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Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal WomenThe Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–3253. doi:10.1001/jama.289.24.3243
Context The Women's Health Initiative trial of combined estrogen plus progestin
was stopped early when overall health risks, including invasive breast cancer,
exceeded benefits. Outstanding issues not previously addressed include characteristics
of breast cancers observed among women using hormones and whether diagnosis
may be influenced by hormone effects on mammography.
Objective To determine the relationship among estrogen plus progestin use, breast
cancer characteristics, and mammography recommendations.
Design, Setting, and Participants Following a comprehensive breast cancer risk assessment, 16 608
postmenopausal women aged 50 to 79 years with an intact uterus were randomly
assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus
medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40
clinical centers. Screening mammography and clinical breast examinations were
performed at baseline and yearly thereafter.
Main Outcome Measures Breast cancer number and characteristics, and frequency of abnormal
mammograms by estrogen plus progestin exposure.
Results In intent-to-treat analyses, estrogen plus progestin increased total
(245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001)
and invasive (199 vs 150 cases; HR, 1.24; weighted P =
.003) breast cancers compared with placebo. The invasive breast cancers diagnosed
in the estrogen plus progestin group were similar in histology and grade but
were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at more advanced stage (regional/metastatic
25.4% vs 16.0%, respectively; P = .04) compared with
those diagnosed in the placebo group. After 1 year, the percentage of women
with abnormal mammograms was substantially greater in the estrogen plus progestin
group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.
Conclusions Relatively short-term combined estrogen plus progestin use increases
incident breast cancers, which are diagnosed at a more advanced stage compared
with placebo use, and also substantially increases the percentage of women
with abnormal mammograms. These results suggest estrogen plus progestin may
stimulate breast cancer growth and hinder breast cancer diagnosis.
Breast cancer is the most common invasive cancer in US women and its
etiology is not fully defined.1,2 Despite
observational studies suggesting increased breast cancer risk with estrogen3 and especially long-duration combined hormone use,4,5 the magnitude of breast cancer risk
associated with menopausal hormone therapy is controversial.6,7
On July 9, 2002, the Women's Health Initiative (WHI) reported results
from the randomized controlled trial of 16 608 postmenopausal women comparing
effects of estrogen plus progestin with placebo on chronic disease risk and
confirmed that combined estrogen plus progestin use increases the risk of
invasive breast cancer.8 To better understand
the relationship between breast cancer and exposure to estrogen plus progestin,
a detailed analysis of the breast cancers that developed among women receiving
active treatment compared with those receiving placebo was performed.
The WHI combined estrogen plus progestin randomized clinical trial enrolled
16 608 postmenopausal women with no prior hysterectomy from 1993 to 1998
at 40 clinical centers following a previously described design.8,9 The
study was approved by human subjects committees at each institution. Women
who were recruited by mass mailings and media were eligible if they were between
50 and 79 years of age at study entry, postmenopausal, and provided written
informed consent. Women with prior hysterectomy, breast cancer, or those with
medical conditions likely to result in death within 3 years were excluded.
Prior menopausal hormone use required a 3-month wash out period before baseline
testing. All women had baseline mammogram and clinical breast examinations;
abnormal findings required clearance before study entry.
Women were randomly assigned to receive estrogen plus progestin taken
as a single daily tablet containing conjugated equine estrogens (0.625 mg)
and medroxyprogesterone acetate (2.5 mg) (Prempro, Wyeth Ayerst, Philadelphia,
Pa) or to receive an identical-appearing placebo. Randomization by the WHI
clinical coordinating center was implemented locally by using a distributed
study database and study medication bottles with unique bar codes for blinded
dispensing. Descriptive characteristics for the 2 groups were assessed at
baseline (Table 1a).
Study medication was discontinued for development of breast cancer;
endometrial pathology (hyperplasia not responsive to treatment, atypia, or
cancer); deep-vein thrombosis or pulmonary emboli; malignant melanoma; meningeoma;
triglyceride level of more than 1000 mg/dL (11.3 mmol/L); or use of any nonstudy
estrogen, progestin, androgen, tamoxifen, or raloxifene. Comprehensive breast
cancer risk was assessed at baseline by interview (lifetime hormone use) or
by self-report (other covariates) by using standardized questionnaires.
