Risk of Breast Cancer with Progestins in Combination with Estrogen as Hormone Replacement Therapy
Richard J. Santen,
JoAnn Pinkerton,
Christopher McCartney and
Gina R. Petroni
University of Virginia Health System, Departments of Medicine,
Obstetrics and Gynecology, and Health Evaluation Sciences,
Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. Richard Stanten, Division of Endocrinology, University of Virginia Health System, P.O. Box 800379, Charlottesville, Virginia 22908.
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Introduction
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Two recent studies have suggested that progestins
substantially increase the relative risk (RR) of breast cancer
when added to estrogens as hormone replacement therapy (HRT)
(1, 2) (see Figs. 1
and 2
). If
correct, this information could substantially change clinical practice.
Here, we review biological, epidemiological, and clinical data
regarding the effects of progestins on the breast. From this analysis,
we conclude that no definitive proof exists to establish a causal
relationship between progestins and breast cancer risk. However, a wide
range of biological and clinical data provides strong supportive
evidence of such an effect. Based on this, we believe that it is
prudent to inform patients that progestin use may add to the increased
risk imparted by estrogens. Patients should understand, however, that
this increased risk is small, particularly when associated with the
short-term use of HRT.

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Figure 1. Estimated increase in RR of breast cancer as
a function of taking estrogen alone as HRT. The shaded
area represents the confidence limits of the percent increase
in risk per year. Redrawn from Ref. 1 .
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Figure 2. Estimated increase in RR of breast cancer as
a function of taking estrogen plus a progestin. The shaded
area represents the confidence limits of the percent increase
in risk per year. Redrawn from Ref. 1 .
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Data linking estrogens with an increased breast cancer risk
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Before examining the effects of progestins, it is first necessary
to question whether estrogen alone increases the risk of breast cancer.
Substantial data from animal and human studies provide support for a
link between estrogen use and breast cancer risk. Administration of
exogenous estrogen to rodents results in a high incidence of breast
cancer (3). The use of antiestrogens or blockers of
estrogen biosynthesis (aromatase inhibitors) abrogates the development
of breast tumors that occur spontaneously or are induced by carcinogens
in rats (4, 5). In women, early menarche, late menopause,
and increased endogenous circulating estrogen levels increase the RR of
developing breast cancer (3, 6, 7). Removal of both
ovaries before age 35 lowers the risk of breast cancer by 75% over a
25-yr period of observation (8, 9). Finally, antiestrogens
such as tamoxifen and raloxifene reduce the incidence of newly
diagnosed breast cancer as demonstrated by randomized,
placebo-controlled trials in women (10, 11).
More than 50 observational studies in patients have examined whether
estrogens cause an increased risk of breast cancer. Individual studies
report an increase, decrease, or no change in the risk of breast cancer
in menopausal women taking estrogen replacement therapy (ERT)
(6). A recent meta-analysis from the Collaborative Group
on Hormonal Factors in Breast Cancer (CGHFBC) (6)
identified several objective factors that potentially explain differing
conclusions among these studies. We draw the following conclusions from
this meta-analysis. First, the RR of breast cancer from ERT is small
and very large numbers of women must be studied to minimize type I and
type II statistical errors.1
Second, the risk of breast cancer seems to increase linearly with
duration of use. Consequently, studies comparing "ever users" of
estrogen with "never users" have limited validity because they do
not consider duration of estrogen use. Third, the increased risk of
breast cancer imparted by estrogens seems to dissipate within 4 yr of
cessation of therapy. Accordingly, only women using estrogen within 4
yr of study might be found to be at increased risk. Fourth, breast
cancer risk seems to diminish over the 4-yr period following the
menopause, presumably as a reflection of decreased estrogen levels. As
a result, analyses of observational studies need to match users
vs. nonusers as to time following menopause. Finally, the
increased risk of breast cancer seems to be limited to nonobese women
[i.e. body mass index (BMI), <25
kg/m2]. Inclusion of a large proportion of obese
women might obscure the association between estrogen use and breast
cancer risk.
The CGHFBC meta-analysis (6) was sufficiently large
(i.e. 52,705 women with breast cancer and 108,411 without)
to take each of these five factors into account. The key finding was a
linear 2.3% increase in the RR of breast cancer for each year of HRT
use for up to 25 yr. Both the slope of this linear increase in risk and
the overall risk of breast cancer among HRT users was found to be
highly statistically significant. In the authors opinion, the CGHFBC
meta-analysis provides substantial evidence that ERT increases the risk
of breast cancer. However, the inferences from this study must be
considered provisional because they are based on observational data and
are subject to various biases.
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Relationship between cell proliferation and breast cancer
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A general theory of carcinogenesis holds that agents that increase
the rate of cell proliferation can enhance the development of new
genetic mutations (12). Mutations are thought to be
necessary for the process of initiation of cancer. Once mutations are
present, they need to be propagated by cell replication, a process
considered to be responsible for tumor promotion. Estrogens are known
to enhance the rate of cell proliferation in glandular tissue of the
breast and, thus, could potentially act both in the initiation and
promotion of breast cancer.
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Effect of progestins on human breast proliferation
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A key issue is whether progestins exert proliferative or
antiproliferative effects on the human breast. Progestins oppose the
proliferative effects of estrogens on the human endometrium and reduce
the risk of endometrial cancer. Gambrell (13) has
hypothesized that progestins might abrogate the carcinogenic effects of
estrogen on the breast through a similar antiproliferative action.
Others argue that progestins exert proliferative and, thus,
procarcinogenic effects on the breast (14). This
controversy has stimulated a wide range of in vitro and
in vivo studies to delineate the effects of progestins on
breast tissue. The resulting reports highlight various complexities
underlying the effects of progestins on breast tissue.
