Breast Cancer Research and Treatment 2, 203-211(1982)0167-6806/82/030203-9500.20/0 © 1982, Martinus Nijhoff Publishers, The Hague. Printed in the Netherlands

Review

Non-contraceptive exogenous estrogens and risk of breast cancer: a review

David B. Thomas, M.D., Dr;P.H. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Keywords: breast cancer risk, estrogens, menopausal estrogens

Summary

Results from epidemiologic and related studies of non-contraceptive estrogens and breast cancer are reviewed. Exogenous estrogens in high doses can enhance the risk of breast cancer. Moderate use o.f estrogens for menopausal symptoms probably has little effect on risk, but long-term users, and women who take high- strength preparations, appear to be at slightly increased risk. Exogenous estrogens probably reduce the protective effect of premenopausal oophorectomy, and may preferentially enhance the risk of breast cancer in women with some types of benign breast disease, although data from some studies do not support these conclusions. There is no evidence that the influence on risk of breast cancer is different for synthetic and conjugated estrogens. Needs for reanalyses of data from existing studies, and for additional investigations, are summarized.

Introduction

Breast cancer does not occur before menarche. Subsequently, the incidence rate increases rapidly with age until menopause, and more gradually thereafter. Risk, especially during the menstruating years, is inversely related to age at menarche. In older women, an early natural menopause and premenopausal oophorectomy are protective, and the degree of protection increases as the age at cessation of ovarian function decreases. These epidemiologic observations strongly suggest that endogenous ovarian hormones play a role in the genesis of breast cancer (1).

If either natural or artificial cessation of ovarian function at an early age is protective, it is reason-

able to hypothesize that exogenous estrogens ad- ministered during and after menopause might have the opposite effect and increase the risk of breast cancer. A number of epidemiologic studies have been conducted to address this question. The purposes of this review are to summarize and critically evaluate the published results of these studies, and to identify unanswered questions that should be the subject of additional investigations.

Summary of published results

Estrogens used to treat and prevent menopausal symptoms (hereafter referred to as menopausal estrogens) have become widely used in the United

Address for reprints." David B. Thomas, M.D., Dr.P.H., Program in Epidemiology and Biostatistics, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104, USA.

204 DB Thomas

States. Their use increased four-fold from 1962 to 1975 (2). This rise was followed by a parallel increase in the incidence of endometrial cancer in postmenopausal women (2). Subsequently, many case-control, as well as some prospective, epi- demiologic studies have clearly shown a strong relationship between the risk of this disease and use of menopausal estrogens (3). These findings prompted a decline in use of estrogens, which was followed in turn by a decrease in the incidence of endometrial cancer, virtually proving that the ob- served relationships between estrogen use and endometrial cancer were causal. The possible in- fluence of menopausal estrogens on risk of breast cancer has been studied with equal vigor, but results to date are not nearly as clear as for endometrial cancer.

Time trends

Mortali ty rates of breast cancer have remained remarkably stable in the United States since the widespread use of menopausal estrogens (4, 5). Incidence rates have increased very gradually

during the past 15 years (5), but this may be due, at least in part, to an improvement in diagnosis. There has been no dramatic increase in rates in any age group that paralleled the increase in use of menopausal estrogens.

Overall relative risks

Table 1 summarizes results from 10 case-control studies (6-15) of menopausal estrogens and breast

cancer that have been conducted since 1974. In two of the studies (13, 14) risk in women who ever took menopausal estrogens, relative to the risk in non- users, was increased with borderline statistical sig- nificance (the lower 95~ confidence limit of the relative risk = 1.0). The overall relative risk was not significantly altered in any of the others. Some of these were hospital-based, some were population- based, and one was conducted through a screening program, but these variations in study design can- not explain the discrepant results summarized in

• Table 1, or subsequently. In all of these studies, some attempt was made to

control for the possible confounding effects of age,

Table 1. Estimates from ten case-control studies of relative risk of breast cancer in women who ever used menopausal estrogens.

