WHI study: effect of CEE only or placebo The findings of a consistent reduction in the HR of breast cancer during 6.8 years of treatment of hysterectomized postmenopausal women with CEE alone was highly surprising . In total, the relative risk was 0.77 (95% CI ), narrowly missing statistical significance. According to the available data on the effect of HRT in overweight women [4,9,26], it would have been acceptable if the WHI study had revealed no influ-
9 H. Kuhl / Maturitas 51 (2005) ence of estrogens on breast cancer risk. The mean BMI of the women participating in the estrogen-only arm was even higher than in the CEE/MPA arm, and was in the range of obesity (30.1 kg/m 2 ). Only 21% had a BMI < 25 kg/m 2, while 34% had a BMI of kg/m 2 and 45% of 30 kg/m 2 (Table 4) . The reduction in breast cancer risk is difficult to explain. Although in postmenopausal women increasing BMI correlates with increasing serum levels of estradiol , and breast cancer risk correlates with serum estradiol within a very low concentration range [56 58], it is not very probable that the rise of estrogen levels during use of mg CEE directly protects from the development of breast cancer. On the contrary, it is generally believed that high estrogen serum concentrations or high local tissue concentrations stimulate growth of breast tumors. So far, the available epidemiological data did not show any difference between the effect on breast cancer risk of low and high estrogen doses [4,21]. Another explanation might be derived from the association between breast cancer risk, obesity, insulin resistance and hyperinsulinemia, as outlined above (Table 3). According to the high proportion of overweight and obese women in the WHI study in whom a high prevalence of the metabolic syndrome and insulin resistance can be assumed, long-term treatment with mg CEE might have improved insulin resistance and reduced the elevated insulin levels. This might have attenuated the stimulatory effect of insulin on tumor growth resulting in a reduction of breast cancer diagnoses. 7. How to reduce breast cancer risk? 7.1. Nutrition and body weight Western lifestyle is associated with overweight, abdominal obesity, insulin resistance and low physical activity. Higher age, estrogen deficiency and obesity increase the prevalence of insulin resistance, and dietary habits may play a critical role. Even in non-obese postmenopausal women the prevalence of fasting hyperinsulinemia is high . The risk of breast cancer in Western countries is five-fold that in Japan, but migration of Japanese women to the USA results in adaptation of risk . Early menarche is to a certain degree associated with fat mass and high caloric nutrition, and is known as a risk factor for breast cancer. Abdominal obesity in childhood which is related to early menarche, tends to continue into adult life and may be associated with an earlier onset of insulin resistance . Moreover, late pregnancies are associated with the development of insulin resistance which may persist post partum in overweight women . On the other hand, obesity in teenage women may lead to anovulatory cycles which are associated with a reduced risk of breast cancer . In contrast, the manifestation of obesity after teenage increases the risk of postmenopausal breast cancer . In a case-control study with Mexican women characterized by a low fat intake, carbohydrate consumption was associated with increased breast cancer risk . In another study, a direct association with breast cancer risk was observed for glycemic index and glycemic load, but more in postmenopausal than in premenopausal women . High levels of insulin were also found to be associated with poorer survival for postmenopausal women, while higher dietary protein intake was associated with better survival . The question is, whether or not a change in dietary habits leading to weight loss and maintenance of normal body weight, can normalize the elevated breast cancer risk in overweight women. The results of various animal experiments suggest that an energyrestricted state induced by reduced caloric intake and/or an increased energy expenditure might be a suitable measure to prevent breast cancer . In contrast to endocrine treatments this strategy would also include receptor-negative carcinoma. It might reduce both the carcinogen-induced initiation and the growth of existing tumors. Interestingly, caloric restriction was accompanied by a persistent reduction in insulin levels . A case-control study revealed that in adult obese women weight loss at younger ages may reduce the risk of postmenopausal breast cancer, whereas weight loss after age 45 was ineffective. Fluctuating weight, i.e., weight loss followed by weight gain did not influence breast cancer risk . There are various studies on the association between diet composition and recurrence rate and survival following breast cancer diagnosis. Most studies did not adjust for energy intake and the results are contradictory, but suggest an increase in mortality with energy intake and a protective effect of elevated intake of protein,
10 92 H. Kuhl / Maturitas 51 (2005) beta-carotene, Vitamin C, fruit and vegetables . For postmenopausal women, there is no epidemiological evidence for a prophylactic effect of intake of soy or phytoestrogens concerning the risk of breast cancer. Two large NIH-funded clinical trials are currently investigating the influence of diet composition on recurrence and survival in breast cancer patients Medical treatment of hyperinsulinemia Even though diet and exercise are recommended as the primary intervention to improve insulin resistance, the use of insulin-sensitizing agents in patients with insulin resistance might be an option to reduce the incidence of postmenopausal breast cancer. Metformin has been demonstrated to decrease gluconeogenesis and intestinal absorption of glucose, to increase peripheral glucose uptake and utilization, and to improve insulin sensitivity and hyperinsulinemia . In combination with diet it has been shown