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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-60590 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 post-menopausal 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.

© 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Breast cancer risk; Postmenopause; Obesity; Hyperinsulinemia; Hormone replacement therapy

Tel.: +49 69 6301 5692; fax: +49 69 6301 5522. E-mail address: h.kuhl@em.uni-frankfurt.de.

0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2005.02.018

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1. Introduction

Breast cancer is the most frequent malignant dis-ease 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 investi-gation 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 deter-mine 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 [3]

Age – 25 years:45 years 1:20 [5]

Body weight – normal weight:obesity

1:2.5 [6]

Age at menopause – 42 years:52 years

1:2.0 [1]

Age at menarche – 14 years:11 years

1:1.3 [1]

Parity – multiparous:nulliparous 1:1.3 [7,8]

Age at first birth – 20 years:35 years

1:1.4 [7,8]

Total duration of lactation – 5 years:never

1:1.2 [2]

Benign breast disease – no:yes 1:1.57 [9]

Oral contraceptives – never user:ever user

1:1.1 [10,11]

Hormone replacement – never:5 or more years

1:1.3 [4,12]

Alcohol consumption – none:≥20 g daily

1:1.3 [13]

Serum lipids – normal:raised 1:1.6 [14]

Physical activity – active:inactive 1:1.2 [15]

Shift work – never:shift work > 30 years

1:1.36 [16]

Antibiotic use – never:50 days in total

1:1.5 [17]

and BRCA2) must be accepted as an unchangeable predisposition. Many other risk factors, e.g., obesity or hormone replacement therapy (HRT) can, how-ever, be avoided or changed. Early menarche and late menopause indicate a prolonged exposition to estro-gens 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

suppres-sion 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[3]. 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 resis-tance, disorders of lipid metabolism and elevated alco-hol 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 cumula-tive association of use of antibiotics with the risk of breast cancer might reflect a weakened immune

func-tion (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 [4]. 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 can-cers 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 [4].

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3.2. Randomised controlled trials

Randomised placebo-controlled trials are regarded as the non-plus-ultra for the investigation of the im-pact 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,

how-ever, 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 partic-ipating women were selected as to suffer not from cli-macteric 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/m2).

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 0.625 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[18]. 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[12]. Moreover, that arm of the

WHI study which investigated the effect of CEE alone in hysterectomized women, revealed a highly surpris-ing result: after 6.8 years of treatment the relative risk

of breast cancer was 0.77[19]. 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[20].

3.3. 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

combina-tions. There was no difference in risk between the dose

of≤0.625 mg and≥1.85 mg conjugated estrogens[4].

The Million Women Study (MWS) reported on an in-crease 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[18] Current 6.8 years 1.27 (0.84–1.94)a

WHI[19,23] Current 6.8/5.2 years 0.77 (0.59–1.01) 1.24 (1.01–1.54)a

MWS[20] Current 2.6 years 1.30 (1.22–1.38) 2.00 (1.91–2.09)b

Magnusson et al.[22] Ever 1.94 (1.47–2.55) 1.63 (1.37–1.94)b

Ross et al.[25] Ever 5 years 1.06 (0.97–1.15) 1.24 (1.07–1.45)b

Colditz and Rosner[9] Ever 10 years 1.23 (1.06–1.42) 1.67 (1.18–2.36)b

Schairer et al.[26] Current 1.10 (1.00–1.30) 1.40 (1.10–1.90)b

Kirsh and Kreiger[27] Ever≥10 years 1.74 (0.93–3.24) 3.48 (1.00–12.1)b Porch et al.[28] Current≥5 years 0.99 (0.65–1.53) 1.82 (1.34–2.48)b Daling et al.[29] Ever≥5 years lobular 1.30 (0.80–2.20) 2.50 (1.40–4.30)a Daling et al.[29] Ever≥5 years, ductal 0.70 (0.60–1.00) 1.20 (0.90–1.70)a Weiss et al.[30] Current≥5 years 0.81 (0.63–1.04) 1.54 (1.10–2.17)a