It is important to understand that not all progestins are alike in
structure and function. Progestins can be classified into two major
subtypes, the 17
-acetoxyprogesterone and the nortestosterone
derivatives (15). The 17
-acetoxyprogesterone
derivatives, such as medroxyprogesterone acetate (MPA), possess
glucocorticoid-like as well as progestational activity. The group of
19-nortestosterone compounds includes two subclasses, the estranes and
gonanes. The estranes, such as norethindrone acetate and ethynodiol
diacetate, are more androgenic, and the gestanes, such as
gestodene and desogestrel, are more
progestational. Depending on their structure and the tissues in which
they are studied, the various progestins can exert either androgenic,
synandrogenic, antiandrogenic, estrogenic, glucocorticoid-like, or
progestational effects (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28).
These disparate actions of progestins on human breast cells in culture
have confounded interpretation regarding effects on proliferation. For
example, various studies report that human breast cancer cell lines
such as MCF-7, T47-D, and ZR-751 can be either stimulated or
inhibited by progestins through their androgenic, estrogenic, or
progestational effects (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). Normal human breast cells
obtained at reduction mammoplasty and grown in primary culture also
respond to various progestins with either proliferative or
antiproliferative responses.
A recent series of studies by Horwitz and colleagues
(29, 30, 31) highlight the complexity of mechanisms whereby
progestins regulate the proliferative process. They demonstrated that
progestins act to up-regulate growth factor and cytokine receptors and
interact with key downstream cell cycle mediators such as cyclin D.
Substantial cross-talk between progesterone receptors and growth
factor-related pathways occurs. Progestins increase the level of
epidermal growth factor receptors, activate the transcription factor
stat 5, and result in stimulation of several factors involved in
regulating the proliferative process such as mitogen-activated
protein kinase, p38 kinase, and
c-jun-NH2-kinase. Whereas much
is now known about the in vitro effects of progestins from
these studies, critical evaluation of these data do not establish
whether the predominant effect of progestins is to stimulate or inhibit
breast cell proliferation.
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Clinical studies regarding progestin effects in patients
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A clearer understanding that the predominant effects of progestins
on breast are to induce proliferation has emerged from patient studies.
Anderson and colleagues (14, 32) examined breast biopsies
taken from women during the follicular phase when estradiol is the
predominant circulating hormone and again during the luteal phase when
progesterone increases. They found a substantial increase in tritiated
thymidine uptake in association with luteal phase progesterone
increments and with use of progestin containing oral contraceptives.
These observations were confirmed by an additional study using
fine-needle aspiration and markers of cell proliferation (Ki67 or MIB
1) to assess differences between follicular and luteal phase
proliferation (33). Some doubt persisted, however, as a
result of findings from topical administration of progestins that
reduced breast epithelial cell proliferation. However, the amounts of
topical progestin used were sufficient to increase tissue levels to
pharmacological levels and, thus, may not reflect normal physiology
(34).
More compelling data regarding the proliferative effects of progestins
resulted from histological studies of breast tissue in postmenopausal
women receiving either estrogen alone, estrogen plus a progestin, or no
HRT for varying periods of time up to 10 yr. Hofseth et al.
(35) examined breast tissue from women undergoing
excisional biopsy for mammographic lesions. Tissue for assessment was
taken from areas distant from the focal lesion. These investigators
assessed proliferation by proliferating cell nuclear antigen (PCNA) and
Ki67 measurements and quantitated the percent area of breast occupied
by glandular tissue with computer-assisted morphometry. The results
demonstrated that long-term estrogen use increased the rate of cell
proliferation, the number of cells present in terminal ductal lobular
units, and the percentage of breast tissue made up of glandular tissue
as opposed to adipose and stromal tissue (Fig. 3
). Notably, the addition of a progestin
to estrogen replacement enhanced the rate of cell proliferation,
terminal duct lobular units (TDLUs), and glandular mass. These effects
of progestins appeared to increase linearly with time.

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Figure 3. Top, The percentage of cells that
stain positively for the proliferation marker PCNA in ductal tissue and
in TDLUs. The number under each bar represents the number of
individuals from whom ducts or TDLUs could be analyzed. *, P
< 0.002 that the percentages of PCNA-positive cells in the TDLUs of
the E+P group were significantly greater than in the TDLUs or ducts of
the no HRT group or E alone group; +, P < 0.007 that the
percentages of PCNA-positive cells in the TDLUs or ducts of the E group
or ducts of the E+P group were significantly greater than in the TDLUs
or ducts of the no HRT group; ±, P < 0.005 that the
percentages of PCNA-positive cells in the TDLU of the luteal phase
group were significantly greater than in the TDLUs of the
follicular phase group; §, P < 0.05 that the percentages
of PCNA-positive cells were greater in TDLUs than in the ducts of the
same group. E, Estrogen; P, progestin; L, luteal phase; F, follicular
phase. Middle, The percentage of cells that stain positively
for the proliferation marker Ki67 in ductal tissue and in TDLUs. The
number under each bar represents the number of individuals
from whom ducts or TDLUs could be analyzed. *, P < 0.002
that the percentages of Ki67-positive cells in the TDLUs of the E+P
group were significantly greater than in the TDLUs or ducts of the no
HRT group or E alone group; +, P < 0.007 that the
percentages of Ki67-positive cells in the TDLUs or ducts of the E group
or ducts of the E+P group were significantly greater than in the TDLUs
or ducts of the no HRT group; ±, P < 0.05 that the
percentages of Ki67-positive cells in the TDLUs of the luteal phase
group were significantly greater than in the TDLUs of the
follicular phase group; §, P < 0.05 that the percentages
of PCNA-positive cells were greater in TDLUs than in the ducts of the
same group. Bottom, Effects of HRT on breast
epithelial density in postmenopausal women. The number under each
bar represents the number of individuals for whom epithelial
density was determined. *, P < 0.001 that the percentages
of epithelial area in the E or E+P groups were significantly greater
than that of the no HRT group; + P < 0.02 that the
percentage of epithelial area in the E+P group was significantly
greater than that of the E alone group.