Participants were contacted after 6 weeks to assess symptoms and promote
adherence, at 6-month intervals for clinical outcome, and annually for clinic
visits. Yearly mammography and clinical breast examination were required,
and study medications were withheld if they were not completed. Participants
were followed for clinical outcomes regardless of medication adherence.
Initial reports of outcomes were ascertained by self-administered questionnaires.
Breast cancer end points were confirmed by review of medical records and pathology
reports (available in 98.2% of participants) by physician adjudicators at
the local clinics. Women with in situ breast cancers, which at a later date
were diagnosed with a new invasive breast cancer, were considered to have
2 separate breast cancer events (3 cases). All cases were subsequently centrally
adjudicated using the Surveillance, Epidemiology, and End Results coding system.
Invasive cancers originally classified as mixed ductal and lobular underwent
additional blinded review by an oncologist (R.T.C.).
With the exception of these trial conduct procedures, the WHI clinical
centers did not provide comprehensive health care. Mammograms in the WHI were
performed at more than 3000 clinics, hospitals, and practice settings. Medical
decisions regarding workup of breast findings were directed by community physicians.
Mammogram reports were obtained from performance sites and were reviewed
locally and coded for recommendation (negative, benign finding-negative, short
interval follow-up suggested, suspicious abnormality, and highly suggestive
of malignancy). Mammograms with suspicious abnormalities or highly suggestive
of malignancy required clearance before dispensing additional study medication.
The study sample size was based on the estimated influence of estrogen
plus progestin on coronary heart disease. For monitoring purposes, a global
index of benefit and risk was defined to include coronary heart disease, stroke,
colorectal cancer, endometrial cancer, pulmonary embolus, hip fracture, and
death due to other causes as well as invasive breast cancer.
After a mean (SD) follow-up of 5.2 years (1.3) (including end points
through April 2002), the WHI data and safety monitoring board recommended
stopping the trial based on the breast cancer comparison exceeding the predefined
stopping boundary and overall risks exceeding benefits as measured by the
global index. At that time, 290 locally adjudicated invasive breast cancers
were described and the in situ breast cancers were not quantitated.8 This report provides an updated analysis based on
a mean (SD) follow-up of 5.6 years (1.3) with detailed analyses of the centrally
adjudicated breast cancers (349 invasive and 84 in situ) diagnosed before
July 8, 2002, the date participants were instructed to stop their study pills.
A major hypothesis of the current analysis was that invasive breast
cancer characteristics in the estrogen plus progestin group differed from
the placebo group. In addition, given the influence of menopausal hormones
on breast density10-12 and
the suggestion that hormones can complicate mammographic interpretation,13 associations among estrogen plus progestin use, mammographic
results, and breast cancer diagnoses were explored.
Primary results are assessed with time-to-event methods, based on the
intent-to-treat principle. Hazard ratios (HRs) are reported from unweighted
Cox proportional hazards regression analyses. P values
from Wald Z statistics are reported from weighted Cox proportional hazards
regression analyses stratified by age and randomization status in the dietary
modification trial of the WHI. This weighting was specified in the trial design
and motivated by observational reports suggesting lag to full effect of hormone
on breast cancer incidence. The weighting, reflecting this hypothesis, varied
linearly from zero at time of randomization to a maximum of 1 beginning at
follow-up year 10.
Nominal confidence intervals (CIs) for inference regarding invasive
breast cancer are used as these are considered final trial results for the
primary safety outcome. The multiple testing over time is acknowledged in
adjusted CIs derived from the monitoring plan, as previously described.8 The fact that this outcome was a key factor in the
early stopping of the trial could lead to some anticonservatism in the reported
Hazard ratios by time since randomization were calculated by using unweighted
Cox proportional hazards regression models for all women and separately for
women who had either received or not received menopausal hormone therapy before
entering the study. Tests of trends with time were performed in an unweighted
Cox proportional hazards regression model incorporating a linear time interaction
term. Kaplan-Meier method plots describe breast cancer event rates over time.