Chen et al.[31] Current lobular 1.98 (1.04–3.78) 3.91 (2.05–7.44)b

Chen et al.[31] Current non-lobular 1.08 (0.78–1.50) 1.25 (0.86–1.81)b

Jernstr¨om et al.[32] Ever 1.50 (0.84–2.50) 3.30 (1.90–5.60)a

Li et al.[33] Current lobular 1.30 (0.80–2.20) 3.10 (1.90–5.20)b

Li et al.[33] Current ductal 1.00 (0.70–1.30) 1.70 (1.20–2.40)b

Bakken et al.[34] Current 1.80 (1.10–2.90) 2.50 (1.90–3.20)b

Stahlberg et al.[35] Current 1.96 (1.16–3.35) 2.70 (1.96–3.73)b

Stahlberg et al.[36] Current ductal 2.03 (1.10–3.75) 4.10 (2.29–7.30)a

a Continuous combined estrogen/progestin therapy.

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alone and by 100% using estrogen/progestin

combi-nations [21]. 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 es-trogen/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

con-tinuous treatment[21].

During the last years evidence has accumulated that the increase in breast cancer risk is relatively low during use of unopposed estrogens, and is consider-ably enhanced by the addition of progestins (Table 2) [9,18–36]. The only exception was a Swedish case-control study which found the highest risk with

estro-gen only[22].

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 [24]. Recent studies confirmed the elevated

breast cancer risk using estrogen/progestin combina-tions. 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

com-binations by 67%[9]. 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 [28]. Three

Scandi-navian cohort studies revealed a considerably higher relative risk in women treated with estrogen/progestin combinations than with estrogen alone (Table 2) [32,34,35].

3.4. Histological types and receptor status of breast tumors

In most studies continuous combined HRT was as-sociated with the highest relative risk of breast can-cer, particularly of hormone receptor-positive carci-noma. While the use of estrogens alone was as-sociated with no or a slightly elevated risk, estro-gen/progestin combinations increased the incidence of lobular cancers to a much greater extent than that of

ductal carcinoma[29,31,33,37]. Treatment with

estro-gen/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

car-cinoma was less pronounced[33,36,37]. Current use

of hormones was associated with a higher incidence of

tumors with the low malignancy grade1[36]. The

anal-ysis 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[38].

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 initia-tion of breast cancer, a carcinogenic/mutagenic role of sex steroids is rather improbable. The available exper-imental, 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 40–50

years[39]. 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 ef-fects both on normal mammary epithelium and breast cancers of estrogens which is enhanced by the pres-ence 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[40]. Similarly,

the mitosis rate of healthy breast epithelium was high-est in the luteal phase, and higher during treatment of postmenopausal women with CEE/MPA as

com-pared to CEE alone[41,42]. Similar effects of CEE and

CEE/MPA were observed in the monkey model[43].

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 combina-tions were found to be associated with an increased risk

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ques-tionable whether the effects of different HRT prepara-tions on healthy mammary epithelium reflect those on breast carcinoma.

4.2. Regulation of growth in benign and malignant breast tissue

There are profound differences between healthy and malignant breast tissue concerning the hormone-dependent 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 [46]. 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[47].

While in healthy tissue ER␣ is expressed only in

resting cells, the transition of benign to malignant mam-mary 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 [50]. 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

proliferat-ing ER−cells or they become ER+ progenitor cells

which proliferate and in addition stimulate growth of

ER− cells by producing paracrine factors[50]. 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

differenti-ated, more aggressive, and have a poor prognosis. Their growth is neither influenced by HRT nor by SERMs

[50]. 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

transito-rily respond to HRT and antiestrogens, but would not

have lasting effects, because proliferation of ER−cells

continues. Therefore, HRT should not increase

signif-icantly the risk of this subtype of breast cancer[50].

A third subtype may arise through transformation of ER+ progenitor cells and consists of more differenti-ated cells. Their growth may be slowed down by treat-ment with antiestrogens and accelerated during HRT, and in both cases this subtype has the best prognosis [50].

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 asso-ciation between body mass index (BMI) and the

rela-tive risk of breast cancer, increasing by 3.1% per kg/m2

[4]. Moreover, the relative breast cancer risk associ-ated with HRT decreased progressively with increasing weight or BMI. It was 1.73 in postmenopausal women

with a BMI below 22.5 kg/m2 and 1.02 for BMI of

≥25.0 kg/m2(Table 3)[4]. Estrogen therapy was found

to increase the risk of breast cancer only in women

with a BMI of less than 24.5 kg/m2[26]. In the Nurses

Health Study, the risk of breast cancer correlated with the BMI in postmenopausal women without HRT, but

less in premenopausal women[9].