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Further evidence of the proliferative effect of
progestins derives from quantitative studies of mammographic density in
women receiving HRT (36, 37, 38, 39, 40). Glandular tissue enhances
the density of mammograms, and adipose tissue reduces it. Thus, breast
density can serve as a surrogate marker for long-term glandular cell
proliferation. The Postmenopausal Estrogen/Progestin Interventions
trial analyzed mammographic density (36) in 307 eligible
candidates out of a total of 875 women in the entire trial. Eligibility
criteria required having a baseline mammogram; a follow-up mammogram at
12, 24, or 36 months available for review; 80% compliance with the
assigned medication; and no use of estrogen for 5 yr before the
baseline mammogram. At 12 months, the percentage of women with density
grade increases was 0% [95% confidence interval (CI), 0.04.6%]
in the placebo group; 3.5% (95% CI, 1.012.0%) in the conjugated
estrogens alone group; 23.5% (95% CI, 11.935.1%) in the conjugated
estrogens plus cyclic MPA group; 19.4% (95% CI, 9.928.9%) in the
conjugated estrogens plus daily MPA group; and 16.4% (95% CI,
2.473.3%) with the conjugated estrogens plus cyclic micronized
progesterone group. Mammographic density may be a marker for increased
risk for breast cancer. If so, the above incremental changes seen when
a progestin is added to estrogen therapy may be important. These
results are consistent with other studies (37, 38, 39, 40) and
provide compelling evidence of the proliferative, as opposed to the
antiproliferative, effects of the progestins on human breast tissue
in vivo.
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Recent data regarding progestin use and breast cancer
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The two recent studies, published within 1 month of each other in
the winter of 2000 (1, 2), reported that progestins add to
the risk of breast cancer attributable to ERT. Although these studies
are observational with a potential for inherent biases, they are
remarkably consistent and supported by most, but not all, prior
studies. To evaluate the validity of the conclusions from these
studies, we have chosen to review existing data from prior studies
meeting certain very stringent criteria. We believe that demonstration
of the concordance of findings among these key studies provides the
best means of reaching tentative conclusions from presently available
data. We do not believe that a point-by-point analysis of potential
biases in each individual study will serve to override these
conclusions.
In our opinion, the experience gained from the CGHFBC meta-analysis
allows identification of certain stringent criteria required for study
validity (6). First, the study must be large enough to
compare risks among various subgroups. Second, women must have used HRT
within at least 4 yr before assessment of breast cancer risk. Third,
the duration of HRT use must be taken into account. For these reasons,
we have chosen to focus on individual studies meeting the following
criteria: 1) involvement of at least 1500 women with breast cancer; 2)
inclusion of data on women receiving HRT within 4 yr of breast cancer
risk assessment; 3) examination of risk after long duration
(i.e. at least 4 yr) of HRT exposure; and 4) comparison of
estrogen alone with the combination of estrogen plus a progestin. Five
studies met these four criteria (Table 1
).
The study published in the Journal of the American Medical
Association in January 2000 by Shairer et al.
(1) represents a cohort study of 46,355 postmenopausal
women followed long term in a mammographic screening program. The
investigators report that the RR of breast cancer from estrogen alone
was 1.2 (95% CI, 1.01.4) and that the RR from estrogen plus a
progestin was 1.4 (95% CI, 1.11.8). Strikingly, the RR increased by
1% (95% CI, 0.23%) per year of estrogen use alone and 8% (95%
CI, 216%) per year of use of estrogen plus a progestin (Figs. 1
and 2
). No increase in risk was observed in women with a BMI
(kg/m2) greater than 24.4. However, in women with
a BMI equal to or less than 24.4, the yearly increase in risk was 3%
(95% CI, 16%) with estrogen alone and 12% (95% CI, 225%) with
estrogen plus a progestin.
The study by Ross et al. (2) used the case
control method and compared HRT use in a group of 1897 postmenopausal
women with diagnosed breast cancer and 1637 controls. The risk of
breast cancer with ERT alone was only increased for women taking this
medication for 15 yr or more (odds ratio, 1.24; no CI listed). With
continuous estrogen plus a progestin, the odds ratio after 10 yr was
1.51 (no CI listed). Expressed as a yearly increase in odds ratio, ERT
was associated with a 1.2% per year increment, whereas estrogen in
combination with a progestin was associated with a 4.8% per year
increment. These were reported as risks per 5 yr with confidence limits
indicated (ERT alone 1.06 with 95% CI 0.971.15; estrogen-progestin
combination 1.24 with 95% CI 1.071.45). The risk of sequential
progestin use seemed to be higher (but was not significantly different
statistically) than that associated with continuous progestin use.
After 10 yr, the odds ratio for the sequential regimen was 1.79
vs. 1.23 for the continuous regimen.
The Nurses Health Study, reported only in abstract form, involved
980,000 person years and 16 yr of follow-up (41). In all,
2035 women developed breast cancer and provided information regarding
use of hormones. Yearly breast cancer risk increased with estrogen use
alone by 3.3% (SEM, 0.84%) and with estrogen plus a
progestin by 9.0% per year (SEM, 2.5%).
