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Menopausal Hormone Replacement Therapy and Risk of Ovarian Cancer
James V. Lacey, Jr, PhD;
Pamela J. Mink, PhD;
Jay H. Lubin, PhD;
Mark E. Sherman, MD;
Rebecca Troisi, ScD;
Patricia Hartge, ScD;
Arthur Schatzkin, MD, DrPH;
Catherine Schairer, PhD
JAMA. 2002;288:334-341.
ABSTRACT
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Context The association between menopausal hormone replacement therapy and ovarian
cancer is unclear.
Objective To determine whether hormone replacement therapy using estrogen only,
estrogen-progestin only, or both estrogen only and estrogen-progestin increases
ovarian cancer risk.
Design A 1979-1998 cohort study of former participants in the Breast Cancer
Detection Demonstration Project, a nationwide breast cancer screening program.
Setting Twenty-nine US clinical centers.
Participants A total of 44 241 postmenopausal women (mean age at start of follow-up,
56.6 years).
Main Outcome Measure Incident ovarian cancer.
Results We identified 329 women who developed ovarian cancer during follow-up.
In time-dependent analyses adjusted for age, menopause type, and oral contraceptive
use, ever use of estrogen only was significantly associated with ovarian cancer
(rate ratio [RR], 1.6; 95% confidence interval [CI], 1.2-2.0). Increasing
duration of estrogen-only use was significantly associated with ovarian cancer:
RRs for 10 to 19 years and 20 or more years were 1.8 (95% CI, 1.1-3.0) and
3.2 (95% CI, 1.7-5.7), respectively (P value for
trend <.001), and we observed a 7% (95% CI, 2%-13%) increase in RR per
year of use. We observed significantly elevated RRs with increasing duration
of estrogen-only use across all strata of other ovarian cancer risk factors,
including women with hysterectomy. The RR for estrogen-progestin use after
prior estrogen-only use was 1.5 (95% CI, 0.91-2.4), but the RR for estrogen-progestin–only
use was 1.1 (95% CI, 0.64-1.7). The RRs for less than 2 years and 2 or more
years of estrogen-progestin–only use were 1.6 (95% CI, 0.78-3.3) and
0.80 (95% CI, 0.35-1.8), respectively, and there was no evidence of a duration
response (P value for trend = .30).
Conclusion Women who used estrogen-only replacement therapy, particularly for 10
or more years, were at significantly increased risk of ovarian cancer in this
study. Women who used short-term estrogen-progestin–only replacement
therapy were not at increased risk, but risk associated with short-term and
longer-term estrogen-progestin replacement therapy warrants further investigation.
INTRODUCTION
Despite case-control studies,1 pooled
analyses,2-3 and meta-analyses,4-5 the potential association between menopausal
hormone replacement therapy (HRT) and ovarian cancer remains unresolved. Most
retrospective studies found no association, and the studies that showed increased
risks predominantly included weak, nonsignificant associations and an absence
of dose response.6 Small size7
and incomplete information about other ovarian cancer risk factors8 limited the few available prospective studies of incident
ovarian cancer. A large, prospective study recently reported a significant
2-fold increased risk of ovarian cancer mortality among long-term users of
estrogen replacement therapy (ERT), but did not include exposure information
after 1982.9 Although use of combined estrogen-progestin
replacement therapy (EPRT) has increased recently,10
epidemiological data on EPRT and ovarian cancer are limited8, 11-12;
most studies have assessed HRT use without distinguishing between ERT and
EPRT. To explore the potential association between ERT and EPRT and ovarian
cancer, we analyzed data from the Breast Cancer Detection Demonstration Project
(BCDDP) follow-up study, a large prospective cohort. Multiple data collections
between 1979 and 1998 included specific information on ERT and EPRT.