First author Year Source Type of Number Potential confounders considered 1 Relative Statist-

(reference) of cases controls of cases risk 2 ical MRCH AFB MENO F H BBD signifi-

cance 5

BCDSP (6) 1974 hospital hospital 51 no no no no no 0.963 NS

Craig (7) 1974 population population 34 no no no no no 1.03 NS

Casagrande (8) 1976 population(?) doctors office 60 no no yes no no 0.75 NS neighborhood 33 no no yes no no 3.1 NS

Sartwell (9) 1977 hospital hospital 284 no yes yes no no 0.82 NS

Ravnihar (10) 1979 hospital hospital 177 yes yes yes yes no 0.733 NS

Jick (11) 1980 hospital hospital 97 no no no no no 0.973, 4 NS

Ross (12) 1980 community community 131 yes yes yes yes yes 1.1 NS

Brinton (13) 1981 screenees screenees 881 yes yes yes yes yes 1.24 B Hoover (14) 1981 population population 345 no yes yes no yes 1.4 B

Kelsey (15) 1981 hospital hospital 332 yes yes yes yes yes 0.9 NS

1 MRCH = age at menarche, AFB = age at first birth, MENO = menopausal status or age at menopause, FH = family history of breast

cancer, BBD = history of benign breast disease.

z Risk in ever-users relative to never-users of menopausal estrogens. 3 Calculated from published data on cases and controls.

Risks in current and past users relative to non-users. s NS = not significant (p >0.05 or 95~ confidence limits include 1.0), B = borderline significance (lower 95~ confidence limit equals

1.0).

race, marital status, and socioeconomic status. The

studies do differ in the degree of control for more

specific risk factors for breast cancer that may have been confounders. Table 1 shows in which studies

the results were adequately controlled for age at menarche, age at birth of first child, menopausal

status or age at menopause, a family history of breast cancer, and a history of benign breast dis- ease. The discrepant results cannot be explained by

the degree to which these potentially confounding

variables were controlled. Results of two prospective studies of menopausal

estrogens and breast cancer have been published.

Burch et al. (16) and later Byrd et al. (17) reported results of a prospective study of 1016 women who

were treated with conjugated estrogens, usually 1.25 mg per day, for an average of 13.5 years, following

hysterectomy. Incidence rates of breast cancer were compared with expected rates based on data from the

Third National Cancer Survey for the Atlanta area. This study purports to show a four-fold increase in

incidence of breast cancer in women who used estrogens for less than 10 years, but little or no

increase thereafter. However, a serious error in the

design of this study very likely renders these find-

ings erroneous: any patient who developed breast

cancer after 90 days from initiation of estrogen therapy was included in the study, but those who did not develop breast cancer (or a fracture or died) were only included in the study if they took estro-

gens for 3 years or more. Also, the authors claim a 100% follow-up which is always very suspect in our

highly mobile society.

In a more methodologically sound study, Hoover

et al. (18) compared the incidence of breast cancer

in 1891 women who were treated with conjugated estrogens and followed for an average of 12 years, with the expected incidence based on the Second

and Third National Cancer Surveys. The overall relative risk was estimated to be 1.3 (p = 0.06).

Parity was the only potentially confounding vari- able that was considered. Also, the study popula- tion was probably of a higher average socioecon- omic class than the general population, and hence

at higher risk of breast cancer. The observed 30% increase in risk, of borderline statistical signifi-

cance, must therefore be interpreted cautiously.

Exogenous estrogens and breast cancer 205

Dose response

Evidence that the risk of breast cancer is increased

by use of estrogens would be strengthened if relative risks were found to increase with the quantity of estrogens consumed. This was investigated in a

variety of ways in five of the case-control studies (10, 12-15), and one of the prospective studies (18).

The results are summarized in Table 2. Ross et al. (12) found a relative risk of 1.8 in users of more

than 7 years duration, and Brinton et al. (13) found

a weak (but statistically significant) increase in risk

with duration of use, but Ravnihar et al. (10) did

not. Hoover et al. (14) observed an increase in relative risk with number of prescriptions for estro-

gens on record in a prepaid health plan. They, as well as Brinton et al. (13) and Hoover et al. (18) also

Table 2. Summary of results from studies of relative risk of breast cancer in relation to various doses of menopausal estrogens.