A Swedish case control study (42) reported on 3345
postmenopausal women with invasive breast cancer. After 10 yr of use,
the odds ratio for breast cancer risk associated with estrogen alone
was 2.7 (95% CI, 1.474.96), whereas that associated with estrogen
plus a progestin was 2.95 (95% CI, 1.844.72). The yearly risk was
3% (95% CI, 0.981.08) with estrogens alone and 7% (95% CI,
1.021.11) for estrogen plus a progestin. This study also compared
thin with obese women. The risks of HRT taken for more than 10 yr
(either estrogen alone or estrogen plus a progestin) were not increased
for those with a BMI more than 27 kg/m2 (odds
ratio, 1.33; 95% CI, 0.622.85) as opposed to those with BMIs of
2227 kg/m2 (odds ratio, 3.12; 95% CI,
2.094.66), and BMIs of less than 22 kg/m2 (odds
ratio, 1.97; 95% CI, 1.053.70). The final study (43),
the results of which conflicted with those of the other four, reported
that the RR associated with estrogen use alone was 0.81(95% CI,
0.651.00), whereas that associated with estrogen plus a progestin was
1.06 (95% CI, 0.681.64).
Other reported studies not meeting the stringent criteria defined above
are generally consistent with an adverse effect of progestins. Persson
et al. (44, 45) reported two studies from
Sweden within the past 5 yr. One reported a RR of 1.4 (95% CI,
1.11.8) for an estrogen-progestin (levonorgestrel) combination for 10
yr vs. a RR of 0.8 (95% CI, 0.61.1) for estrogen alone
(44). The other reported a RR of 2.4 (95% CI, 0.78.6)
for the estrogen-progestin combination vs. a RR of 1.3 (95%
CI, 0.53.7) for estrogen alone (45). Another study
reported a RR of 1.7 (95% CI, 0.93.3) for estrogen plus a progestin
vs. 1.2 (95% CI, 1.01.4) for estrogen alone
(46). In contrast, four additional studies including
relatively large numbers of women with breast cancer (1486, 742, 800,
and 660 women respectively) (47, 48, 49, 50) detected no increased
risk of adding progestins to estrogens. Several other studies included
too few women with breast cancer to detect trends (i.e. all
<100 breast cancer cases) (51, 52, 53). Interestingly, the
CGHFBC meta-analysis contained minimal information regarding estrogen
plus progestin use, and no conclusions were drawn regarding the added
effects of progestins on breast cancer risk (6).
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Unanswered questions regarding progestins and breast cancer
risk
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Biological data suggest that synthetic progestins may exert
various hormonal actions in addition to their progestational effects.
Accordingly, the various synthetic progestins used by patients could
exert divergent actions depending on their intrinsic properties.
Clinical data will be required to determine whether there are
differences in breast cancer risk associated with the use of these
compounds. The case control study of Magnussen et al.
(42) suggests that this might be the case. They noted a
trend toward greater risk of breast cancer in association with the
19-nortestosterone derivatives as opposed to the 17-
-derived
progestins.
The schedule of progestin administration may also alter breast cancer
risk. Available clinical data relate primarily to use of cyclic
progestins, whereas clinical practice now favors use of continuous
estrogen-progestin combinations. A trend observed in the study by Ross
et al. (2) indicated that the cyclic regimen,
after 10 yr of use, incurred a RR of 1.79 whereas the RR for the
combined regimen was 1.23. Finally, the beneficial reduction of
endometrial cancer with progestins may be offset by the increased risk
of breast cancer. Careful risk/benefit analyses need to readdress the
recommendations regarding long-term progestin use to prevent
endometrial cancer. Notably, should progestins be avoided in HRT
regimens? The increased risk of breast cancer from progestins may
outweigh its beneficial effects to prevent endometrial cancer.
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Attributable risk of breast cancer from HRT with estrogens plus a
progestin
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Epidemiological data examining the risk of breast cancer from HRT
report "relative risk" statistics to determine statistical
significance (6). This methodology provides substantial
statistical power to detect the effects of these agents that might be
quite small in magnitude. As discussed extensively in a prior
publication (54), the lay press, patients, and many
physicians confuse the term " relative risk" with "attributable
risk." An understanding of the precise definitions of these terms, as
detailed below, is important to judge the actual magnitude of risks
involved.
RR represents the ratio of the risk of breast cancer in women taking
HRT to those not taking HRT. The term does not take into account the
actual frequency of breast cancer in the group being considered.
Absolute risk is determined by multiplying the usual rate of breast
cancer in the group being considered by the RR. For example, average
50-yr-old women have an average risk of developing breast cancer of
2.52 per 100 women over a 10-yr period. A 10% increase in RR from
estrogens alone would increase the absolute chance of getting a breast
cancer over a 10-yr period to 2.77 per 100 women. Attributable risk
refers to the number of women who would develop a breast cancer that
would not have otherwise occurred without use of estrogen replacement.
Using the example above, the difference between breast cancer risk of
2.52 per 100 and 2.77 per 100 represents the increased risk
attributable to estrogen, or 0.252 per 100 women. Stated in another
way, 1 in 397 women taking ERT over 10 yr would develop a breast cancer
that would not have ordinarily occurred if ERT were not used (Table 2
).
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What are the attributable risks of breast cancer from estrogen
alone vs. an estrogen-progestin combination?
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Calculation of attributable risk requires data regarding the
age-specific incidence of breast cancer in the population under
consideration and the increase in RR with duration of hormone use. One
can use the data of Schairer et al. (1) (Figs. 1
and 2
) to calculate attributable risk. In 50-yr-old women, use of
estrogen for only 2 yr increases the RR of breast cancer by 2% (1%
per year over 2 yr). According to Surveillance, Epidemiology, and End
Results (SEER) data, 2.02 in 400 50-yr-old women will have a new
breast cancer diagnosed over a 2-yr period. With a 2% increase in RR,
the 50-yr-old patient taking ERT would then have a 2.06 in 400 chance
of getting a breast cancer. The attributable risk due to HRT is then
0.04 per 400 women. Stated in another way, 1 in 9925 women would
develop a breast cancer as a direct result of taking estrogen. Similar
calculations for an estrogen-progestin combination indicate an
attributable risk of 1 in 1241 women. This small absolute increase in
risk occurs even though the RR is increased by 8% per year over 2 yr,
or 16% in total.
