Postmenopausal estrogen and the risk of breast cancer

COMMENTARY

Postmenopausal Estrogen and the Risk of Breast Cancer ELIZABETH BARRETT-CONNOR,

MD

The increasing extended use of noncontraceptive estrogen by postmenopausal women, intended to prevent osteoporosis and heart disease, may at the same time increase their risk of other conditions. Among these, breast cancer is the most common life-threatening outcome and most feared. As reviewed elsewhere (l), many characteristics of women who develop breast cancer suggest an etiologic or promotional role for endogenous estrogens. Breast cancer is more common in nulliparous women or women with a late first pregnancy, and in women with a long menstrual history due to early menarche or late menopause. Women castrated before the age of 35 have only one-third the incidence of breast cancer observed in intact women; nearly one-third of women with advanced breast cancer have a remission after oophorectomy. The reduced recurrence rate following tamoxifen therapy is attributed to an antiestrogen effect. Age-specific rates also suggest an etiologic role for estrogen and breast cancer. The risk of breast cancer rises steeply with age to around 50, the average age of menopause, after which there is a much shallower rise in the slope, compatible with estrogen deficiency (Figure 1) (2). Further, in the United States the incidence of breast cancer has increased 32% since 1982, coincident with the increasing use of hormone replacement therapy (3). This increase has occurred exclusively in women aged 45 years and older. In the Oregon population-based tumor registry, the incidence of estrogen receptor-positive tumors increased an average of 13 1% from ,,?/A. *nor lyou to lYo3, aiso compatibie with a hormonai effect (4j. Nevertheless, it has been surprisingly difficult to demonstrate an increased risk of breast cancer in studies of postmenopausal women taking estrogens. Two (5, 6) of four

Ann Epidemiol 1994;4: 177-180. From the Department of Community and Family Medicine, University of California, San Diego, La Jolla, CA 92093.0607. Address reprint requests to: Elizabeth Barrett-Connor, MD, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0607. Received May 26, 1993; revised September 9, 1993. 0

1994 by

Elxuier Science Inc.

recent meta-analyses concluded that risk; the other two (7, 8) concluded small increased risk associated with nrnhnhlv the I). _Armstrong _,. ~~~~~____..~15) \_, WRS -_ I-------, ----

there was no increased that there is only a long-term use (Table first WIIAV .wtrnum ____” to _- ___-_, _I___ b---

and breast cancer using the meta-analysis method, and to document the remarkable heterogeneity in study results. In their meta-analysis, DuPont and Page (6) found no overall increased risk, but could not exclude an effect of high-dose estrogen. Steinberg and coworkers (7) found a significant 1.3-fold increased risk after 15 years of use, but no increase in risk with 5 or fewer years of use. Sillero-Arenas and colleagues (8) analyzed 27 studies and concluded that there was a small but statistically significant increased risk (relative risk (RR) = 1.06) of breast cancer in estrogen-treated women. There are a number of limitations to these studies. Because long-term estrogen replacement therapy was not common until the 197Os, most of the women in the early studies had used estrogen for less than 10 years. None of the studies has had the power to exclude risk after prolonged use. Older studies included women treated with much higher doses than those commonly used today; women who were treated longer also started estrogen in the era of high-dose estrogens, making it difficult to separate dose from duration. Earlier studies often had poor study design and were the studies most likely to show no association. Steinberg and colleagues (7) reported that an increased risk was least equivocal in the studies that were rated as having the best design by reviewers who were biinded to the resuits of the study. In meta-analysis it is possible to aggregate subgroups of women thought to be at particular risk, increasing the usual sample size for special characteristics. Selected subgroup meta-analyses from Steinberg and colleagues (7) are shown in Table 2. The risk associated with estrogen was similar in parous and nulliparous women, but was greater in women with a family history of breast cancer. There was no increased risk associated with estrogen in four of five studies of women with benign breast disease. However, the single largest study of women with histologically proved breast atypia found a significantly reduced risk of breast cancer lC47-2797/94/$07.00

178

Barrett-Connor ERT AND BREAST CANCER RISK

AEP Vol. 4, No. 3 May 1994: 177-180

TABLE

HEART

1. Meta-analyses of breast cancer risk

Author(s)

Year

No. of studies reviewed

Armstrong (5) DuPont and Page (6) Steinberg et al. (7) Sillero-Arenas et al. (8)

1988 1991 1991 1992

23 28 16 27

is better than a comparison

Increased risk No No Yes Yes

of cases from a registry or prac-

tice with national or regional rates. This is because internal comparison

groups are more likely to be comparable

regard to other important

differences

with

such as parity and

social class. Women of higher social class have a higher risk of breast cancer and are more apt to be prescribed estrogen. Meta-analyses do not correct for biases in observational studies; pooling of studies with similar bias only improves statistical significance.

As shown in Table 3, five of seven

plausible biases would be expected to artificially reduce the true risk of breast cancer associated with hormone ment.

