Merja B. Marttunen a, Paivi Hietanen b, Seppo Pyrhonen b, Aila Tiitinen a, Olavi Ylikorkalaa,*
a Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, PO Box 140, Helsinki, FIN-00029 HUS, Finlandю
b Department of Oncology, Helsinki University Central Hospital, Helsinki, FIN-00029 HUS, Finland.
* Corresponding author. Tel: +358-9-47172900; fax: +358-9-2412192. E-mail address: olavi.ylikorkala@huch.fi (O. Ylikorkala).
Abstract
Objective: Because a categorical refusal of estrogen replacement therapy (ERT) from postmenopausal patients with a history of breast cancer is not based on any research evidence and may be more harmful than beneficial, we evaluated the safety and efficacy of ERT in these women.
Methods: We recruited 131 patients who had been treated for breast cancer for a mean of 4.2 years (range 1 month to 20 years) before. Eighty-eight decided to use ERT, whereas 43 refused or had no need for ERT. At recruitment, the patients were carefully examined for breast and gynaecologic findings. Non-hysterectomized patients wishing to receive ERT (n = 54) then started using estradiol as oral tablets (2 mg/day) (n = 44) or as transdermal gel (1.5 mg/day) (n = 10) in combination with 10-day courses of oral medroxyprogesterone acetate at 4-week intervals, whereas hysterectomized patients (n = 34) used only estradiol, orally (2 mg/day) (n = 31) or transdermally (1.5 mg/day) (n = 3). The patients using ERT were carefully examined 6 and 12 months later, and then annually at a specific outpatient department, and the mean follow-up time is now 2.5 years (range from 1 month to 5.2 years, 216 woman-years). The 43 patients not wishing to receive ERT were followed annually at the oncologic department for a mean of 2.6 years (range from 1 month to 4.7 years), and served as a control group.
Results: ERT significantly reduced climacteric symptoms, and the Kupperman score fell by 63%, from 26.9 + 8.6 to 9.9 + 6.7 (mean ± SD). In non-hysterectomized women, medroxyprogesterone acetate triggered withdrawal bleeding in all except seven women. Seven patients (13%) experienced spotting during ERT. In 27 women, endometrial thickness exceeded 10 mm, and two of the total of 54 patients (3.7%) had simple hyperplasia. This vanished spontaneously in 3-6 months. Ten patients terminated the use of ERT within the first 12 to 39 months due to the lack of severe vasomotor symptoms (n = 4) or due to the recurrence of breast cancer or to cancer of the contralateral breast (n = 6). Eighty-one of the 88 patients (92%) using ERT showed no evidence of recurrence, whereas five patients (5.7%) had recurrence in 12-36 months and two patients (2.3%) developed a cancer of the contralateral breast in 14-24 months; another one of those wanted to continue with ERT. Thus the combined risk of recurrence or a new cancer of the contralateral breast in ERT users was 7/216 woman-years (3% per year). In the control group, 38 of 43 patients (88.4%) showed no evidence of recurrence or contralateral cancer, whereas four patients had recurrence and one developed a contralateral breast cancer (5/112 woman-years, 4% per year). Conclusions: Symptomatic climacteric patients with a history of breast cancer benefited from ERT without increasing their risk of recurrence, but the short follow-up and the small number of patients limit any definitive recommendations. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Estrogen replacement therapy; Breast cancer; Contralateral.
1. Introduction
At present, approximately 80-90% of breast cancer patients survive for at least 5 years [1 -3]. Due to earlier diagnosis of breast cancer by effective screening programs, and also to improved treatments, the number of women surviving breast cancer will drastically increase [4,5]. Thus, an increasing number of patients with a history of breast cancer will enter the menopause, which may even start earlier in these patients due to adjuvant chemotherapy [6,7]. In vitro [8] and epidemiological evidence [9] linking estrogens to the development of breast cancer has led to rather uniform denial of, or at least strong reservations about, the use of estrogen replacement therapy (ERT) in these patients, because of the fear that ERT could increase the risk of cancer recurrence or cancer in the contralateral breast [10-12]. This policy can be a double-edged sword, because it also denies these patients all the immediate and long-term health benefits of ERT [13,14]. Therefore, the wisdom of the categoric denial of ERT to breast cancer patients has been seriously questioned [15 -17] and, indeed, some retrospective surveys on breast cancer patients using ERT may lend support for this criticism [18-25]. We felt it imperative to study the issue of ERT in breast cancer patients in a carefully controlled prospective research setting.