to improve the symptoms of the metabolic syndrome in women with polycystic ovarian syndrome. Metformin has been used in type 2 diabetes for many years and is recommended particularly for overweight patients with type 2 diabetes. Long-term treatment with insulin-sensitizer may be associated with gastrointestinal side-effects and Vitamin B12 deficiency . It remains, however, to be proven that long-term metformin-induced normalization of insulin levels leads to a reduction in breast cancer risk Alcohol and smoking Moderate alcohol consumption is associated with a slightly elevated risk which increases with the amount of consumed alcohol [13,83]. Therefore, abstinence or reduction of alcohol consumption may have a favourable effect. A slight increase in breast cancer risk was found in postmenopausal women who started smoking before 16 years of age. Current smoking has a favourable rather than an unfavourable effect on the risk of breast cancer, because the proportion of infertile women is higher among smokers and smokers reach their menopause earlier  Physical activity The WHI study revealed that an increased physical activity is associated with a reduced risk for breast cancer in postmenopausal women. The protection correlated with the duration and intensity of physical activity and was most pronounced in women with a lower BMI (<24.1 kg/m 2 ) . In another study with postmenopausal women it was shown that vigorous exercise was associated with the lowest plasma insulin levels and the highest insulin sensitivity, and this effect was enhanced by HRT . There are, however, no clear data on the type and intensity of exercise necessary for a significant beneficial effect Inherited predisposition The risk of breast cancer is elevated in women with a mother or sister with breast cancer, and increases further if there are more affected relatives, particularly at young age. In women with genetic mutations associated with a very high risk for breast cancer, prophylactic bilateral mastectomy may reduce the risk by 90% . Chemoprevention is also an option to reduce the probability of developing the disease early in life. Before long-term treatment with tamoxifen or raloxifene, GnRH analogs or aromatase inhibitors will be considered, the risks, side-effects and benefits must be carefully evaluated. It is not clarified whether and to what extent the use of HRT in carriers of BRCA1 or BRCA2 increases the risk of breast cancer Benign breast disease Benign breast disease, especially fibrocystic disease, epithelial hyperplasia and the presence of atypia enhance the risk of breast cancer two- to four-fold . It was highest in young women with breast cysts and decreased with age . In postmenopausal women benign breast disease was associated with a relative risk of breast cancer of about 1.6 [9,35], and the use of HRT may increase the occurrence of atypical hyperplasia . In premenopausal women with benign breast disease long-term treatment with daily 8 10 mg norethisterone, but not progesterone derivatives, was found to reduce the risk of breast cancer by 50% . Whether or not this was associated with a reduction of blood flow in the breast , remains an open question.
11 H. Kuhl / Maturitas 51 (2005) Mammographic density Women with an elevated mammographic density have a four to six times higher risk of developing breast cancer. Mammographic density in more than 75% of the breast area was found to be associated with a relative risk of about 14 for hyperplasia and of 9 for atypical hyperplasia and/or carcinoma in situ . Histological investigation of biopsies revealed that the increase in mammographic density does not reflect changes in ductal or lobular epithelium, but a significantly higher expression of proteoglycans in the stroma which is the major breast tissue compartment by volume . These proteoglycans are a highly abundant component of breast tissue stroma and may be involved in the development of benign (e.g. fibrocystic changes) and malignant breast pathologies . Proteoglycans may aggregate to form collagen fibres, but can also form macromolecules with a high capacity for water storage. Therefore, the increase in mammographic density observed in postmenopausal women during treatment with estrogen/progestin preparations may reflect an increased water storage in breast stroma which may also cause breast tenderness. A similar phenomenon can be observed in younger women with premenstrual syndrome who show an increased capillary permeability during the luteal phase . It is unknown whether or not this reversible phenomenon induced by HRT is associated with an elevated risk for breast cancer. As an increased density may impair the sensitivity and accuracy of mammographic screening, transitory discontinuation of HRT for 3 weeks may reverse mammographic density increase and improve the diagnostic sensitivity . During this time, the administration of low-dose estrogens may prevent the recurrence of climacteric symptoms Do we need an indication for the use of progestins? The only indication for the addition of progestins to estrogen replacement therapy is the endometrial protection. Besides other specific progestin-related adverse effects, the progestin component increases considerably the risk of breast cancer (Table 2). Considering the emotional and clinical impact of breast cancer as compared with that of endometrial cancer, the demand for a regular addition of progestins might be reconsidered. Moreover, the general recommendations to individualize HRT may include the need of an indication for the use of a progestin. There is little doubt that treatment with unopposed estrogens increases dose-dependently the risk of endometrial hyperplasia and cancer. It has been suggested that the use of low-dose estrogens might be associated with a lower relative risk of endometrial cancer, but the results of clinical trials are inconsistent. Whereas no difference in the risk of endometrial cancer was found between the use of 0.3 and mg of unopposed CEE, the incidence of endometrial hyperplasia