Measurement First author Dose Relative of dose (reference) category risk

Duration Ravnihar (10) <2 years 0.73 of use _>2 years 0.74

Ross (12) >_7 years 1.8 Brinton (13) <5 years 1.19

5-9 years 1.29 10+ years 1.21

Number of Hoover (14) 1 1.0 prescriptions 24 1.3

5-9 1.5 _>10 1.7

Daily dose Hoover (14) < 1.25 mg 1.1 >- 1.25 mg 1.5

Brinton (13) 0.3 mg 0.79 0.6 mg 1.34 1.25 mg 1.18 2.5 mg. 1.70

Hoover (18) 0.3 mg 1.2 0.625 mg 1.1 >0.625 mg 1.9

Cumulative dose Ross (12) 1 1499 mg/life 0.8 >- 1500 mg/life 1.9

Kelsey (15) 149 mg-months 0.84 _>50 mg-months 0.65

206 DB Thomas

found the relative risk to increase with the daily

dose of estrogens taken. Paradoxically, however, in the latter study, risk was lower in women who took

estrogens daily than in those who took them less frequently. Ross et al. (12) also observed the rela- tive risk to increase with the total cumulative amount of estrogens received, but Kelsey (15) did

not.

In summary, some results from all of the studies

shown in Table 2 except those of Ravnihar (10) and

Kelsey (15) suggest a weak dose-response relation- ship between estrogen intake and risk of breast

cancer. Reasons for the discrepant findings are not

apparent.

Types of estrogens

The menopausal estrogens used by women in all of

the studies cited above were predominantly con- jugated estrogens, and the findings presented thus

largely reflect the influences of these preparations

on risk of breast cancer. Additional evidence for a

dose-response comes from three studies of women

treated with diethylstilbestrol (DES) during preg- nancy for threatened abortion (19-21), and two

case-control studies of DES used for menopausal therapy (14, 15)i As shown in Table 3, excess risk

was greatest in the study in which the mean total

dose of DES during pregnancy was 16.3 gm (19); a small excess was found in the study in which the

mean dose was 11 gm (20); and no excess risk was

observed in the study in which women received an

average of 1.5 gm (21). The total doses received by

users of DES included in the two case-control studies are unknown, but the usual daily dose for menopausal symptoms is 0.2 to 0.5 mg. At the

higher level of use, a woman would receive a total of one gram after about 5½ years of continuous therapy. This amount is of the same order of

magnitude as that received by the women in the

prospective study of Brian (21), and the observed relative risks o f 1.0, 1.1, and 0.9 are all comparable.

It thus appears that high doses of DES given during

pregnancy enhance the risk of breast cancer, but that smaller amounts like those usually given for

menopausal symptoms do not, whether they are

received over a long period of time for that purpose, or over a shorter period of time during pregnancy.

Additional evidence that high doses of estrogens

can cause breast cancer comes from a report of two

transvestite males who received massive doses of estrogens to induce breast development, and who

subsequently developed breast cancer (22). There is no evidence that DES and conjugated

estrogens exert qualitatively different effects on the risk of breast cancer. Any observed differences are readily explainable on the basis of differences in doses received by women in various studies. In two

case-control studies in which DES and conjugated estrogens were both used for menopausal symp-

toms, and hence in comparable doses (14, 15), the relative risks of breast cancer did not differ ap-

preciably or consistently between users of the two

types of estrogens (Tables 3 and 4 ) .

Table 3. Estimates from five studies of relative risk of breast cancer in users of DES.

First author Type of study Reason for DES (reference) treatment

Average cumulative dose (gins)

Relative risk

Beral (19) Randomized trial Prevent fetal loss 1 Bibbo (20) Randomized trial Prevent fetal loss Brian (21) Prospective Prevent fetal loss Kelsey (15) Case-control Menopausal symptoms Hoover (14) Case-control Menopausal symptoms

16.3 11.0 1.5

unknown 2 unknown 2

3.4 1.5 1.0 1.13 0.94

1 DES given simultaneously with ethisterone (average cumulative dose = 13.8 gm). 2 See text. 3 Based on observations on women with intact ovaries. 4 Limited to women with more than one prescription; ovarian status unknown.