METHODS
Study participants were selected from the BCDDP, a mammography screening
program conducted at 29 US screening centers between 1973 and 1980 by the
American Cancer Society and the National Cancer Institute.13
In 1979, the National Cancer Institute initiated a follow-up study of 64 182
of the original 283 222 participants: (1) all 4275 women diagnosed as
having breast cancer during the BCDDP; (2) all 25 114 women who underwent
breast surgery during the BCDDP, but had no evidence of malignant disease;
(3) all 9628 women who were recommended by the BCDDP for surgical consultation,
but for whom neither biopsy nor aspiration was performed; and (4) 25 165
women sampled from participants who had neither surgery nor recommendation
for surgical consultation during screening.14
An institutional review board at the National Cancer Institute approved the
study. All participants provided informed consent.
The BCDDP follow-up study consisted of 4 phases. Phase 1 (1979-1986)
involved a baseline telephone interview (completed by 61 431 women, or
96%) and up to 6 (usually 4) annual telephone follow-up interviews through
1986. Phases 2, 3, and 4 each used single, self-administered, mailed questionnaires
between 1987 and 1989, 1993 and 1995, and 1995 and 1998, respectively. Respondents
who were not known to be deceased at the end of the previous phase were sent
each subsequent questionnaire. Nonrespondents to mailed questionnaires were
interviewed by telephone, if possible.
Phase 1 interviews collected information on age at first use and duration
of use of female hormones (excluding creams), but did not distinguish ERT
from EPRT. The phase 2 questionnaire included use of menopausal hormones in
the form of injections, creams, patches, or pills since the last interview.
For pill use, this questionnaire queried menopausal ERT and EPRT, duration
of ERT and EPRT, and number of days in the month progestins were used. Phases
3 and 4 updated these data for pill users and collected pill names and doses.
Each phase included questions about current menopausal status, gynecologic
surgeries (including hysterectomy, partial or complete unilateral or bilateral
oophorectomy, and dates for each reported surgery) and other risk factors.
Interviews during the screening phase (1973-1980) collected demographic data
(eg, education level and ethnicity) and measured height and weight, which
were updated during phase 2.
Analytic Data Set
We excluded 12 581 women who reported a bilateral oophorectomy,
4 women who died, 30 women diagnosed as having ovarian cancer, and 4086 women
diagnosed as having breast cancer before the start of follow-up. We limited
analysis to the remaining women who were menopausal before the start of follow-up
or who became menopausal during follow-up. We defined menopause as no menstrual
period for at least 3 months or as a result of hysterectomy with at least
1 ovary retained. Women who stopped menstruating because of hysterectomy,
but who retained at least 1 ovary or whose ovarian status was uncertain were
considered to have reached menopause at age 57 years (the 75th percentile
for age at menopause in the study population) or their age at hysterectomy,
whichever was later. They maintained an unknown value for analysis of age
at menopause. We excluded 483 women whose menopausal status remained unknown
throughout the follow-up study. Analysis therefore included 44 247 participants
who completed a phase 1 interview. The numbers who subsequently completed
phase 2, 3, and 4 questionnaires were 37 657 (85%), 32 891 (74%),
and 31 354 (71%), respectively. Death (998; 2%), refusal (1609; 4%),
and illness or inability to contact before the end of the questionnaire period
(3977; 9%) accounted for missing phase 2 questionnaires. Respective numbers
and proportions for missing phase 3 and phase 4 questionnaires were 3572 (8%),
1263 (3%), and 6515 (15%); and 5462 (12%), 1974 (4%), and 5451 (12%).
Case Ascertainment
Lifetime history of ovarian cancer was first ascertained in phase 2.
Phases 3 and 4 ascertained ovarian cancer diagnoses since the previous interview.
We verified reported ovarian cancer diagnoses through medical record review.
Trained personnel completed standardized abstract forms when records were
retrieved, and 2 of the authors (J.V.L. Jr and M.E.S.) reviewed those original
records for this analysis. We linked the cohort to state cancer registries
to identify additional cancer diagnoses and to the National Death Index to
identify deaths during follow-up (with death certificate retrieval for study
deaths). A total of 44 139 women (72% of the 61 431 women who completed
a baseline interview; 85% of the women who completed a phase 2 questionnaire)
were linked against state cancer registries.