Sensitivity analyses examining the effect of nonadherence were conducted by
repeating these analyses after censoring events that occurred 6 months after
a woman became nonadherent (prospectively defined for adherence monitoring
purposes as consuming <80% of study pills or starting hormone therapy during
most recent study interval).
Comparisons of participant baseline and breast cancer tumor characteristics
were based on χ2, Fisher exact, or t tests.
Interactions between baseline characteristics and randomization assignment
were assessed in Cox proportional hazards regression models (weighted and
unweighted) that included both the risk factor (where applicable as a continuous
variable for computing the test statistic and P value)
and randomization assignment as main effects. P values
for assessing possible interactions were computed from likelihood ratio tests
by comparing models with and without the interaction term. Women with missing
values for a risk factor were omitted from these analyses. Twenty-three subgroup
comparisons were tested and, accordingly, 1 test would be expected to be significant
at the .05 level by chance alone. Ten comparisons are presented.
Calculated variables included (1) Gail Risk Assessment14 that
incorporated age, history of benign breast disease (atypia status unknown
in WHI), age at menarche, age at first live birth, race/ethnicity, and numbers
of mothers and sisters with breast cancer; (2) duration and recency of menopausal
hormone therapy and oral contraceptive use; (3) body mass index (calculated
as weight in kilograms divided by the square of height in meters); (4) dietary
variables, including energy, percentage energy from fat, and alcohol use;
and (5) physical activity (metabolic equivalent–hours per week of activity).
Analyses were performed by using SAS version 8.02 (SAS Institute Inc, Cary,
NC); P<.05 was considered significant.
Breast cancer risk characteristics were closely comparable in the 2
study groups including factors related to prior hormonal exposure, family
history, dietary intake, education, ethnicity, and the Gail Risk Assessment
(Table 1). Participants were at
moderate breast cancer risk for their age given a mean (SD) Gail 5-year risk
estimate of 1.50% (0.67%).
Recent (within 18 months) outcome information was available on 15 931
women (95.9% of randomized participants). Survival status was known for 16 067
participants (96.7%), including 485 (2.9%) known to be deceased. At the time
of this study, the mean follow-up was 5.6 years with a maximum of 8.6 years.
As previously described,8 at the time of our
interim study, 42% of estrogen plus progestin and 38% of placebo participants
stopped their study medications for at least some period. Drop-ins, based
on women who self-reported discontinuation of study medication and subsequently
received any menopausal hormones through other sources, were 6.2% in the estrogen
plus progestin group and 10.7% in the placebo group.
In intent-to-treat analyses, estrogen plus progestin increased total
(245 vs 185 cases; HR, 1.24; weighted P<.001)
and invasive (199 vs 150 cases; HR, 1.24; weighted P =
.003) breast cancers compared with placebo (P values
from weighted Cox proportional hazards regression models, Figure 1). The nominal 95% CI for the unweighted HR for invasive
breast cancer was 1.01 to 1.54. Accounting for the sequential monitoring gives
an adjusted 95% CI of 0.97 to 1.59. There was also a suggestion of an increase
for in situ breast cancers in the estrogen plus progestin group (47 vs 37
cases; HR, 1.18; weighted P = .09).
Sensitivity analyses examining the impact of nonadherence suggest a
stronger effect on invasive breast cancer incidence when events in nonadherent
women are excluded (HR, 1.49; weighted P<.001),
including the possibility of an earlier divergence in the cumulative hazard
estimates (Figure 2).