Exogenous estrogens and breast cancer

Table 4. Estimates from six studies of relative risk of breast cancer in ever-users of estrogens by ovarian status.

207

First author Type of estrogens Relative risks: (reference)

Ovaries removed Ovaries retained

Hoover (18) Conjugated 1.3 1.1 Ross (12) Conjugated 0.8 (0.5-3.5) 1.4 (0.7-2.4) Brinton (13) Conjugated 1..54 (0.9-2.8) 1.20 (0.9-1.5) Hoover (14) Conjugated 1.5 (0.34.6) 1.3 (0.8-2.1) 2 Kelsey (15) Conjugated 0.9 (0.5-1.8) 0.8 (0.5-1.1)

DES 1.5 (0.2-9.1) 1.1 (0.4-3.0) Thomas (24) Conjugated 1 1.64 (0.484.50) 3 1.02 (0.48-2.14) a

1 Largely conjugated estrogens, but other forms also included. 2 Restricted to postmenopausal women. a History of artificial menopause, not specifically oophorectomy.

Latent period

In the two randomized trials of high doses of DES in young women (Table 3), breast cancer did not develop until ten (20) and 18 (19) years after treatment. However, the prospective study of women who received conjugated estrogens at menopause by Hoover et al. (18) showed the relative risk in users to increase gradually with time since initial estrogen use, and three case-control studies that addressed the latency issue (12, 13, 15) found no increase at all in relative risk with time since first exposure to menopausal estrogens.

These discrepant findings may be explainable if one assumes that estrogens increase risk of breast cancer by acting as tumor promotors, and increase the growth of m a m m a r y ductal epithelial cells that are the targets for whatever else causes breast cancer (i.e., initiators). I f this is true, few breast cancers would be expected to develop in young estrogen-treated women until enough time had elapsed for them to be sufficiently exposed to tumor initiators. On the other hand, older women who are already likely to have been so exposed, would be expected to more rapidly develop breast cancer in response to exogenous estrogens as these substances enhance the growth of already transformed cells. This hypothesized effect of estrogens has been more fully developed in a two-stage mathematical model by Moolgavkar et al. (23).

Ovarian status

Early natural or artificial cessation of ovarian function reduces the risk o f breast cancer, and exogenous estrogens could simply restore such women to their 'natural ' risk but not necessarily further enhance their risk or increase the risk in women who go through menopause at a normal age; i.e., there may be a threshold level of (endo- genous or exogenous) estrogens, below which risk is reduced, but above which risk might not be further enhanced. I f this were so, one would expect the risks in estrogen users relative to non-users to be greater in women whose ovaries were removed than in women with intact ovaries. As shown in Table 4, most studies show this to be true. In the one case- control study that definitely does not (12), the estimate of the relat ive risk in women without

ovaries is based on only 13 cases. Caution should be exercised in interpreting the results in Table 4, however. None of the relative risks shown differ significantly from unity.

Four studies, summarized in Table 5, provide direct estimates of the protective effect of an oophorectomy in women with and without estrogen replacement therapy. The results are conflicting. All four show oophorectomy without estrogen replace- ment to provide some degree of protection (line 3), but only two show this protective effect to be eliminated by exogenous estrogens (13, 24). Similar

208 DB Thomas

Table 5. Estimates from four studies of relative risk of breast cancer in relation to ovarian status and use of estrogens.

Oophorec tomy Exogenous estrogens

First author (reference)

Ross (12) 1 Kelsey (15) 1 Brinton (13) Thomas (24) 2

no no 1.00 1.00 1.00 1.00 yes 1.25 0.81 1.20 1.02

yes no 0.92 0.75 0.57 0.85 yes 0.72 0.63 1.05 1.40

1 Calculated from published daia. z Based on history of artificial menopause, not specifically oophorectomy.

analyses of data from other studies would help clarify this issue.