The final analytic cohort included 329 women who developed ovarian cancer
identified from medical records (n = 118), registry data (n = 79), death certificates
(n = 114), and self-report (n = 18). Medical records were not available for
those 18 because they were not received by the end of the study period, nonresponse
of physicians or hospitals, or participants did not grant permission for record
retrieval. We further classified tumors according to histological data from
records or cancer registries: 65 serous, 40 endometrioid, 13 mucinous, 8 clear
cell, 71 other unclassified, and 132 unavailable (for cancers identified via
death certificates or because medical records were not available). Fifty-seven
additional women reported ovarian cancer, but medical record review revealed
another primary tumor (n = 43), metastatic tumors (n = 2), benign lesions
or tumors of low malignant potential (n = 6), or nonepithelial cancer (n =
6). We excluded the 6 women who developed nonepithelial cancer during follow-up.
We defined diagnosis date hierarchically from medical records, state cancer
registry data, or self-report. When only death certificate information was
available, we used time since cancer onset to estimate diagnosis date or used
the date of death.
Analysis
Follow-up began at the baseline interview date or menopause date, whichever
was later. Person-years accrued until the earliest of the following dates:
ovarian cancer diagnosis, bilateral (or second) oophorectomy, death from any
cause, phase 4 questionnaire completion, or end of study date. For women without
a phase 4 questionnaire, but with whom we had some contact (eg, telephone
or notice of refusal) during phase 4, the end of study date was that contact
date. We assumed all other women without a phase 4 questionnaire whom we could
not contact and whom our National Death Index search did not identify as deceased
were still alive. We assigned their study end date by calculating the mean
intervals between questionnaire completion dates for phases 2 through 4 (for
all women who completed those questionnaires) and adding those mean intervals
to the date of last completed questionnaire for these nonrespondents. To avoid
biased end point ascertainment among these participants, deaths from National
Death Index and cancer diagnoses from state cancer registries were included
only if they occurred before the study end date.
Poisson regression modeled the rate of developing ovarian cancer during
follow-up and generated rate ratios (RRs) with 95% confidence intervals (CIs)
for categorized variables using standard likelihood ratio methods.15 Likelihood-based methods produced CIs for the linear
excess RR model.16 We assessed statistical
significance of trends via score tests.
We based the time-dependent HRT variables on the reported ages at which
exposure occurred. To calculate person-years for each woman, we updated time-dependent
HRT and age covariates at 1-year intervals, but we used 5-year intervals for
attained age in Poisson models. Women who had more than 1 exposure type during
follow-up could contribute person-time to multiple exposure categories during
follow-up. When exposure status or duration became unknown, subsequent person-years
were assigned to the "unknown" category. Use of HRT was calculated to 1 year
prior to attained (or current) age to eliminate exposure that was most likely
not causal. Because information on progestin use was not collected until the
phase 2 questionnaire, progestin use was unknown for the 6586 participants
who did not answer this interview (and for other participants who could not
recall whether they had used progestin replacement therapy). For these women,
exposed person-time and cancers among ERT users were included in the category
ever use of ERT with unknown use of progestins if the woman reported a natural
menopause; otherwise, they were included in the ERT-only category because
women with a surgical menopause are less likely to use progestins.
We calculated body mass index (BMI) in kilograms per meters squared
from measurements obtained during the screening visit closest in time to the
baseline follow-up interview. To assess potential confounding by BMI, parity,
and other suspected risk factors, we assessed associations between exposure
and ovarian cancer and then evaluated parameter estimate changes in models
before and after stratification by (ie, adjustment for) confounding variables.
Fully adjusted models included stratification on age, menopause type (natural,
surgical, or unknown), and duration of oral contraceptive use (none,  2
years, or >2 years).