The number of invasive breast cancers by year and treatment group for
all women and stratified by prior hormone use are shown in Table 2. For women with no menopausal hormone use before entering
the study, invasive breast cancer rates were lower for the initial 2 years
in the estrogen plus progestin group compared with placebo, and similar in
the third year. In the fourth year and thereafter, invasive breast cancer
rates were higher in the estrogen plus progestin group, with a significant
trend for increasing breast cancer risk over time (Z = 2.31). In women with
prior menopausal hormone use, the rate of invasive breast cancer incidence
was greater in the third year and beyond for women receiving estrogen plus
The relationship between variables in Table 1 and treatment were examined in the form of interactions,
none of which were significant, although power was limited by small sample
size within subgroups. These results, as well as subgroup specific analyses,
are presented for selected covariates in Table 3. Overall, findings in specific risk categories underscored
the consistency of the main results; women assigned to estrogen plus progestin
had higher rates of invasive breast cancer in nearly all subgroups. Effects
by race/ethnicity were examined and no differences were found.
These data suggest that women reporting prior menopausal hormone use
may have had higher HRs for breast cancer associated with estrogen plus progestin
use than those who never used menopausal hormones (among never users, 141
vs 121; HR, 1.09; for women with <5 years of prior use, 37 vs 21; HR, 1.70;
and women with ≥5 years of prior use, 21 vs 8; HR, 2.27), but the trend
with duration of use was not statistically significant (weighted P = .15).
Invasive breast cancers associated with estrogen plus progestin use
were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04), were more likely to be node positive (25.9% vs
15.8%, respectively; P = .03), and were diagnosed
at a significantly more advanced stage (regional/metastatic 25.4% vs 16.0%,
respectively; P = .04) compared with placebo use
(Table 4). There was no difference
in tumor grade by treatment group. The percentages and distribution of invasive
ductal, invasive lobular, mixed ductal, and lobular as well as tubular carcinomas
were similar in the estrogen plus progestin group vs the placebo group.
The number of both receptor-positive and receptor-negative breast cancers
were greater in the estrogen plus progestin group; the distribution of estrogen
receptor-positive and progesterone-receptor cancers did not differ significantly
between the estrogen plus progestin and placebo groups when considering tumors
with known receptor status. There was a modest difference in receptor status
ascertainment between treatment groups that could not be attributed to tumor
size differences (data not shown).
For in situ breast cancers, the tumor grade did not differ between study
groups (P = .56). The size of the in situ cancers
was slightly larger in the estrogen plus progestin group (mean [SD], 1.6 cm
[2.0] vs 1.1 cm[0.6], respectively), but the difference was not statistically
significant (P = .33), and a substantial number of
in situ cancers had no measurable size. At this time, few deaths have been
attributed to breast cancer (4 in the estrogen plus progestin group and 4
in the placebo group).
Mammography clearance was required before entry for all participants.
Eighty-two women with mammographic abnormalities suspicious or highly suggestive
of malignancy were entered after medical clearance; only 3 subsequently developed
invasive breast cancers. Detailed mammogram reading results (other than cancer/no
cancer) were available for 14 607 women at baseline. At baseline, the
percentage of women with an abnormal mammogram was closely comparable with
the 2 treatment groups (Table 5).
After the first year, the percentage of women with abnormal mammograms
(with recommendations for either short interval follow-up, a suspicious abnormality,
or highly suggestive of malignancy) was substantially higher in the estrogen
plus progestin group vs the placebo group (716 [9.4%] of 7656 vs 398 [5.4%]
of 7310 women with abnormal mammograms, respectively; P<.001). The frequency of abnormal mammograms was higher in women
aged 50 to 59 years in the hormone therapy group after 1 year as well (8.8%
vs 5.9%, respectively; P<.001). In each year thereafter,
the percentage of women with abnormal mammograms was significantly higher
in the estrogen plus progestin group vs the placebo group. In total, 31.5%
of women in the estrogen plus progestin group had at least 1 abnormal mammogram
vs 21.2% of women in the placebo group (P<.001).
Thus, even short-term estrogen plus progestin use resulted in a substantial
increase in abnormal mammograms requiring medical evaluation.
This report provides randomized clinical trial evidence that postmenopausal
estrogen plus progestin use significantly increases the incidence of breast
cancer within a 5-year period. The breast cancers diagnosed in women in the
hormone therapy group had similar histology and grade but were more likely
to have advanced stage vs women in the placebo group. These results suggest
that invasive breast cancers developing in women receiving estrogen plus progestin
therapy may have an unfavorable prognosis. Follow-up continues in these women
to determine survival outcome.