A major problem with all of the data presented in Tables 4 and 5 is that age at oophorectomy is not considered. If estrogens only eliminate the pro- tective effect of early menopause, the relative risk of breast cancer in estrogen users should be greatest in those with the earliest cessation of ovarian function, and near unity in those with an o0phorectomy after menopause; and inclusion of women in the latter category in Tables 4 and 5 would tend to mask any true effect of estrogens on risk in women oophor- ectomized premenopausally. Existing data should be analyzed to take into account the influence of age of oophorectomy (and of natural menopause) on relative risks in estrogen users.

Benign breast diseases

If women with benign breast lesions are at increased risk of breast cancer because some of these lesions progress to a malignant stage, and if estrogens act as mammary tumor promotors, then o n e would expect the relative risk of breast cancer in estrogen users to be greater in women with than without a history of benign breast disease. This was observed in the case-control studies of Ross et al. (12) and Brinton et al. (13), but not in those of Hoover et al. (14) and Kelsey et al. (15). Results from all but the last were published in summarizable form and are shown in Table 6. The findings of Brinton et al. (13) were restricted to oophorectomized women, and relative risks based on data from all women in that study may not have differed from those of Hoover and Kelsey. The discrepant results of Ross et al.

(12), however, cannot be explained on this basis because most women in that study had intact ovaries.

The influence of estrogens on the relative risk of breast cancer in women with benign breast disease was not reported separately for women with and without ovaries in any of the case-control studies except that of Brinton. However, the findings of Brinton are supported by results from a prospective study of breast cancer in women with benign breast lesions (24). Although based on only a subset of the total study group, and not statistically significant (p>0.05), the relative risks of breast cancer in estrogen users in that study were estimated to be 1.02 and 1.64 in women without and with surgical menopause, respectively. Data from other studies should be analyzed to confirm or refute these findings.

If the risk of breast cancer is increased by use of estrogens in women with a history of benign breast lesions, it would be important to know whether this occurs if the estrogens are taken before or after the benign lesion develops, or under both circum- stances, These temporal relationships were not considered in any of the case-control studies. In the prospective study of women with benign breast lesions (24), the increase in risk was observed only in women who used estrogens after the benign lesion developed, but history of estrogen use prior to the benign lesion was quite limited. Conversely, in the prospective study of Hoover et al. (18), the risk of breast cancer was doubled in women given estrogens after a diagnosis of benign breast disease, but increased four-fold in women whose benign lesion developed after estrogen use began. These

Exogenous estrogens and breast cancer 209

Table 6. Estimates from three studies of relative risks of breast cancer in estrogen users with and without a history of benign breast disease.

First author Measurement of dose Dose category (reference)

History of benign breast disease

yes no

Ross (12) Total milligrams taken 1-1499 2.7 0.6 1500+ 4.7 2.1

Hoover (14) Number of prescriptions < 5 0.8 1.2 >5 1.1 1.6

Brinton (13) 1 Any use - - 2.2 1.4

1 Results shown limited to women with bilateral oophorectomy.

findings were based on small numbers of cases, and further studies, or additional analyses of existing

data sets, are needed to clarify this issue. The influence of menopausal estrogens on risk of

breast cancer in women with various histologic types of benign breast lesions has been examined

only in the prospective study of Thomas et al. (24).

In that study, women with fibrocystic disease char-

acterized by epithelial tiyperplasia or papillomato-

sis were at increased risk, and their risk was greater

yet if there was histologic evidence of calcification in the benign lesion. Their risk was further in-

creased if they had taken estrogens, so that the risk in women with calcified proliferative lesions of the ductal epithelium who took estrogens was 7.8 times greater than non-users with other types of lesions.

These findings are based on small numbers, are not statistically significant (p>0.05), and need

independent confirmation.

Effect o f estrogens in high risk women

To date, there is little evidence that the effect of estrogens on risk of breast cancer is altered by any

of the menstrual or reproductive risk factors for this disease. Brinton et al. (13) reported that the relative risk in estrogen users was greater in nulliparous than parous women, but this was observed only in oophorectomized women, and was not found in two other studies (14, 18). No significant inter- action of exogenous estrogens with age at first birth

(13, 14), or with age at menopause (13), have been

observed.