RESULTS
The 44 241 women accrued 589 213 person-years of follow-up,
with a mean follow-up of 13.4 years (range, 1 month to 19.8 years). The mean
age at the start of follow-up was 56.6 years (range, 36-89 years).
Risk Factors
Ovarian cancer was inversely associated with parity, oral contraceptive
use, and hysterectomy, and not associated with age at menopause or BMI in
our data. Family history of ovarian cancer was not collected until the phase
4 questionnaire and was therefore unavailable for 29% of the cohort (data
not shown). One quarter of women who developed ovarian cancer reported breast
or ovarian cancer in first-degree relatives.
Women who were older, had a surgical menopause, or had a younger age
at menopause were more likely to use ERT. Women who had a natural menopause,
an older age at menopause, oral contraceptive use for longer durations, or
a lower BMI were more likely to use EPRT (Table 1). Person-years associated with HRT use did not differ by
parity.
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Table 1. Prevalence of HRT Use by Selected
Factors*
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ERT Use
Compared with no HRT use, ever use of ERT only was significantly associated
with ovarian cancer in models adjusted for attained age, menopause type, and
oral contraceptive use (RR, 1.6; 95% CI, 1.2-2.0; Table 2). Use of ERT only with unknown use of progestins (32 565
person-years and 40 ovarian cancers) was also significantly associated with
ovarian cancer (RR, 2.6; 95% CI, 1.8-3.7). The person-year weighted mean durations
of ERT use in these 2 categories were 6.2 and 4.4 years, respectively. The
RR for unknown HRT use (30 043 person-years and 14 ovarian cancers) was
1.1 (95% CI, 0.63-1.9).
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Table 2. Use of Hormone Replacement Therapy
(HRT) and Ovarian Cancer*
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The RRs increased with increasing duration of ERT-only use, and the
RR for 20 or more years of use was 3.2 (95% CI, 1.7-5.7; Table 3). The RR increased by 0.07 (95% CI, 0.02-0.13) for each
additional year of use. Risk estimates in Table 3 reflect ERT-only use, but models that included duration
of ERT use with unknown use of progestins generated similar associations (RR,
3.4; 95% CI, 2.0-5.7 for  20 years of use; P =
.001 for trend).
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Table 3. Duration of ERT-Only Use*
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Duration of ERT Use and Hysterectomy Status
Most women who reported long-term ERT use reported a prior hysterectomy
(Table 4). Total person-years
for less than 10 years of ERT-only use were equally distributed according
to hysterectomy status, but almost all person-years and ovarian cancers for
10 or more years of ERT-only use were attributed to women with a hysterectomy.
Among women with a hysterectomy, the RR was 2.0 (95% CI, 0.96-4.3) for between
10 and 19 years of use and 3.4 (95% CI, 1.6-7.5) for 20 or more years of use
(P = .001 for trend). The RR increased 0.08 per year
of use (95% CI, 0.02-0.18). Among women without a hysterectomy, the RR was
1.4 (95% CI, 0.92-2.0) for ERT-only use for less than 4 years and 2.1 (95%
CI, 1.3-3.5) for between 4 and 9 years. As expected, long-term ERT-only use
was less frequent among women without a hysterectomy.
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Table 4. Duration of ERT-Only Use by Hysterectomy
Status at Baseline*
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Duration of ERT Use and Tumor Histology
The associations with ERT did not appear to be restricted to particular
histological subtypes of ovarian cancer.17
Ten or more years of ERT-only use was positively associated with serous tumors
(6 ovarian cancers among long-term users; RR, 2.2 [95% CI, 0.78-6.1]), endometrioid
tumors (7 ovarian cancers among long-term users; RR, 5.5 [95% CI, 1.9-16.2]),
tumors with unavailable histology (16 ovarian cancers among long-term users;
RR, 1.9 [95% CI, 0.98-3.5]), and other unclassified tumors (7 ovarian cancers
among long-term users; RR, 1.6 [95% CI, 0.63-4.3]). Only 2 ovarian cancers
with mucinous histology occurred in women who had ERT-only use.