Mammographic breast density was not routinely measured, but when the
mammographic results were examined over time by treatment group, a substantial
and statistically significant increase in the percentage of women with abnormal
mammograms requiring additional medical evaluation was observed beginning
in the first year of hormone use. The absolute increase in abnormal mammograms
of about 4% per year in women receiving estrogen plus progestin translates
into approximately 120 000 otherwise avoidable abnormal mammograms annually
for the estimated 3 million US postmenopausal women currently using this hormone
regimen. Prior reports of menopausal hormone therapy influence on mammographic
interpretation have been mixed, varying from no effect to substantial negative
influence.13,15 Our literature
review found no prior large randomized trials with comprehensive serial mammographic
assessment reporting the effects of estrogen plus progestin on the frequency
of abnormal mammograms.
Estrogen plus progestin use increases mammographic breast density vs
estrogen alone or placebo,10-12 but
the biological significance of such changes or their effect on mammographic
interpretation is not established.12 An ongoing
ancillary study in the WHI, formally evaluating mammographic breast density
on a subset of participants, may provide additional information on the relationships
among mammographic breast density change, mammographic interpretation, and
breast cancer risk.
Given the known psychological sequelae and requirement for medical evaluations
associated with any abnormal mammography report,16,17 the
substantially increased frequency of women receiving estrogen plus progestin
who have abnormal mammograms represents an additional adverse effect of menopausal
hormone use. This is an important consideration for women choosing even short-term
estrogen plus progestin therapy, because the increase in women with abnormal
mammograms was observed within the first year.
The breast cancers among women in the estrogen plus progestin group
vs those in the placebo group were diagnosed initially at a slightly lower
rate, subsequently at a higher rate, and were at a similar grade but a more
advanced stage at the time of diagnosis. This pattern, coupled with the increased
frequency of women with abnormal mammograms, suggests the hypothesis that
estrogen plus progestin stimulates breast cancer growth and delays breast
cancer diagnosis, perhaps mediated through differences in mammographic detection.
Although a longer time to diagnosis could explain some of the increases
in tumor size observed in the hormone therapy group, direct effects of estrogen
plus progestin on tumor growth cannot be excluded. The pattern of differential
breast cancer diagnosis observed over time is also consistent with the delay
hypothesis. This problem supports the use of weighted Cox proportional hazards
regression model statistics that are not highly sensitive to events early
in the follow-up period for comparisons between treatment groups.
Observational studies linking the characteristics of breast cancers
associated with menopausal hormone therapy, mostly involving the use of estrogen
alone, have given mixed results.18,19 Overall,
most report favorable stage20-22 and
favorable prognostic characteristics23-25 with
a predominance of receptor-positive cancers.21,26 In
the WHI randomized trial, breast cancers that occurred among women taking
estrogen plus progestin did not have such favorable characteristics. The demonstration
of an increased number of more advanced breast cancers without favorable characteristics
directly challenges the concept that hormone therapy might simply lead to
earlier diagnosis of more favorable cancers. This discrepancy could be related
to differential mammography use in women receiving hormones in observational
studies, an issue difficult to address directly since retrospectively recalled
frequency of mammography has proven relatively unreliable.27
not all20 recent observational studies evaluating
combined estrogen plus progestin therapy report a striking and, in some cases,
almost exclusive increase in invasive lobular breast cancers with little effect
on invasive ductal cancers. In the WHI trial, the number of cases in most
subtypes is small, but there is no evidence of a differential effect; all
major categories of invasive breast cancer were increased in the estrogen
plus progestin group, with only a slight excess in the invasive lobular or
mixed invasive ductal and lobular carcinoma categories.
The relatively early development of more breast cancers in the estrogen
plus progestin group was unexpected because most recent reviews of observational
studies suggest that breast cancer risk would be increased mainly with longer
term (>5 years) menopausal hormone use.31-33 This
discrepancy could be related to estrogen plus progestin hindering mammographic
identification of breast cancers as suggested by the current results. If this
is correct, determination of the effect of even short-term estrogen plus progestin
use relative to breast cancer risk becomes a vexing clinical problem.