The use of HRT over a 10-yr period increases the attributable risk
substantially. The cumulative incidence of breast cancer increases over
this time period, and the risk increases linearly per year. For
estrogen alone, the risk is increased by 1% per year or 10% over 10
yr. The reported rate of breast cancer in a 50-yr-old woman is 10 per
400 women at 10 yr. A 10% increase would make the rate of breast
cancer 11 per 400 over 10 yr. The attributable risk related to estrogen
is, thus, 1 in 397. With the combination of estrogen plus a progestin,
the RR increases by 8% per year or 80% overall. The attributable risk
for this group is now 1 in 50.
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Practical use of attributable risks and benefits in decision
making
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Short-term use of ERT/HRT for menopausal symptoms. Use of ERT
or HRT for less than 2 yr causes only a negligible increase in risk of
breast cancer in a 50-yr-old woman (1 in 9925 attributable risk from
estrogen alone and 1 in 1241 for estrogen plus a progestin).
Consequently, a woman could be encouraged to take short-term ERT or HRT
for menopausal symptoms without a great deal of concern regarding risk
of breast cancer.
Long-term use of ERT/HRT to prevent heart disease or
osteoporosis. The longer a woman takes estrogen, the greater is
her risk of developing breast cancer attributable to this hormone. The
attributable risk associated with estrogen alone, when taken by the
average 50-yr-old woman for 10 yr, is a 1 in 397 increase in the chance
of getting a breast cancer. For 60-yr-old women, the respective risk is
1 in 286. If we accept the data of Schairer et al.
(1) as valid, the RR of breast cancer increases by 8% per
year with use of an estrogen plus a progestin. Using these data, we may
calculate that, for the 50-yr-old taking HRT for a 10-yr period, the
breast cancer risk attributable to hormonal therapy would be 1 in 50.
For the 60-yr-old, the risk increases to 1 in 36.
In the average woman, this risk of developing breast cancer would
exceed the benefits of preventing a cardiovascular event. If one
accepts the Nurses Health Study data (55), HRT prevents a
new cardiovascular event in only 1 of 270 50-yr-old women taking this
medication for 10 yr. In the 60-yr-old women taking HRT for 10 yr, 1 in
152 will have a cardiovascular event prevented. However, this must be
interpreted in light of recent information from the Heart and
Estrogen/Progestin Replacement study, the Estrogen and
Atherosclerosis study, and other trials that raise valid questions
whether estrogen usage actually results in primary cardiovascular
prevention (56, 57, 58).
Weighing the pros and cons of HRT, many women will still choose
hormonal therapy because the risk of breast cancer is relatively small
in absolute terms. For example, based on the worst case analysis, a
50-yr-old women taking an estrogen/progestin combination as HRT for 10
yr has only a 4% chance of getting breast cancer. Without HRT, her
risk would be 2%. These statistics sound more reassuring if expressed
as the number of women remaining free of breast cancer. For example,
women taking HRT for 10 yr have a 96% chance of remaining free of
breast cancer vs. 98% of those not taking HRT.
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Other factors which influence decision making
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The two most recent studies of HRT and breast cancer risk suggest
that only thin patients (i.e. BMI of <24.4 in one study and
<27 in the other) experience an increased risk of breast cancer from
either estrogen alone or the combination of estrogen and a progestin
(1, 6). When limiting analysis to thin women, only those
taking HRT long term (i.e. greater than 5 yr) had a
statistically significant increase in breast cancer risk. Obese women
did not have an increased risk of breast cancer attributable to HRT. A
family history of breast cancer, early age of menarche, late age of
child bearing, a high-fat diet, obesity, increased breast density on
mammograms, and certain benign breast lesions increase the underlying
risk of developing a breast cancer. Finally, several studies suggest
that the breast cancers that develop in women receiving HRT are less
aggressive in type and are associated with a better prognosis
(59).
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Alternatives to use of ERT or HRT in women at high risk of
developing breast cancer
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A number of alternatives exist that can be used in place of
systemic estrogen to ameliorate problems related to estrogen deficiency
in women concerned about breast cancer risk (60). Vaginal
estrogen can be used to treat the symptoms of urogenital atrophy
without increasing systemic estrogen levels to a measurable degree. The
selective serotonin reuptake inhibitor class of drugs can alleviate
symptoms of depression. Preliminary data from a randomized, controlled
trial indicate that the selective serotonin reuptake inhibitors also
cause 75% relief of hot flashes (61, 62). Other trials
demonstrated that clonidine is more effective than placebo in relieving
hot flashes. For maintenance of bone mineral density and prevention of
osteoporosis and fractures, the bisphosphonates, raloxifene (a
selective estrogen receptor modulator), and calcitonin can be
beneficial. In some postmenopausal patients at high risk for breast
cancer, tamoxifen may be used both for prevention of breast cancer as
well as maintenance of bone density. A series of recent publications
report the surprising finding that the "statins" increase bone
formation and reduce fracture risk (63, 64, 65, 66, 67, 68, 69). Randomized,
controlled, prospective studies will now be required to confirm these
observational studies. For prevention of heart disease, the
HMG-CoA-reductase inhibitors (statins) are proven to be effective.