Brinton et al. (13) and Hoover et al. (14) reported

greater relative risks of breast cancer in estrogen

users with than without a family history of breast cancer. However, this finding was restricted to oophorectomized women in the former study, and

was not statistically significant (p>0.05) in the latterl

Interactions of estrogens with other risk factors

are of considerable importance, and should be

investigated further by more detailed analyses of

data from existing studies. If women with known risk factors for breast cancer were found to be

unusually vulnerable to the effect of estrogens on risk of breast cancer, then particular caution could

be exercised in prescribing estrogen for such indi- viduals.

Prospectus

There is little doubt that estrogens can cause breast

cancer. The development of mammary neoplasms in the two transvestites who received massive doses of estrogens can be attributed to little else; and two

randomized trials have shown women who received high doses of DES during pregnancy to be at increased risk. Thus, we need not ask whether estrogens can cause breast cancer, but rather at what doses and under what circumstances? To date, menopausal estrogens have not been used in high

enough doses for a sufficiently long period of time

by enough women in the United States to cause perceivable increases in age-adjusted or age-specific

210 DB Thomas

incidence or mortality rates. This is not to say, however, that there is not a

small group of menopausal estrogen users who are at increased risk, either because they have taken unusually large amounts, or because their breasts are particularly susceptible to the carcinogenic ef- fects of estrogens. The data summarized in Table 2 suggest that heavy users or users of long duration may be at slightly increased risk (although the risk enhancement is much less than for endometrial cancer). Additional information on long-term users and on women who have taken high doses are needed to provide a more accurate assessment of the dose-response relationship between estrogens and risk of breast cancer. There may well be a dose that will provide the desired therapeutic effect in most women and yet not enhance their risk of breast cancer.

More information is also needed on the influence on breast cancer risk of estrogens given other than according to a continuous daily regimen, such as regularly but less than daily, or daily but with periodic weeks of estrogen abstention.

Additional information on risk long after initial use of menopausal estrogens is also needed. If estrogens given at menopause act as promotors, a long latent period is unlikely. However, other unrecognized mechanisms could be operative, and if they resulted in a latent period of more than 15 or 20 years, then additional case-control studies, con- ducted after sufficient time from initial use, could detect enhanced risks not apparent from many of the existing studies.

As already mentioned, the influence of estrogens on risk in women with varying ages at natural menopause and oophorectomy also needs careful study.

Also discussed above is the need to clarify the influence of estrogens on risk in women with benign breast lesions. Of particular interest is the temporal relationship of estrogen use and the benign lesion. If estrogens given before a benign lesion develops, enhance risk, then women who develop benign lesions while on estrogens should receive special attention. If estrogens given after a woman has had a benign lesion increase risk, then menopausal

estrogen therapy may be contraindicated in women

with a history of benign breast disease. The inter- action of estrogens and specific types of benign lesions also needs clarification.

Possible interactions of estrogens with other risk factors for breast cancer need careful study. If the relative risk in estrogen users is greater in women at relatively high than low risk, then such women should obviously be cautioned against use of estro- gens. It is not so obvious, but also true, that if the relative risk in estrogen users is the same in high and low risk women, then the absolute risk is enhanced more in high risk women, and they should still be cautioned against use of estrogens. High risk women could only use estrogens safely if the relative risk in estrogen users is sufficiently lower in high than low risk women. These relationships need careful clarification and quantification.

A conference on non-contraceptive estrogens and breast cancer was held in December 1980 under the auspices of the National Breast Cancer Task Force of the National Cancer Institute. Almost all in- vestigators who were currently working on this problem, or who had previously done so, attended. Results of their studies were presented, compared, and discussed, and many of the unanswered ques- tions mentioned in this review were identified. Some of these questions can be addressed by careful standardized reanalysis of existing datasets from completed studies. The Task Force is currently coordinating such reanalyses, and all investigators with appropriate data have agreed to collaborate in this important venture. It is hoped and anticipated that this project will provide a clearer picture of the role that menopausal estrogens may play in the development of breast cancer, and lead to the identification of specific questions that will have to be the subject of additional investigations.

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Acknowledgment

This work was supported in part by Cancer Center Support Grant CA-15704 from the National Cancer Institute.