2. Patients and methods
We started this project, with the permission of the local ethics committee, in 1993, when a specific outpatient department for breast cancer patients was opened at our university hospital, serving a female population of approximately 0.8 million. We encouraged oncologists, surgeons, general practitioners and gynaecologists seeing patients with a history of breast cancer who complained of incapacitating climacteric symptoms to admit them freely to our clinic. One gynaecologist (M.M.) interviewed these patients, whose breasts were then carefully examined (mammography, tumour markers such as Ca 15-3) to exclude any recurrence or a cancer in the contralateral breast. Their postmenopausal status was confirmed by serum follicle stimulating hormone (FSH) exceeding 30 IU/l. In addition, because of increased risk of endometrial cancer in these patients [26], each patient underwent a careful pelvic examination, including vaginal sonography (endometrial thickness, and uterine and ovarian morphology). An endometrial biopsy was taken if endometrial thickness (a double layer) exceeded 5 mm at entry or 10 mm on a follow-up visit, or if there had been abnormal uterine bleeding before recruitment or such bleeding appeared during the trial. A Pap smear test was taken. The patients were also carefully interviewed to determine risk factors of cardiovascular diseases (i.e. ischemic heart disease at < 55 years of age in a first-degree relative) or osteoporosis (i.e. family history of osteoporotic fractures; systemic use of corticosteroids). The benefits and risks of ERT in postmenopausal women were explained thoroughly, both orally and in written form, and all patients gave written informed consent.
After the first visit, the patients started recording climacteric symptoms on Kupperman’s scale, and they were seen again 2- 3 weeks later. At this visit, the patients who were judged to have invalidating climacteric symptoms (Kupperman score ≥ 10) (n = 95), and/or had a family tendency to cardiovascular disease (n = 10) or risk factors of osteoporosis (n = 12), were offered ERT, whereas patients having only mild symptoms (Kupperman score < 10) or having no risk factors were advised not to start ERT. ERT consisted of either 2 mg of estradiol valerate daily (Progynova®, Schering, Berlin, Germany), or 1.5 mg of estradiol daily as a transdermal gel (Estrogel®, Leiras, Turku, Finland); the selection between oral and transdermal routes was primarily made by the patient herself. For non-hysterectomized patients, ERT was combined with 10-day courses of 10 mg/day medroxyprogesterone acetate (Provera®, Pharmacia & Upjohn, Kalamazoo, Michigan) at 4-week intervals. Patients starting ERT were seen 6 and 12 months later, and then annually, and the baseline breast and gynaecological examinations were repeated. In addition, the patients were encouraged to contact the research centre whenever they so wished. The patients who decided not to start ERT were seen annually at the oncological department only.
All data are expressed as the mean ± SD. Paired and unpaired Student’s t-test and the chisquare test were used for statistical analysis.
2. Patients and methods
From August 1, 1993 to the end of 1998, 131 breast cancer patients had been admitted to the clinic. They had been operated upon for ductal carcinoma (ca) in situ (n = 4), stage I (n = 87), stage II (n = 37), or stage III (n = 3) breast cancer a mean of 4.2 years (range 1 month to 20 years) before. Sixty-two patients (47%) had experienced mastectomy, 100 patients (76%) had received postoperative radiotherapy and 19 patients (14%), adjuvant chemotherapy (Table 1). Five patients had used antiestrogens before the initiation of the trial, but none used them during the trial.
Of the 131 breast cancer patients, 88 patients (67.2%) finally started ERT (Table 1). The main reason for starting ERT was severe climacteric symptoms (in 85 women); only two patients started ERT primarily for cardiovascular prevention and one for fear of osteoporosis. Twenty- three patients were judged not to be candidates for ERT, six (4.5%) because they were not menopausal (FSH < 30 IU/L), and 17 (13.0%) who had only modest climacteric symptoms (Kupperman score < 10) and no family tendency to cardiovascular diseases or osteoporosis. In addition, 20 patients (15.3%) who were judged to be candidates for ERT refused it for fear of relapse. Thus, 43 patients came to serve as controls. The patient groups with and without ERT were comparable (e.g. in regard to the estrogen receptor status) except for the fact that the women starting ERT were slightly more often node negative (81.8%) than the controls (69.8%) (Table 1). The proliferative activity of tumour cells had been measured by flow cytometry in 40 patients (25 ERT users and 15 controls), and the nuclear protein Ki67 had been determined in 38 patients (22 ERT users and 16 controls); there were no differences in these prognostic factors between the groups.