Time Since Last ERT Use
Compared with never use, the RR for recent ERT-only use (ie, current
use or last use <2 years ago) was 2.0 (95% CI, 1.4-3.0). For last ERT-only
use, the RR was 0.64 (95% CI, 0.24-1.7) for between 2 and 4 years ago; 1.5
(95% CI, 0.88-2.5) for between 5 and 9 years ago; 1.1 (95% CI, 0.59-2.2) for
between 10 and 14 years ago, and 1.3 (95% CI, 0.82-2.1) for 15 or more years
ago. Similar associations emerged in analyses for current users vs all former
users. Because long-term use and recent use are often correlated, we assessed
duration in recent vs former users. The RR for between 10 and 19 years of
ERT-only use was 1.7 (95% CI, 0.78-3.5) among recent users and 1.8 (95% CI,
1.0-3.0) among former users. The RR for 20 or more years of use was 2.1 (95%
CI, 1.2-3.8) among recent users and 1.7 (95% CI, 0.90-3.4) among former users.
EPRT Use
We classified EPRT use on the basis of prior ERT use (Table 2). Compared with no HRT use, the RR for ERT-only use followed
by EPRT use was 1.5 (95% CI, 0.91-2.4). The RR for EPRT-only use was 1.1 (95%
CI, 0.64-1.7). The person-year weighted mean durations of EPRT use in these
2 categories were 3.6 years and 3.5 years, respectively.
The person-year weighted average duration of ERT-only use before EPRT
use was 5.7 years. Among women who used ERT only for less than 5 years (person-year
weighted average = 2.5 years) and then used EPRT, the RR associated with ever
use of EPRT was 1.5 (95% CI, 0.70-3.3). Among women with ERT-only use for
at least 5 years (person-year weighted average = 11.2 years), the RR associated
with ever use of EPRT was 1.9 (95% CI, 0.89-3.9).
The RR was 1.6 (95% CI, 0.78-3.3) for less than 2 years of EPRT-only
use and 0.80 (95% CI, 0.35-1.8) for 2 or more years of EPRT-only use (Table 5). There was no evidence of a duration
response (P = .30). The mean person-year–weighted
duration was 5.6 years for EPRT-only use for 2 or more years. Three ovarian
cancers occurred among women with EPRT-only use for 4 or more years (RR, 0.64
[95% CI, 0.20-2.0]).
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Table 5. Duration of EPRT-Only Use and Ovarian
Cancer*
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We observed no association with duration of EPRT use when we combined
women with EPRT-only use and women with EPRT use after less than 5 years of
ERT-only use. For EPRT use, the RR was 1.3 (95% CI, 0.65-2.5) for less than
2 years, 1.3 (95% CI, 0.51-3.1) for between 2 and 3 years, and 1.0 (95% CI,
0.51-2.4) for 4 or more years.
Almost all women with EPRT use, regardless of prior ERT use, had a natural
menopause. Among women with a natural menopause, the RR for ERT-only use for
less than 5 years followed by EPRT use was 1.4 (95% CI, 0.55-3.4). The RR
for ERT-only use for at least 5 years followed by EPRT use was 2.0 (95% CI,
0.81-5.0).
Too few women recalled the number of days each month they used progestins
to compare sequential vs continuous combined EPRT regimens (data not shown).
The RR for recent EPRT-only use was 0.62 (95% CI, 0.27-1.4) and 2.8 (95% CI,
1.4-5.7) for former EPRT-only use. Too few women used EPRT to assess associations
by duration and time since last use.
Other Results
Excluding women who reported any use of menopausal hormone injections,
patches, or creams (n = 5830; including 34 women who developed ovarian cancer)
did not affect the associations with ERT-only use (RR, 2.6 [95% CI, 1.3-5.2]
for 20 years of use; an increase in RR of 0.06 [95% CI, 0.02-0.13] per
year of use) or EPRT-only use (RR, 0.81 [95% CI, 0.33-2.0] for 4 years
of use).