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

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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 corre-lates with serum estradiol levels

HRT does not increase risk of breast cancer in obese post-menopausal 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 can-cer 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 in-creases 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)[59].

5.2. Hyperinsulinemia and breast cancer risk

The prevalence of insulin resistance and hyperin-sulinemia increases with age, BMI and estrogen

de-ficiency [60]. 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 [61]. Recent investigations suggest that it is in all probability the elevated insulin level in obese post-menopausal women which is responsible for the in-creased risk of breast cancer. A specific protein secreted by adipocytes, adiponectin, correlates with insulin sen-sitivity. Low levels of adiponectin which precede a de-crease in insulin sensitivity, are closely and inversely associated with insulin resistance and hyperinsuline-mia[62]. In postmenopausal women a significant in-verse 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

cor-relation of the levels of C-peptide with the occurrence of epithelial hyperplasia of the breast or breast can-cer suggests a key role of elevated insulin levels in the growth of breast cancer in postmenopausal women [65]. Postmenopausal patients, but not premenopausal women with type 2 diabetes had a 16% higher breast

cancer risk than women without diabetes (Table 3)[66].

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 es-trogens 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 0.625 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 0.625 mg CEE and caused an

18% decrease in insulin sensitivity[60]. Treatment of

postmenopausal women with estrogen-only reduced fasting insulin by 35%, while estrogen/progestin

combinations were less effective[67]. The PEPI study

revealed that treatment of postmenopausal women with 0.625 mg CEE with or without additional progestins led

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In postmenopausal women with impaired glucose tol-erance continuous combined treatment with 0.625 mg CEE and 2.5 mg MPA reduced insulin resistance and fasting glucose levels, while in women with normal glu-cose tolerance the levels of fasting insulin and gluglu-cose

were decreased[69]. The increase in the postchallenge

glucose concentrations during OGTT that was ob-served 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 inci-dence 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[71].

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[4]. 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/m2) and the high

per-centage 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

preva-lence of the metabolic syndrome (Table 4)[12,19]. The

incidence of the metabolic syndrome increases with menopause, and is associated not only with an ele-vated risk of cardiovascular disease, but also with an in-creased 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 el-evated 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 10739 16608 Age at screening

(mean±S.D., years)

63.6±7.3 63.3±7.1 Age group 50–59 years (%) 30.8 33.3 Age group 60–69 years (%) 45.2 45.2 Age group 70–79 years (%) 24.0 21.5 Body mass index

(mean±S.D., kg/m2)

30.1±6.2 28.5±5.8 Body mass

index≤25 kg/m2(%)

20.7 30.6 Body mass index

25–29 kg/m2(%)

34.8 35.3 Body mass

index≥30 kg/m2(%)

44.6 34.1 Current or past smoking (%) 48.8 50.2 Treated for diabetes mellitus

(%)

7.7 4.4 Treated for hypertension (%) 47.7 36.0 Treated for

hypercholesterolemia (%)

15.2 12.7

Use of statins (%) 7.7 6.9

Use of aspirin (%) 19.6 19.6 Past or current hormone use

at screening

48.3 25.8

In the estrogen-only study the women were randomly assigned to be treated with either placebo or 0.625 mg conjugated equine estrogens (CEE)[19], and in the estrogen/progestin study either with placebo or 0.625 mg conjugated equine estrogens plus 2.5 mg medroxypro-gesterone acetate (CEE/MPA)[12].

cancer risk. As it was shown that HRT does not influ-ence breast cancer risk in postmenopausal women with

a BMI above 25 kg/m2[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 [6].

6.2. 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 [12]. The premature

discontinuation of treatment with CEE/MPA after 5.2 years was justified with an increased risk of cardiovas-cular disease and a pretendedly elevated risk of breast

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inva-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 fromTable 2, subanalysis of the WHI study published by Chlebowski et al.[23]). 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[72]).

sive breast cancer was calculated as 1.26 which was, however, not significant. A subsequent updated sub-analysis based on a mean follow-up of 5.6 years re-vealed a significantly elevated HR of breast cancer of 1.24 which just surpassed the border of statistical

sig-nificance[23].

