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]
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.
Three previous studies relate particularly to these issues. One study, published in 1984, 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 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, 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. 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).
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.
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 (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 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. 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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