Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 2

Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 2

ABSTRACT: There are several million breast cancer survivors worldwide. In the United States, 180,000 women were diagnosed with breast cancer in 1997, and approximately 97,000 of these women have an extremely low chance of suffering a recurrence of their cancer. With an average age at diagnosis of 60 years and a 25-year expected duration of survival, the current number of breast cancer survivors in the United States may approach 2.5 million women. Since breast cancer is now being detected at an earlier stage than previously and since adjuvant chemotherapy may cause ovarian failure, an increasing number of women are becoming postmenopausal at a younger age after breast cancer treatment. This conference was convened in September 1997 to consider how menopausal breast cancer survivors should be treated at the present time and what future studies are needed to develop improved therapeutic strategies. A total of 59 breast cancer experts and patient advocates participated. The proceedings of the conference will be published in six installments in successive issues of oncology. The first part, published last month, defined the problem and explored its magnitude and ramifications for patient management. This second part focuses on the benefits and risks of hormone replacement therapy (HRT) in patients with breast cancer. [ONCOLOGY 13(2):245-267, 1999]


Impact of HRT at and Prior to Breast Cancer Diagnosis

Paul Goss, MD: A preliminary analysis of results regarding the
effect of receiving hormone replacement therapy (HRT) at and prior to
the diagnosis of breast cancer could be of significant interest to
clinicians, for several reasons:

  1. It may help determine the appropriate adjuvant therapy for breast
    cancer in this setting.

  2.  If HRT is an important prognostic factor, it should be
    stratified for in randomized clinical trials or included in
    multivariate analyses

  3.  It may be appropriate to reanalyze some of the larger published
    adjuvant therapy trials according to whether or not patients were
    receiving HRT.

Clinical Studies

Three previous studies relate particularly to these issues. One
study, published in 1984,[1] focused on 63 postmenopausal HRT users
and 165 nonusers who were diagnosed with breast cancer. In this
study, Gambrell found that HRT users were more likely than nonusers
to be diagnosed at an earlier stage of presentation and to have
negative axillary lymph nodes.

Harding and colleagues[2] reported on 108 postmenopausal HRT users
(in this study, HRT use was defined as use for more than 3 months
within the year prior to breast cancer diagnosis) vs 325 nonusers who
also developed breast cancers. The researchers found that tumors in
the HRT users were more likely to be well differentiated, or grade 1.
The two groups did not differ significantly with respect to tumor
size, steroid receptor status, or axillary nodal status.

The third study, by Bonnier and colleagues from France,[3] compared
HRT users vs nonusers and found fewer locally advanced cancers in the
user group. In addition, the HRT users had more well-differentiated
(infiltrating lobular and histologic grade 1) tumors. These
researchers also found a lower incidence of estrogen receptor (ER)
positive and progesterone receptor (PR) positive tumors in women
taking HRT. In the study by Bonnier et al, 84% of patients were
taking progesterone plus estrogen (ie, opposed estrogen), while 12%
were receiving estrogen alone (unopposed estrogen).

Toronto Hospital Analysis

My colleagues and I studied the clinical and pathologic presentation
of breast cancer in postmenopausal patients referred to a single
institution in Toronto.[4] Because we required a sample size of 941
patients to detect a common odds ratio of 1.5 for the main primary
end points of ER and PR status and overall nuclear grade of the
tumors, we surveyed over 1,700 women. We included postmenopausal
women who were amenorrheic for ³ 12
months or had undergone a bilateral oophorectomy and who had
histologically confirmed breast cancer or breast cancer in situ. We
identified three groups: HRT nonusers (ie, those who have never used
HRT), past HRT users, and current HRT users (ie, those who were HRT
users at the time of clinical detection of breast cancer).

From a sample of 985 eligible patients, we found 636 non-HRT users,
165 past users, and 184 current users. Among the current users, 40%
were taking estrogen plus progesterone (ie, opposed estrogen) and
53%, unopposed estrogen. The majority of the past HRT users had
received unopposed ERT, a few had received opposed estrogen, and a
large number could not recall the type of HRT that they had taken.

The duration of HRT use was significantly longer, on average, in
current users than in past users. Younger patients were more likely
to be HRT users, as were women who had undergone a hysterectomy or
had previously used oral contraceptives. Women with a family history
of breast cancer were less likely to be HRT users.