Almost all HRT users who provided pill names and doses, which were queried
only after 1992, reported use of conjugated equine estrogens at 0.625 mg or
medroxyprogesterone acetate at doses of 2.5 mg, 5.0 mg, or 10.0 mg. Missing
or unknown pill names and doses for approximately two thirds of HRT users
precluded further analyses of specific preparations or doses.
The RRs for HRT were similar after further stratification by parity
or BMI. Similar associations for duration of ERT emerged after excluding women
whose age at menopause was unknown or assigned to 57 years, women whose menopause
type was unknown, women whose ovarian cancer was based on self-report only,
or women whose cancers were identified via death certificates only. We found
identical results after restricting the analyses based on method of case ascertainment
(medical records, registry data, death certificates, and self-report) and
after considering only HRT exposures that occurred 2 or more years before
attained age. Including the participants diagnosed as having breast cancer
before follow-up did not change the results.
COMMENT
We observed significant associations between ERT use and incident ovarian
cancer in this prospective study of 44 241 postmenopausal US women who
provided multiple exposure assessments over approximately 20 years. In time-dependent
analyses that adjusted for other ovarian cancer risk factors and included
relatively large numbers of long-term ERT users, risk increased significantly
and consistently with increasing duration of use.
Cohort7 and case-control2, 12, 17-26
studies have reported positive associations with ERT use, although numerous
inverse27-30
and null1, 8, 31-34
associations have been published. One meta-analysis of 15 studies concluded
ERT does not increase risk,5 but another meta-analysis
of 9 studies reported statistically significant summary odds ratios (ORs)
for ever use of ERT (OR, 1.15; 95% CI, 1.05-1.27) and more than 10 years of
ERT use (OR, 1.27; 95% CI, 1.00-1.61).4 A recent
prospective study of 944 fatal ovarian cancers among 211 581 postmenopausal
women who reported ERT exposure through 1982 and were followed-up for 14 years
identified 2-fold increased risks associated with 10 or more years of ERT
use.9 That study, which excluded women who
reported a hysterectomy before baseline, and another recent report,12 concluded that long-term ERT use increased ovarian
cancer risk for women without hysterectomy. Our results showed an increased
risk among ERT users without hysterectomy, but also revealed increased risks
for long-term ERT use in women who had received a hysterectomy.
Use of EPRT only was not associated with ovarian cancer in our data,
but our results were based on only 18 women with EPRT-only use who developed
ovarian cancer. Although our analysis captured HRT use through 1998, few women
developed ovarian cancer after EPRT-only use for more than 4 years. Whether
longer durations of EPRT use are associated with ovarian cancer remains unclear.
Women with ERT-only use had nearly identical increases in risk and similar
average durations of ERT use compared with women with EPRT use after prior
ERT-only use. If ERT-only use increases ovarian cancer risk and that risk
remains elevated for many years,9 then the
prior ERT-only use could account for the increased risk among women with EPRT
use after using ERT. Additional studies will need to clarify subsequent cancer
risk among women who used more than 1 type of HRT.
Two case-control studies reported that risk associated with ERT exceeded
risk associated with EPRT, and a record linkage study from Sweden observed
no association between ovarian cancer incidence and EPRT.8
Our results resemble the OR of 1.06 (95% CI, 1.01-1.10) for each year of ERT
use and 1.02 (95% CI, 0.91-1.13) for each year of EPRT use from 1 US study
of 327 nonmucinous cases and 564 controls.17
A Swedish study of 655 cases and 3899 controls reported an elevated OR of
1.4 (95% CI, 1.0-2.0) for ever use of ERT, 1.5 (95% CI, 1.2-2.1) for EPRT
with sequential progestins, and an OR of 1.0 (95% CI, 0.73-1.4) for EPRT with
continuous progestins.12 Whether the progestin
regimen explains the lack of increased risk among women with EPRT-only use
or influences the increased risk among women who used EPRT after ERT-only
use in our study is not clear. More data are required to elucidate the specific
contributions to ovarian cancer risk of ERT duration, EPRT duration, and EPRT
regimen.