These can be chosen in place of estrogens alone or estrogenprogestin
combinations in patients at high risk of breast cancer or fearful of
taking HRT. Aspirin, anti-inflammatory agents, and vitamin E are being
studied as possible alternatives for the prevention of Alzheimers
disease, colon cancer, or macular degenerationdiseases for which
there is preliminary but not definitive evidence that HRT may influence
the rates of development.
 |
Conclusions
|
---|
Biological, epidemiological, and clinical data support the concept
that progestins enhance cell proliferation of breast tissue but inhibit
cell division in the uterus. Based on this reasoning, it is plausible
to postulate that progestins may increase the risk of breast cancer
over and above that resulting from estrogens alone. The attributable
risk from estrogen plus a progestin is minimal for short-term use but
may be substantial in the setting of long-term replacement. Recent data
suggest that the risks of breast cancer associated with HRT relate
primarily to thin but not obese women. We recognize that there is still
much to learn and the picture is confusing. Nonetheless, until
definitive data from randomized, prospective trials are available, it
is prudent to present the "worst case" analysis to patients and
inform them of their actual level of risk from estrogens with or
without a progestin. Based on this assessment, short-term use of HRT is
associated with negligible risk whereas the risks and benefits of
long-term use requires more analysis and careful consideration and
discussion of risks and benefits.
 |
Footnotes
|
---|
1 The type I error or false positive error is the
probability of concluding that a specified difference exists when, in
truth, it does not. The type II error or false negative error is the
probability of concluding that a specified difference does not exist
when, in truth, it does (Piantadosi, 1997). The power of a study is 1
minus the type II error. (Piantadosi, S., Clinical Trials: A
Methodologic Perspective, 1997, Wiley & Sons, Inc.) 
Received June 14, 2000.
Accepted August 18, 2000.
 |
References
|
---|
-
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton
L, Hoover R. 2000 Menopausal estrogen and estrogen-progestin
replacement therapy and breast cancer risk. J Am Med Assoc. 283:485491.[Abstract/Free Full Text]
-
Ross RK, Paganini-Hill A, Wan PC, Pike MC. 2000 Effect of hormone replacement therapy on breast cancer risk: estrogen
vs. estrogen plus progestin. J Natl Cancer Inst. 92:328332.[Abstract/Free Full Text]
-
Zumoff B. 1998 Does postmenopausal estrogen
administration increase the risk of breast cancer? Contributions of
animal, biochemical, and clinical investigative studies to a resolution
of the controversy. Proc Soc Exp Biol Med. 217:3037.[Abstract]
-
Gunson DE, Steele RE, Chau RY. 1995 Prevention of
spontaneous tumors in female rats by fadrozole hydrochloride, an
aromatase inhibitor. Br J Cancer. 72:7275.[Medline]
-
Hollingsworth AB, Lerner MR, Lightfoot SA, et al. 1998 Prevention of DMBA-induced rat mammary carcinomas comparing
leuprolide, oophorectomy, and tamoxifen. Breast Cancer Res Treat. 47:6370.[CrossRef][Medline]
-
Collaborative Group on Hormonal Factors in Breast
Cancer. 1997 Breast cancer and hormone replacement therapy:
collaborative reanalysis of data from 51 epidemiological studies of
52,705 women with breast cancer and 108,411 women without breast
cancer. Lancet. 350:10471059.[CrossRef][Medline]
-
Hankinson SE, Willett WC, Manson JE, et al. 1998 Plasma sex steroid hormone levels and risk of breast cancer in
postmenopausal women. J Natl Cancer Inst. 90:12921299.[Abstract/Free Full Text]
-
Feinlieb M. 1968 Breast cancer and artificial
menopause: a cohort study. J Natl Cancer Inst. 41:315329.[Medline]
-
Trichopoulos D, MacMahon B, Cole P. 1972 Menopause
and breast cancer risk. J Natl Cancer Inst. 48:605613.[Medline]
-
Fisher B, Constantino JP, Wickerman DL, et al. 1998 Tamoxifen for prevention of breast cancer: report of the National
Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl
Cancer Inst. 90:13711388.[Abstract/Free Full Text]
-
Cummings SR, Eckert S, Krueger KA, et al. 1999 The
effect of raloxifene on risk of breast cancer in postmenopausal women;
results from the MORE randomized trial. Multiple outcomes of raloxifene
evaluation. J Am Med Assoc. 281:21892197.[Abstract/Free Full Text]
-
Preston-Martin S, Pike MC, Ross RK, Henderson BE. 1993 Epidemiological evidence for the increased cell proliferation
model of carcinogenesis. Environ Health Perspect. 101(Suppl
5):137138.
-
Gambrell Jr RD. 1986 Role of progestogens in the
prevention of breast cancer. Maturitas. 8:169176.[Medline]
-
Going JJ, Anderson TJ, Battersby S, MacIntyre CCA. 1988 Proliferative and secretory activity in human breast during
natural and artificial menstrual cycles. Am J Pathol. 130:193204.[Abstract]
-
Mishell Jr DR. 1999 Contraception. In: Yen SSC,
Jaffe RB, Barbieri RL, eds. Reproductive endocrinology, physiology,
pathophysiology, and clinical management, chapter 35. Philadelphia: WB
Saunders; 676708.