For example,

oophorectomized

replace-

women ordinarily

have a reduced risk of breast cancer, but women with an early oophorectomy

are those most likely to be prescribed

(and to stay on) estrogen. This would tend to minimize the risk of estrogen observed in studies. Women taking replacement estrogen have typically more physician

contact;

this results in their being more often

examined and more often recommended

for mammography

(10). The resultant earlier diagnosis could lead to a spuriously high risk of breast cancer, a better prognosis, paradoxically

and a

lower risk of fatal breast cancer. This possibil-

ity is strongly suggested by a British report where the incidence of breast cancer was significantly

Ape (5 Year Groups1

FIGURE 1. United States, female, 1962. Semilogarithmic plots of age-specific death rates versus age (“Gompertz” plots) are presented. (Reprinted from Journal of Chronic Diseases, vol. 19, Tracy RE, Sex differences in coronary disease: two opposing views, pp. 1245-5 1, copyright 1966, with permission from Pergamon Press Ltd., Headington Hill Road, Oxford OX3 OBW, UK.)

associated with noncontraceptive

estrogen only in women

whose biopsy preceded estrogen prescription (9). Meta-analysis of observational data has limitations.

increased (RR =

1.59) but the relative risk of fatal breast cancer was significantly reduced (RR = 0.55) in estrogen-treated

women (11).

Similarly, Bergkvist and associates (12) found a significantly better

survival after breast

cancer

diagnosis

in Swedish

women who had used replacement estrogen, compared with women who had not taken estrogen. On the other hand, if women with breast cancer are more apt to be screened for breast cancer before being prescribed hormone replacement, this would tend to reduce the number

of cases in users.

of the best known is reporting bias. Both authors and jour-

Finally, long-term users are compliant women; compliance with placebo improves prognosis in randomized clinical

nals are more likely to publish results that deviate from the

trials.

null. Meta-analysis

In the analysis, it is rarely possible to control for all breast cancer risk factors, some of which may have consciously or

One

also does not correct for design flaws in

unconsciously

prejudiced who is or is not prescribed hor-

appropriateness of the comparison group. Hospital controls (commonly used in case-control studies) are inappropriate because estrogen use probably reduces the chance of being

mones.

the apparent

hospitalized with other conditions such as heart disease or fracture. In cohort studies, an internal comparison group

of hormone replacement for women with a family history of breast cancer. Bergkvist and associates (14) reported a

studies. For example,

results may vary according

to the

Thus,

protective

effect of estrogen

alone or estrogen plus progestin reported by Gambrel1 and coauthors (13) very likely reflects less frequent prescription

179

Barrett-Connor ERT AND BREAST CANCER RISK

AEP Vol. 4, No. 3 May1994: 177-180

TABLE 2. Effect of estrogen replacement therapy on relative risk of breast cancer in women, stratified by risk factors

Type of Strata

stratification

No. of studies

Mean relative risk (95% CI)

Family history of breast cancer

Yes NO

5 5

3.4 (2.0-6.0) 1.5 (1.2-1.7)

Parity

Nulliparous Parous

6 4

1.5 (1.1-2.1) 1.3 (1.0-1.7)

Benign breast disease

Yes No

5 5

1.7 (1.2-2.3) 1.4 (1.2-1.7)

Age at first full-term pregnancy

<20 >30

3 3

1.1 (0.6-2.0) 1.7 (1.0-3.0)

TABLE 4. Observational studies of estrogen replacement therapy and breast cancer where total cohort relative risk (RR) and 65% confidence intervals (Us) did not include one First author

Year

RR

CI

Bland (17) Lawson (18) Hulka (19) Gambrel1 (13) La Vecchia (20) Hunt (11) Mills (21) Colditz (16)

1980 1981 1982 1983 1986 1987 1989 1990

0.38 2.50 1.58 0.32 1.84 1.59 1.74 1.18

0.16-0.88 1.60-4.00 1.09-2.28 0.18-0.57 1.27-2.68 1.18-2.10 1.10-2.74 1.04-1.35

’Relative risk from Sillero-Arenas et al. (8).

C! = conf;dence interva!. From Steinberg et al. (7).

TABLE

3. Biases in observational

hormone

replacement

studies

of

workers

(8) found

estrogen

use after the menopause,

an increased

the 95% confidence

Bias

Increased Decreased Decreased Decreased Decreased

risk risk risk risk risk

Decreased risk Increased risk

SES = socioeconomic status.

studies with statistically

apy and before subgroup analysis) (11, 13, 16-21).

signifiSix of

increased risk and two

found a significantly reduced risk. Possible explanations

for

such divergence include differences in study design, population, and hormone regimen, as well as treatment tainment

and ascer-

biases.

Most studies of long-term noncontraceptive estrogen use and breast cancer come from the United States, and reflect the use of unopposed

conjugated

estrogen.

Reports from

Europe, where more potent estradiols are more commonly used, are disconcerting

number of differences

with

cant differences overall (without regard to duration of therthese studies found a significantly

Who-is-treated bias High SES Early menopause/oophorectomy Symptomatic women = thin women No family history of breast cancer Negative mammogram before treatment After-treatment bias Compliant women More frequent examination/mammogram

cancer

but in 19 of 27 studies

intervals did not include one. Table 4

shows eight observational Effect on breast cancer risk

risk of breast

in the distribution

risk factors in postmenopausal

of breast cancer

women who were or were not

in that they suggest an increased

risk after a shorter duration

of treatment.