In our study, adjustment for hysterectomy and oral contraceptive use
had minimal effect on ever-use risk estimates, but consistently increased
duration risk estimates. Incomplete control for hysterectomy, oral contraceptive
use, and other risk factors may account for null or inverse associations in
other studies. One meta-analysis5 reported
a summary OR for ever use of ERT of 1.1 (95% CI, 0.9-1.3) from 15 heterogeneous
studies and a significant OR of 1.3 (95% CI, 1.0-1.6) from 4 similarly designed
US studies,17, 24-26
which used population-based controls and adjusted for hysterectomy and other
risk factors. A pooled analysis3 showed no
association with ever use (pooled OR, 1.0; 95% CI, 0.9-1.2) in 5 studies,1, 27, 30, 35 which
were unadjusted for hysterectomy, but a significant positive association (pooled
OR, 1.3; 95% CI 1.1-1.5) in 4 studies2, 17, 22, 36
that included adjustment. Those 4 studies also reported positive, but not
significant, associations with increasing ERT duration. Similar reanalysis2 of 4 European studies19-21,23
generated a statistically significant OR for ever use; control for confounders
increased the OR in that reanalysis.
Declining ERT use in the late 1970s3
reduced the number of potential long-term users and may have prevented earlier
studies from detecting an association with ovarian cancer, which develops
over many years. A pooled analysis of 6 case-control studies that used population
controls reported elevated, but nonsignificant ORs for 10 or more years of
ERT use based on 35 exposed cases and 66 exposed controls.1
Three other case-control studies included small numbers of long-term ERT users.17, 30-31 Compared with results
published after 7 years,36 follow-up for 14
years doubled the number of ovarian cancer deaths and produced stronger associations
with ERT in the prospective mortality study.9
We also observed stronger associations with long-term ERT use after almost
20 years of follow-up than in analyses censored in 1986 (phase 1), 1989 (phase
2), or 1995 (phase 3; data not shown). Although earlier studies seemed to
indicate that there was no association with ERT, this recent emergence of
an increased risk in long-term users should remind investigators that it is
premature to conclude that EPRT has no association with ovarian cancer until
other large studies specifically assess ovarian cancer risk among persons
with short-term or long-term EPRT use.
In addition to the inconsistent epidemiological data, lack of functional
steroid receptors and demonstrable estrogen effects in vitro37
raised questions about biologic plausibility of an association with ERT. Recent
data, however, provide biologic support for a relationship. In a rabbit model,
estrogen induced ovarian cancer cell-line growth38
and directly stimulated the ovarian surface epithelium—the suspected
pathological origin of most epithelial ovarian carcinomas.39-40
Normal ovarian surface epithelial cells also proliferated when stimulated
by estrogen.41 Epithelial ovarian cancer cell
lines expressed estrogen receptors,42 and recent
work demonstrated estrogen-receptor  , estrogen-receptor  , and
androgen-receptor expression in both normal and malignant ovarian epithelial
cells.43 Confirmation that progestins account
for the reduced risk associated with oral contraceptive use and pregnancy37 could provide a biologic basis for weak or null associations
with HRT formulations that include progestins.
Several analytic issues warrant mention. Adjustment for family history
of breast cancer did not change our results, but we lacked data to fully address
potential confounding by family history of ovarian cancer because information
on this variable was collected only in the phase 4 questionnaire. Among women
who completed that questionnaire, however, HRT associations did not change
after adjustment for family history of ovarian cancer. Use of ERT that leads
to adverse effects and hysterectomy could theoretically introduce a detection
bias for ovarian cancers detected at hysterectomy. However, only 4 of the
23 women who developed ovarian cancer and reported a hysterectomy during follow-up
had used ERT. Inaccurate reporting of hysterectomy could compromise the ability
to adjust for confounding, but a subset of BCDDP participants reported gynecologic
surgery with reasonable accuracy in a previous study.44
Inclusion of women with unknown age at menopause can bias analyses of breast
cancer and HRT.45-46 However,
age at menopause was not associated with ovarian cancer in our data, and our
results were identical after excluding participants whose age at menopause
was unknown or assigned to 57 years.