-
Bullock LP, Bardin CW, Sherman MR. 1978 Androgenic,
antiandrogenic, and synandrogenic actions of progestins: role of steric
and allosteric interactions with androgen receptors. Endocrinology. 103:17681782.[Medline]
-
Catherino WH, Jeng MH, Jordan VC. 1993 Norgestrel
and gestodene stimulate breast cancer cell growth through
an oestrogen receptor mediated mechanism. Br J Cancer. 67:945952.[Medline]
-
Coldham NG, James VH. 1990 A possible mechanism for
increased breast cell proliferation by progestins through increased
reductive 17 ß-hydroxysteroid dehydrogenase activity. Int J Cancer. 45:174178.[Medline]
-
Dauvois S, Simard J, Dumont M, Haagensen DE, Labrie
F. 1990 Opposite effects of estrogen and progestin R5020 on cell
proliferation and GCDFP-15 expression in ZR-751 human breast cancer
cells. Mol Cell Endocrinol. 73:171178.[CrossRef][Medline]
-
Jordan VC, Jeng MH, Catherino WH, Parker CJ. 1993 The estrogenic activity of synthetic progestins used in oral
contraceptives. Cancer. 71:15011505.[Medline]
-
Kandouz M, Lombet A, Perrot JY, et al. 1999 Proapoptotic effects of antiestrogens, progestins, and androgen in
breast cancer cells. J Steroid Biochem Mol Biol. 69:463471.[CrossRef][Medline]
-
Manni A, Badger B, Wright C, Ahmed SR, Demers LM. 1987 Effects of progestins on growth of experimental breast cancer in
culture: interaction with estradiol and PRL and involvement of the
polyamine pathway. Cancer Res. 47:30663071.[Abstract]
-
Moore MR, Hathaway LD, Bircher JA. 1991 Progestin
stimulation of thymidine kinase in the human breast cancer cell line
T47D. Biochim Biophys Acta. 1096:170174.[Medline]
-
Murphy LC, Dotzlaw H, Alkhalaf M, et al. 1992 Mechanisms of growth inhibition by antiestrogens and progestins in
human breast and endometrial cancer cells. J Steroid Biochem Mol Biol. 43:117121.[CrossRef][Medline]
-
Musgrove EA, Swarbrick A, Lee CS, Cornish AL, Sutherland
RL. 1998 Mechanisms of cyclin-dependent kinase inactivation by
progestins. Mol Cell Biol. 18:18121825.[Abstract/Free Full Text]
-
Poulin R, Baker D, Poirier D, Labrie F. 1991 Multiple actions of synthetic progestins on the growth of ZR-751
human breast cancer cells: an in vitro model for the
simultaneous assay of androgen, progestin, estrogen, and glucocorticoid
agonistic and antagonistic activities of steroids. Breast Cancer Res
Treat. 17:197210.[Medline]
-
Sutherland RL, Lee CS, Feldman RS, Musgrove EA. 1992 Regulation of breast cancer cell cycle progression by growth
factors, steroids and steroid antagonists. J Steroid Biochem Mol Biol. 41:315321.[CrossRef][Medline]
-
van der Burg B, Kalkhoven E, Isbrucker L, de Laat
SW. 1992 Effects of progestins on the proliferation of
estrogen-dependent human breast cancer cells under growth
factor-defined conditions. J Steroid Biochem Mol Biol. 42:457465.[CrossRef][Medline]
-
Lange CA, Richer JK, Horwitz KB. 1999 Hypothesis:
progesterone primes breast cancer cells for cross-talk with
proliferative or antiproliferative signals. Mol Endocrinol. 13:829836.[Free Full Text]
-
Lange CA, Richer JK, Shen T, Horwitz KB. 1998 Convergence of progesterone and epidermal growth factor signaling in
breast cancer. Potentiation of mitogen-activated protein kinase
pathways. J Biol Chem. 273:3130831316.[Abstract/Free Full Text]
-
Richer JK, Lange CA, Manning NG, Owen G, Powell R,
Horwitz KB. 1998 Convergence of progesterone with growth factor
and cytokine signaling in breast cancer. Progesterone receptors
regulate signal transducers and activators of transcription expression
and activity. J Biol Chem. 273:3131731326.[Abstract/Free Full Text]
-
Anderson TJ, Battersby S, King RJ, McPherson K, Going
JJ. 1989 Oral contraceptive use influences resting breast
proliferation. Hum Pathol. 20:11391144.[Medline]
-
Potten CS, Watson RJ, Williams GT, et al. 1988 The
effect of age and menstrual cycle upon proliferative activity of the
normal human breast. Br J Cancer. 58:163170.[Medline]
-
Chang KJ, Lee TT, Linares-Cruz G, Fournier S,
deLignieres B. 1995 Influences of percutaneous administration of
estradiol and progesterone on human breast epithelial cell cycle
in vivo. Fertil Steril. 63:785791.[Medline]
-
Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA,
Haslam SZ. 1999 Hormone replacement therapy with estrogen or
estrogen plus medroxyprogesterone acetate is associated with increased
epithelial proliferation in the normal postmenopausal breast. J
Clin Endocrinol Metab. 84:45594565.[Abstract/Free Full Text]
-
Greendale GA, Reboussin BA, Sie A, et al. 1999 Effects of estrogen and estrogen-progestin on mammographic parenchymal
density. Postmenopausal Estrogen/Progestin Interventions (PEPI)
Investigators. Ann Intern Med. 130:262269.
-
Laya MB, Larson EB, Taplin SH, White E. 1996 Effect
of estrogen replacement therapy on the specificity and sensitivity of
screening mammography. J Natl Cancer Inst. 88:643649.[Abstract/Free Full Text]
-
Litherland JC, Stallard S, Hole D, Cordiner C. 1999 The effect of hormone replacement therapy on the sensitivity of
screening mammograms. Clin Radiol. 54:285288.[Medline]
-
Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von
Schoultz B. 1999 Mammographic breast density during hormone
replacement therapy: differences according to treatment. Am J
Obstet Gynecol. 181:348352.[Medline]
-
Persson I, Thurfjell E, Holmberg L. 1997 Effect of
estrogen and estrogen-progestin replacement regimens on mammographic
breast parenchymal density. J Clin Oncol. 15:32013207.[Abstract]
-
Colditz G, Rosner B. 1998 Use of estrogen plus
progestin is associated with greater increase in breast cancer risk
than estrogen alone. Am J Epidemiol. 147:S45S45.