did not differ between placebo and 0.3 mg unopposed esterified estrogens taken for 2 years [93 95]. It is generally accepted that an endometrial thickness of 5 mm is an appropriate cut-off level in screening for endometrial hyperplasia. Monitoring of endometrial growth during estrogen therapy by means of vaginalsonography has been suggested as a suitable diagnostic tool to evaluate the need for the addition of progestins in patients treated with low-dose estrogens-only. The choice of patients suitable for this therapy may be facilitated by the outcome of a progestogen challenge test. In postmenopausal women, there are large variations in the endometrial response to unopposed estrogen therapy. Treatment with mg CEE, 1 2 mg estradiol or 50 g transdermal estradiol revealed that about 20% of the women were fast growers with an increase in endometrial thickness by more than 1 mm in 5 weeks, whereas 50% were slow growers with an increase by 1 mm or less over a period of more than 20 weeks . Only a few women developed hyperplasia within 2 months, and no hyperplasia was observed in women with endometrial thickness of 4 mm or less [96,97]. In 11% of the patients, there was no or only a slow proliferation rate and after 2 years of treatment endometrial thickness was below 8 mm showing normal biopsies . In about two third of the patients the administration of progestin could be postponed until at least to the fourth month without inducing endometrial hyperplasia . Long-cycle HRT using quarterly progestin may, therefore, be an option for the majority of postmenopausal women, but the most suitable regimens remain to be elucidated. There are several clinical trials on the risk of endometrial hyperplasia and cancer in postmenopausal women during long-cycle HRT which
12 94 H. Kuhl / Maturitas 51 (2005) revealed contradictory results. Whereas some longcycle regimens taken for 1 5 years did not increase the incidence of endometrial hyperplasia as compared with the use of normal sequential preparations [98 102],an elevated rate of endometrial hyperplasia and cancer was observed in two Scandinavian studies [103,104].In one of the latter studies, the progestin phase of 10 days might have been too short and in the other study, many of the women who developed endometrial cancer, have been treated with hormones including unopposed estrogen prior to the study [103,104]. Long-cycle HRT might be applicable to patients who respond to estrogens with slow endometrial proliferation and have weak or no withdrawal bleeding during sequential HRT. The most suitable progestins are compounds with strong endometrial activity, and should be taken for 14 days. 8. Conclusion HRT may stimulate growth of occult breast tumors in postmenopausal women. This concerns primarily hormone receptor-positive cancers, and the effect of estrogens is enhanced by progestins. Observational and randomised studies suggest that HRT with estrogen/progestin combinations increases the relative risk of breast cancer in postmenopausal women more than estrogens alone. Besides many other risk factors, overweight and obesity is associated with an elevated risk of breast cancer in postmenopausal women, which is not enhanced by HRT. As most participants in the WHI study were overweight, it was not suitable for the investigation of breast cancer risk. The increase in risk during treatment with estrogen/progestin concerned only those women who had been pretreated with hormones prior to the WHI study, suggesting a selection bias. Moreover, treatment of postmenopausal women with estrogens alone during 6.8 years caused a consistent decrease in the incidence of breast cancer. Overweight women have a high risk for the development of insulin resistance, and the growth-stimulating effect of elevated insulin levels may explain the elevated breast cancer risk in the postmenopause. As low-dose estrogens may improve insulin resistance and hyperinsulinemia, the elevated breast cancer risk in obese women may be reduced. This could explain the favourable results of the estrogen-only arm of the WHI study. The lacking effect in the estrogen/progestin combination arm may be due to the impairment by the progestin component of the beneficial effect of estrogens on insulin resistance. With regard to the breast cancer risk, the development of overweight and obesity should be avoided, and an appropriate diet and lifestyle should be recommended early in life. In postmenopausal women with insulin resistance, treatment with insulin-sensitizing agents like metformin might be an option, but a favourable effect on breast cancer risk remains to be proven. In healthy postmenopausal women with climacteric symptoms, low-dose estrogen therapy is the treatment of choice, and the exposure to progestins should be kept minimal in non-hysterectomized women. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Vaginalsonographic surveillance and the intensity of withdrawal bleeding may help to identify those women who may profit from long-cycle regimens of HRT or may be candidates for therapy with low-dose estrogens-only. References  Kvale G. Reproductive factors in breast cancer epidemiology. Acta Oncol 1992;31:  Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including women with breast cancer and women without the disease. Lancet 2002;360:  Garland M, Hunter DJ, Colditz GA, et al. Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol 1998;147:  Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies with women with breast cancer and women without breast cancer. Lancet 1997;350:  Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas 2002;42(Suppl 1):  Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women s Health Initiative (United States). Cancer Causes Contr 2002;13:  Adami HO, Adams G, Boyle P, et al. Breast cancer etiology. Int J Cancer 1990;(Suppl 5):  Ewertz M, Duffy SW, Adami HO, et al. Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the Nordic countries. Int J Cancer 1990;46:
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