In two of these

studies, the highest risk after the shortest duration of treat-

taking estrogen. Not all of these differences were protective,

ment was seen in women treated with estrogen plus a proges-

however.

tin or other androgen.

It has been calculated that very large samples, with over

In a Swedish study, there was a fourfold increased risk of

1000 cases, would be required to exclude an estrogen-breast

breast cancer in women after more than 4 years of treatment

cancer association (15). When a meta-analysis, designed to n~-rr-r\..nC- L,.,, ,c ,,,ll‘ ,, ,+..A,, . c”q.J~LmaLr L”L tl.0 LllC Lm;cnrl ll‘l.lLLU _r...IP.. p”wcL “I JILIaLIcL JLUUIL-D) 1s

with estrogen plus a progestin, but the 95% confidence interval for this association __L_____.___ was -- vcrv .--I wide (0,9 to 22.41 --- .I (22). \--I-

weighted by sample size, the findings may not be representa-

These results are compatible

tive of overall risk. The largest prospective

case-control study from Denmark, where sequential therapy

study is that

with a large population-based

reported by Colditz and colleagues (16), who examined the

with estrogen

incidence of breast cancer in 23,607 postmenopausal American nurses who were followed from 1976 to 1986. The over-

cantly increased risk of breast cancer (RR = 1.31) not ob-

and progestin was associated with a signifi-

served with estrogen use overall (23). These results support

all age-adjusted risk was significantly higher in women who

the hypothesis of Kay and Pike (24) that estrogen plus pro-

currently used noncontraceptive

gestin could be more carcinogenic

confidence

estrogen (RR = 1.36; 95%

intervals = 1.11 to 1.67); past users were not at

contrast,

than estrogen alone. In

in women in Britain there was a significant 2.38-

= 0.81 to

fold risk associated with 10 or more years of estrogen, but

1.18). However, women in this cohort were relatively young, aged 30 to 55 years at baseline, so that most postmenopausal

the risk was not further increased in women who also used a progestin (11).

long-term users must have had either oophorectomy or premature menopause, factors that are ordinarily protective

The only randomized long-term (lo-year) clinical trial reported to date found a significantly lower risk of breast cancer

against

in 84 institutionalized

increased risk (RR = 0.98; confidence

breast

cancer.

The

intervals

true risk could be larger in

woman with a (more usual) later age at menopause. Many of the studies reviewed by Sillero-Arenas

and co-

women assigned to receive Premarin,

2.5 mg daily, plus cyclic medroxyprogesterone

(10 mg daily

for 7 days), compared with women assigned to placebo (25).

180

Barrett-Connor ERT AND BREAST

CANCER

AEP Vol. 4, No. 3 May 1994: 177-180

RISK

Unfortunately, this study cannot exclude a progestin-breast cancer association with current therapies, because this dose of estrogen may have been high enough to offset the effect of progesterone increasing breast cell mitosis. In summary, essentially all of the data on the risks of long-term estrogen therapy in postmenopausal women are based on observational studies, subject to the usual caveats of interpretation. Factors related to who receives replacement estrogen and who remains on it, and the known biases, would tend to alter risk. It would be premature to conclude that currently recommended doses of estrogen do not significantly increase the risk of breast cancer in postmenopausal women, particularly when estrogen is continued for more than 5 years. Whether the addition of a progestin augments this risk is unknown, but biologically plausible. The answer is obviously important. If a hormone-induced 30% increase in risk is extrapolated to 3 million postmenopausal women in the United States, 4700 new cases and 1500 breast cancer deaths per year would result. However, the fear of breast cancer may prevent estrogen use by women at high risk of estrogen deficiency disease. Unfortunately, the possibility that replacement estrogen alone or with a progestin increases the risk of breast cancer is unlikely to be resolved by clinical trails. Clinical trials are designed to test putative benefits, not risks. It is unethical to conduct a clinical trial with an increased risk of cancer as the outcome. If the clinical trial is designed to study beneficial outcomes, the earlier effect on heart attacks will most likely preclude continuation of the placebo group for I_-_ ___..-L .._ -i_,_:_ ue‘ 1_L_:,:.._- ^._.--^ aU”uL _l-_..& Cblr”grll ^^.._____ rvrig enuugri L” “IJLaul lIull”e ailbwrlb and breast cancer. In this setting, there is no simple answer for every woman. Physicians must be careful not to be overly eager to promote or deny hormone replacement to healthy women. Instead, they need the time necessary to explain the uncertainties as well as the probable benefits, allowing their postmenopausal patients to make informed choices about when and how to use estrogen. Currently, individual fears, preferences, risk, and quality of life seem to be the most valid deciding factors.

Presented

in part at a Nova Nordisk International

Aspects of Hormone

Replacement

lished in the Proceedings Copenhagen,

Denmark,

pects of Hormone

Therapy,

Symposium

September

of the Nova Nordisk International September

Replacement

4-5,

on Safety

5, 1992, and pubSymposium,

1992, under the title “Safety As-

Therapy.”

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