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 treat-ment with CEE/MPA only in those patients who

re-ported HRT prior to WHI study[23]. 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.[23], arouses suspicion that the elevated risk calcu-lated in this group is an artifact due to a

pretreatment-associated selection bias[72]. 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 1.09. 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

ex-tremely 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 eleva-tion in breast cancer risk decreased within 2 years after cessation of treatment and remained lowered during

the first 5 years without hormones[73]. 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/m2or more. This has been observed in the

col-laborative study in 1997[4], in cohort studies[26,54],

but also in the large WHI Observational Study[6].

6.3. 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 hysterec-tomized postmenopausal women with CEE alone was

highly surprising[19]. In total, the relative risk was 0.77

(95% CI 0.59–1.01), narrowly missing statistical sig-nificance. According to the available data on the effect

of HRT in overweight women[4,9,26], it would have

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influ-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/m2). Only 21% had a

BMI < 25 kg/m2, while 34% had a BMI of 25–29 kg/m2

and 45% of≥30 kg/m2(Table 4)[19].

The reduction in breast cancer risk is difficult to explain. Although in postmenopausal women increas-ing BMI correlates with increasincreas-ing serum levels of

estradiol [74], 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 estro-gen levels during use of 0.625 mg CEE directly protects from the development of breast cancer. On the contrary, it is generally believed that high estrogen serum con-centrations or high local tissue concon-centrations stimulate growth of breast tumors. So far, the available epidemi-ological 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 as-sociation between breast cancer risk, obesity, insulin resistance and hyperinsulinemia, as outlined above (Table 3). According to the high proportion of over-weight and obese women in the WHI study in whom a high prevalence of the metabolic syndrome and in-sulin resistance can be assumed, long-term treatment with 0.625 mg CEE might have improved insulin re-sistance and reduced the elevated insulin levels. This might have attenuated the stimulatory effect of insulin on tumor growth resulting in a reduction of breast can-cer diagnoses.

7. How to reduce breast cancer risk?

7.1. Nutrition and body weight

Western lifestyle is associated with overweight, ab-dominal obesity, insulin resistance and low physical activity. Higher age, estrogen deficiency and obesity increase the prevalence of insulin resistance, and di-etary habits may play a critical role. Even in non-obese postmenopausal women the prevalence of fasting

hy-perinsulinemia is high[60]. The risk of breast cancer in

Western countries is five-fold that in Japan, but migra-tion of Japanese women to the USA results in

adapta-tion of risk[59]. 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 menar-che, tends to continue into adult life and may be

asso-ciated with an earlier onset of insulin resistance[59].

Moreover, late pregnancies are associated with the de-velopment of insulin resistance which may persist post

partum in overweight women[59]. On the other hand,

obesity in teenage women may lead to anovulatory cy-cles which are associated with a reduced risk of breast

cancer[3]. In contrast, the manifestation of obesity

af-ter teenage increases the risk of postmenopausal breast

cancer[75].

In a case-control study with Mexican women char-acterized by a low fat intake, carbohydrate consump-tion was associated with increased breast cancer risk [76]. In another study, a direct association with breast cancer risk was observed for glycemic index and glycemic load, but more in postmenopausal than in

pre-menopausal women[77]. 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[78].

The question is, whether or not a change in di-etary 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 energy-restricted state induced by reduced caloric intake and/or an increased energy expenditure might be a suitable

measure to prevent breast cancer[79]. 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 exist-ing tumors. Interestexist-ingly, caloric restriction was ac-companied by a persistent reduction in insulin levels [79]. 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[80].

There are various studies on the association between diet composition and recurrence rate and survival fol-lowing breast cancer diagnosis. Most studies did not ad-just 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,

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beta-carotene, Vitamin C, fruit and vegetables [81]. For postmenopausal women, there is no epidemiolog-ical evidence for a prophylactic effect of intake of soy or phytoestrogens concerning the risk of breast can-cer. Two large NIH-funded clinical trials are currently investigating the influence of diet composition on re-currence and survival in breast cancer patients.