Breast cancer was diagnosed by mammography more frequently in HRT
users than in nonusers. Users were also more likely to be practicing
breast self-examination (BSE) than nonusers and also were more likely
to be undergoing regular mammographic surveillance.

Women who used HRT generally had their first mammogram at a younger
age, and more commonly underwent needle localization as a method of
diagnosis. Surprisingly, however, stage at presentation did not
differ between users and nonusers. There was a small difference
between past users and nonusers with respect to tumor size, but this
was probably clinically irrelevant. There was no difference between
users and nonusers with regard to the number of positive lymph nodes.

More HRT users than nonusers had grade 1 tumors, however. This was
true for both overall grade and nuclear grade. No difference was
found in ER and PR status between the user and nonuser groups.
However, there was a difference in ER positivity between women who
received unopposed vs opposed estrogen: Patients who took opposed
estrogen had fewer numbers of ER positive tumors than those who
received unopposed therapy. These findings are consistent with
progesterone’s ability to reduce ER levels.

Our analysis thus confirmed previous clinical findings of more grade
1 and well-differentiated tumors overall among HRT users than
nonusers but did not find the expected differences in ER and PR
status. We did, however, show reduced ER positivity in women
receiving opposed vs unopposed hormone replacement.


Melody Cobleigh, MD, asked whether the issue of tumor differentiation
was significant in multivariate or univariate analysis. Dr. Goss
replied that the results presented were from a univariate analysis
and that this analysis had not been completed.

Dr. Elizabeth Barrett-Connor asked how many patients in the study had
in situ carcinoma. Dr. Goss answered that there were only 46 women
with ductal carcinoma in situ (DCIS).

Trials of Estrogen in Breast Cancer Patients

Kathleen Pritchard, MD: Minimal data exist regarding the effects of
estrogen replacement therapy (ERT) in women who have been diagnosed
with breast cancer. The data used to counsel patients in this
situation are extrapolated largely from those available in healthy
women and, therefore, represent the etiologic risk associated with
ERT/HRT. Extrapolation of these data is based on the implicit
assumption that the increased risk of recurrence for a patient with a
diagnosis of breast cancer is proportionately similar to the
etiologic risk of developing breast cancer in a well woman taking
ERT/HRT. In fact, we do not know whether this assumption is correct.

Observational Data

Currently available data are observational and of several types.
First, some studies suggest that women who develop breast cancer
during or in close temporal proximity to pregnancy have a worse
prognosis. In contrast, Clark and Chua from the Princess Margaret
Hospital[5] (as well as other researchers) have published series
showing that women who became pregnant more than 1 year after a
diagnosis of breast cancer seemed to do as well as matched controls
who did not become pregnant. Undoubtedly, however, these series are
subject to a “selection bias,” in that women who became
pregnant after a diagnosis of breast cancer were self-selected for
good prognostic features.

Vassilopolou-Sellin and Zolinski[6] surveyed 224 randomly selected
women with a previous diagnosis of breast cancer, 77% of whom were
postmenopausal, about their attitudes concerning ERT/HRT. They found
that 8% of the women had taken ERT after their cancer diagnosis. The
majority (78%) were afraid that they would develop a recurrence if
they took ERT, but 70% were concerned about osteoporosis and heart
disease. Slightly less than half (44%) of the women said that they
would consider taking estrogen replacement under medical supervision.

Dr. Pamela Goodwin has developed a decision-tree model suggesting
that, in women with node-negative breast cancer who have substantial
menopausal symptoms, the decision to use ERT or HRT may be
reasonable. This model assigns a number of risk estimates,however,
some of which are quite uncertain.

In 1995, Dhodapkar et al described a small series of four patients
who developed metastatic breast cancer while taking ERT/HRT.[7] Three
of the women had been diagnosed between 8 and 15 years earlier and
had been taking HRT for a protracted period. The fourth patient
presented with metastatic disease while taking ERT.

All four women had a partial response of their cancer when the
estrogen was withdrawn. This somewhat paradoxical observation shows
that, even in women who have been tak-

ing estrogen for a prolonged period without breast cancer development
or recurrence, once the cancer recurs or progresses, it may shrink in
response to estrogen withdrawal.


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