The HRT preparations used today differ from the HRT used during this
study's early years, but our repeated exposure assessment through 1998 ensured
current and generalizable data on HRT. Much of the long-term ERT use likely
included higher average daily doses of estrogen than what is currently recommended.47 Our analysis could not determine whether duration,
dose, or duration and dose explained the elevated risks among long-term ERT
users. Whether long-term use of lower-dose ERT increases the risk of ovarian
cancer is not known.
In this large prospective study, women who used ERT, particularly for
10 or more years, were at significantly increased risk of ovarian cancer.
We observed an elevated risk of ovarian cancer among long-term ERT users with
hysterectomy and among ERT users without hysterectomy who had switched to
EPRT. Women with short-term EPRT-only use were not at increased risk in this
study, but risk associated with EPRT remains unclear. Use of ERT and EPRT
differentially affects both breast14 and endometrial48 cancer risk and may do the same for ovarian cancer.
Additional data on long-term ERT and EPRT use, with particular attention to
duration, dose, and regimen, will be necessary to confirm these observations.
AUTHOR INFORMATION
Author Contributions: Study
concept and design: Lacey, Mink, Troisi, Hartge, Schatzkin, Schairer.
Acquisition of data: Lacey, Sherman, Troisi,
Schatzkin, Schairer.
Analysis and interpretation of data: Lacey,
Mink, Lubin, Sherman, Troisi, Hartge, Schatzkin, Schairer.
Drafting of the manuscript: Lacey, Mink, Hartge,
Schairer.
Critical revision of the manuscript for important
intellectual content: Lacey, Mink, Lubin, Sherman, Troisi, Hartge,
Schatzkin, Schairer.
Statistical expertise: Lacey, Lubin, Hartge,
Schairer.
Obtained funding: Schatzkin, Schairer.
Administrative, technical, or material support:
Schatzkin, Schairer.
Study supervision: Lacey, Schatzkin, Schairer.
Funding/Support: This research was funded by
National Cancer Institute intramural funds.
Acknowledgment: We thank the BCDDP participants;
Susan Englehart, MS, Catherine Ann Grundmayer, BA, and the members of the
BCDDP staff at Westat Inc, Rockville, Md; and Leslie Carroll, BA, Franklin
Demuth, BS, and Jennifer Boyd-Morin, BS, of IMS Inc, Silver Spring, Md, for
computer support.
We acknowledge the California Department of Health Services, Cancer
Surveillance Section; Florida Cancer Data System, under contract with the
Florida Department of Health; Maryland Cancer Registry, Maryland Department
of Health and Mental Hygiene; Michigan Cancer Surveillance Program within
the Division of Vital Records and Health Statistics, Michigan Department of
Community Health; Pennsylvania Department of Health; Tennessee Cancer Registry;
Texas Department of Health; and the states of Arizona, Georgia, Hawaii, Idaho,
Iowa, New Jersey, New York, North Carolina, Ohio, Oregon, and Rhode Island
for providing data from their cancer registries.
Disclaimer: The views expressed in this article
are solely those of the authors, and do not necessarily reflect the opinions
of any state agency listed above.
Previous Presentation: Portions of this article
were presented at the 92nd Annual Meeting of the American Association for
Cancer Research, New Orleans, La, March 24-28, 2001.
Corresponding Author and Reprints: James
V. Lacey, Jr, PhD, National Cancer Institute, Division of Cancer Epidemiology
and Genetics, 6120 Executive Blvd, MSC 7234, Rockville, MD 20852 (e-mail: jimlacey{at}nih.gov).
Author Affiliations: Division of Cancer Epidemiology
and Genetics, National Cancer Institute, Rockville, Md.
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