A nonsignificant trend for higher HRs for breast cancer in women randomized
to estrogen plus progestin was observed for women reporting prior menopausal
hormone use. This observation suggests a role for cumulative exposure. However,
this finding could also reflect selection biases and, for this reason, reliable
interpretation is precluded. Despite the somewhat increased breast cancer
risk for estrogen plus progestin vs placebo use among prior hormone users,
prior hormone users were at somewhat lower risk vs never users (Table 2). It is unclear whether this is due to a successful user
effect, wherein prior long-term users already demonstrated themselves to be
less susceptible to breast cancer, or to other factors such as greater vasomotor
symptoms reflecting lower estrogen levels.
The magnitude of the increased breast cancer risk observed with estrogen
plus progestin in this clinical trial closely parallels observational study
results,4,5 but the fact that
the cancers developed after a shorter than predicted interval suggests an
effect on growth of established breast cancers. Evidence from other randomized
trials on this question is limited. In the Heart and Estrogen Replacement
Study trial, which included women with coronary heart disease, more breast
cancers occurred with estrogen plus progestin therapy compared with placebo
(34 vs 25 cases, respectively), but the difference was not statistically significant.34
The strengths of the WHI study of estrogen plus progestin include the
randomized double-blind study design, the large ethnically diverse study population,
comprehensive and detailed assessment of a range of breast cancer risk factors
at baseline, use of placebo controls, the requirement for baseline and ongoing
yearly mammography and clinical breast examination in both study groups, and
the central adjudication of the breast cancer end point via pathology report
review. The rates of discontinuation of study medications in both study groups
are limitations. However, these discontinuation rates are comparable with
those observed in other trials of menopausal hormones and are less than observed
in current clinical practice.35 Furthermore,
the discontinuation of study hormones in the WHI trial is likely to dilute
the estimate of effects of estrogen plus progestin, suggesting that the underlying
biological effect may be greater. Finally, the early stopping based on these
results provides less precision and may have introduced some anticonservative
bias in the HR estimates.
Because vaginal bleeding led to a high prevalence of de facto unblinding,
some potential for detection bias exists. The amount of bias, if any, is likely
to be small based on several factors. First, the WHI achieved very high compliance
with annual mammography, which was nearly identical between study groups throughout
follow-up. Furthermore, the readings and response to mammographic findings
were managed by the women's own physicians, independent of WHI and with no
access to study reports, thereby minimizing the opportunity for reported bleeding
to influence these findings. The potential influence of estrogen plus progestin
on breast cancer diagnostic decisions and procedures, including sensitivity
and specificity of mammograms and clinical breast examinations, represents
a complex issue that will be the focus of future analyses.
The WHI evaluated a single drug regimen, conjugated equine estrogens
(0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d), and therefore cannot
inform questions regarding risk associated with other oral or topical menopausal
hormone therapies. A parallel study of the WHI evaluating conjugated equine
estrogens alone compared with placebo for women with prior hysterectomy continues
in a blinded fashion with data and safety monitoring board oversight (scheduled
to be completed in 2005). Importantly, the data and safety monitoring board
indicated on May 31, 2002, that at this time no increase in breast cancer
has been observed in the trial of conjugated equine estrogens.
In summary, results from this prospective randomized trial indicate
that combined estrogen plus progestin use increases the risk of incident breast
cancers, which are diagnosed at a more advanced stage compared with placebo
use, and substantially increases the frequency of abnormal mammograms. In
light of these findings, abnormal mammograms in women receiving menopausal
hormone therapy deserve heightened scrutiny. The increased frequency of abnormal
mammograms requiring medical evaluation and increased breast cancer risk should
be added to the already known risks of short-duration menopausal hormone use.
Consideration for use of estrogen plus progestin for any duration by postmenopausal
women should incorporate the current findings into established8,36,37 and
emerging38 risks and benefits of these agents.