7.2. Medical treatment of hyperinsulinemia

Even though diet and exercise are recommended as the primary intervention to improve insulin resistance, the use of insulsensitizing agents in patients with in-sulin resistance might be an option to reduce the inci-dence of postmenopausal breast cancer. Metformin has been demonstrated to decrease gluconeogenesis and in-testinal absorption of glucose, to increase peripheral glucose uptake and utilization, and to improve insulin

sensitivity and hyperinsulinemia[82]. 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 par-ticularly for overweight patients with type 2 diabetes. Long-term treatment with insulin-sensitizer may be as-sociated with gastrointestinal side-effects and Vitamin

B12 deficiency[82]. It remains, however, to be proven

that long-term metforminduced normalization of in-sulin levels leads to a reduction in breast cancer risk.

7.3. 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 infer-tile women is higher among smokers and smokers reach

their menopause earlier[83].

7.4. Physical activity

The WHI study revealed that an increased phys-ical activity is associated with a reduced risk for

breast cancer in postmenopausal women. The pro-tection correlated with the duration and intensity of physical activity and was most pronounced in

women with a lower BMI (<24.1 kg/m2) [15]. In

another study with postmenopausal women it was shown that vigorous exercise was associated with the lowest plasma insulin levels and the highest in-sulin sensitivity, and this effect was enhanced by HRT [67].

There are, however, no clear data on the type and in-tensity of exercise necessary for a significant beneficial effect.

7.5. 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% [83]. 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.

7.6. Benign breast disease

Benign breast disease, especially fibrocystic dis-ease, epithelial hyperplasia and the presence of atypia

enhance the risk of breast cancer two- to four-fold[84].

It was highest in young women with breast cysts and

decreased with age [85]. 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

hy-perplasia[86]. 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%[87].

Whether or not this was associated with a reduction of

blood flow in the breast[88], remains an open

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7.7. 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[89].

Histologi-cal 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[90].

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[90]. Proteoglycans may

aggregate to form collagen fibres, but can also form macromolecules with a high capacity for water stor-age. Therefore, the increase in mammographic density observed in postmenopausal women during treatment with estrogen/progestin preparations may reflect an in-creased water storage in breast stroma which may also cause breast tenderness. A similar phenomenon can be observed in younger women with premenstrual syn-drome who show an increased capillary permeability

during the luteal phase[91].

It is unknown whether or not this reversible phe-nomenon induced by HRT is associated with an ele-vated risk for breast cancer. As an increased density may impair the sensitivity and accuracy of mammo-graphic screening, transitory discontinuation of HRT for 3 weeks may reverse mammographic density

in-crease and improve the diagnostic sensitivity[92].

Dur-ing this time, the administration of low-dose estrogens may prevent the recurrence of climacteric symptoms.

7.8. 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 rec-ommendations 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 en-dometrial 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 0.625 mg of unop-posed 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 varia-tions in the endometrial response to unopposed estro-gen therapy. Treatment with 0.625 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[96]. Only a few women developed

hyperpla-sia within 2 months, and no hyperplahyperpla-sia 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

nor-mal biopsies[97]. 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[97].

Long-cycle HRT using quarterly progestin may, therefore, be an option for the majority of post-menopausal women, but the most suitable regimens remain to be elucidated. There are several clinical tri-als on the risk of endometrial hyperplasia and cancer in postmenopausal women during long-cycle HRT which

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revealed contradictory results. Whereas some long-cycle 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

es-trogen prior to the study[103,104].

Long-cycle HRT might be applicable to patients who respond to estrogens with slow endometrial pro-liferation 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 estro-gen/progestin combinations increases the relative risk of breast cancer in postmenopausal women more than estrogens alone. Besides many other risk factors, over-weight 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 over-weight, 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 dur-ing 6.8 years caused a consistent decrease in the in-cidence 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 im-prove insulin resistance and hyperinsulinemia, the el-evated breast cancer risk in obese women may be re-duced. 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 develop-ment of overweight and obesity should be avoided, and an appropriate diet and lifestyle should be recom-mended 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 pro-gestins should be kept minimal in non-hysterectomized women. There are large inter-individual variations in the proliferative response to estrogens of the en-dometrium. 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.

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Figure

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

References

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