-
Magnusson C, Baron JA, Correia N, Bergstrom R, Adami HO,
Persson I. 1999 Breast-cancer risk following long-term oestrogen-
and oestrogen-progestin-replacement therapy. Int J Cancer. 81:339344.[CrossRef][Medline]
-
Newcomb PA, Longnecker MP, Storer BE, et al. 1995 Long-term hormone replacement therapy and risk of breast cancer in
postmenopausal women. Am J Epidemiol. 142:788795.[Abstract]
-
Persson I, Yuen J, Bergkvist L, Schairer C. 1996 Cancer incidence and mortality in women receiving estrogen and
estrogen-progestin replacement therapylong term follow-up of a
Swedish cohort. Int J Cancer. 67:37332.[CrossRef]
-
Persson I, Thurfjell E, Bergstrom R, Holmberg L. 1997 Hormone replacement therapy and the risk of breast cancer. Nested
case control study in a cohort of Swedish women attending mammography
screening. Int J Cancer. 72:758761.[CrossRef][Medline]
-
Kaufman DW, Palmer JR, de Mouzon J, et al. 1991 Estrogen replacement therapy and the risk of breast cancer: results
from the case-control surveillance study. Am J Epidemiol. 134:13751401.[Abstract]
-
Ewertz, M. 1988 Influence of noncontraceptive
exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer. 42:832838.[Medline]
-
Risch RA, Howe GR. 1994 Menopausal hormone usage
and breast cancer in Saskatchewan: a record-linkage cohort study. Am J Epidemiol. 139:670683.[Abstract]
-
Palmer JR, Rosenberg L, Clarke EA, Miller D, Shapiro
S. 1991 Breast cancer risk after estrogen replacement therapy:
results from the Toronto Breast Cancer Study. Am J Epidemiol. 134:13861401.[Abstract]
-
Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA,
Rossing MA. 1995 Combined estrogen and progestin hormone
replacement therapy in relation to risk of breast cancer in middle-aged
women. J Am Med Assoc. 274:137142.[Abstract]
-
Nachtigall MJ, Smilen SW, Nachtigall RD, Nachtigall RH,
Nachtigall LE. 1992 Incidence of breast cancer in a 22-year study
of women receiving estrogen-progestin replacement therapy. Obstet
Gynecol. 80:827830.[Abstract]
-
Yang CP, Daling JR, Band PR, Gallagher RP, White E,
Weiss NS. 1992 Noncontraceptive hormone use and risk of breast
cancer. Cancer Causes Control. 3:475479.[Medline]
-
Hunt K, Vessey M, McPherson K, Coleman M. 1987 Long-term surveillance of mortality and cancer incidence in women
receiving hormone replacement therapy. Br J Obstet Gynaecol. 94:620635.[Medline]
-
Santen RJ, Petroni GR. 1999 Relative vs.
attributable risk of breast cancer from estrogen replacement therapy. J Clin Endocrinol Metab. 84:18751881.[Free Full Text]
-
Grodstein F, Stampfer MJ, Manson JE, et al. 1996 Postmenopausal estrogen and progestin use and the risk of
cardiovascular disease. N Engl J Med. 335:453461.[Abstract/Free Full Text]
-
Hulley S, Grady D, Bush T, et al. 1998 Randomized
trial of estrogen and progestin for secondary prevention of coronary
heart disease in postmenopausal women. J Am Med Assoc. 280:605613.[Abstract/Free Full Text]
-
Herrington DM, Reboussin DM, Brosnihan KB, et al. 2000 Effects of estrogen replacement on the progression of
coronary-artery atherosclerosis. N Engl J Med. 343:522529.[Abstract/Free Full Text]
-
Kolata G. 2000 Estrogen tied to slight increase in
risks to heart, a study hints (newspaper report of letter sent to study
participants by the study coordinators). The New York Times, April 5,
2000; A-1.
-
Schairer C, Gail M, Byrne C, et al. 1999 Estrogen
replacement therapy and breast cancer survival in a large screening
study. J Natl Cancer Inst. 91:264270.[Abstract/Free Full Text]
-
Pinkerton JV, Santen RJ. 1999 Alternatives to the
use of estrogen in postmenopausal women. Endocr Rev. 20:308320.[Abstract/Free Full Text]
-
Loprinzi CL, Kugler JW, Sloan J, et al. 2000 Venlafaxine alleviates hot flashes: an NCCTG trial. Proceedings of
ASCO. J Clin Oncol. 19:4.
-
Loprinzi CL, Quella SK, Sloan JA, et al. 1999 Preliminary evaluation of fluoxetine (Prozac) for treating hot flashes
in breast cancer survivors. Proceedings of the 22nd Annual San Antonio
Breast Cancer Symposium. Breast Cancer Res Treat. 58:34.
-
Mundy G, Garrett R, Harris S, et al. 2000 Stimulation of bone formation in vitro and in rodents by
statins. Science. 286:19461949.[Abstract/Free Full Text]
-
Bauer DC, Mundy GR, Jamal SA, et al. 1999 Statin
use, bone mass, and fracture: an analysis of two prospective studies.
J Bone Miner Res. 14(Suppl 1):S179.
-
Chung YS, Lee MD, Lee SK, Kim HM, Fitzpatrick LA. 2000 HMG-CoA reductase inhibitors increase BMD in type 2 diabetes
mellitus patients. J Clin Endocrinol Metab. 85:11371142.[Abstract/Free Full Text]
-
Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick
H. 2000 HMG-CoA reductase inhibitors and the risk of fractures. J Am Med Assoc. 283:32053210.[Abstract/Free Full Text]
-
Wang PS, Solomon DH, Mogun H, Avorn J. 2000 HMG-CoA
reductase inhibitors and the risk of hip fractures in elderly patients.
J Am Med Assoc. 283: 32113216.
-
Cummings SR, Bauer DC. 2000 Do statins prevent both
cardiovascular disease and fracture? J Am Med Assoc. 283:32553257.[Free Full Text]
-
Chan KA, Andrade SE, Boles M, et al. 2000 Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of
fracture among older women. Lancet. 355:21852188.[CrossRef][Medline]