Table 1. Clinical characteristics (mean ± SD or %) (range) of postmenopausal women with a history of breast cancer (n = 131) who either started estrogen replacement therapy (ERT) (n = 88) or who were followed without it (n = 43)
Seventy-five patients (44 non-hysterectomized, 31 hysterectomized) elected to use oral ERT, whereas 13 patients (ten non-hysterectomized, three hysterectomized) preferred transdermal ERT. All patients offered ERT alone or in combination with medroxyprogesterone acetate could use it as instructed. ERT reduced the Kupperman score significantly; in this regard the oral and transdermal regimens were equally effective (Fig. 1). The Kupperman score was reduced by 63% at the first 6-month follow-up visit and no further improvement was seen in this score at later visits. Five patients increased the dose of oral estradiol to 3 mg between 6 and 12 months to control symptoms, and three women reduced the dose of estradiol to 1 mg between 1 and 4 months because of breast tenderness. Three non-hysterectomized patients experienced PMS-like symptoms (depression, fatigue, oedema) during the progestin phase, and in these women progestin was given for 14 days at 2-month intervals. Four patients decided to discontinue ERT within 1.4-3.3 years because of the lack of climacteric symptoms.
Figure 1. The Kupperman score before and during a one-year course estrogen replacement therapy. (a and b = p < 0.0001).
Of the 54 patients with an intact uterus, the endometrial thickness (double layer) was less than 5 mm at entry in all except one patient, who had a benign endometrial polyp; the polyp was removed through hysteroscopy before the start of ERT. Regular withdrawal bleeds after the progestin phase ensued in all women except for seven who did not bleed at all. During ERT, seven patients (13%) experienced spotting, four of them after 1 year’s use and three patients after 2 years’ use. In these cases, endometrial biopsies showed normal proliferation (n = 4) or secretion (n = 3). No hyperplasia was seen. Endometrial thickness exceeded 10 mm after 2 (n = 20) or 3 (n = 7) years use of ERT in 27 patients, and endometrial biopsy showed proliferative (n = 18) or secretory (n = 10) changes in all except for two patients (endometrial thickness 12 and 18 mm, respectively) whose endometrium showed simple hyperplasia. In these two women, repeat biopsies were collected 3 and 6 months later, and then the endometrium was proliferative. There were no abnormal findings in the ultrasound examinations of the ovaries during the study.
Before the initiation of ERT, 49 of the 54 non-hysterectomized women had normal Pap smears, atypical squamous cells of undetermined significance were detected in three women and benign reactive changes in two women. All these changes had vanished in the control Pap smear 3 to 6 months later. During the follow-up time, 13 patients had atypical squamous cells and two patients reactive changes; ten of these improved spontaneously. Colposcopy was performed in five women with repeated atypia, and no precancerous cervical lesions were detected.
So far, 36 women have used ERT for more than 3 years, 20 women for 2- 3 years, 20 women for 1-2 years, and 12 women for less than 1 year. The mean (± SD) duration of ERT is 2.5 ± 1.5 years (range 1 month to 5.2 years), which corresponds to 216 woman-years. In careful oncological examinations, 81 of the 88 patients (92%) have shown entirely normal findings and no signs of relapse. Seven women (7.9%) (four with estrogen receptor positive cancer) have experienced either recurrence (n = 5) or a new cancer of the contralateral breast (n = 2); two patients have died of breast cancer (Table 2). The incidence of recurrence or new cancer per woman-year with ERT was 3%. Another of the patients with contralateral breast cancer wanted to continue ERT. Of 43 patients not using ERT, four had relapses and one had a contralateral breast cancer (three with estrogen receptor positive cancer) in 10-14 months’ time. Thus the recurrence rate was 4% per follow-up year. Three of the controls have died of the breast cancer.
Table 2. Clinical data on patients who had relapses or a new cancer in the contralateral breast during the ERT or follow-up (f-u)
4. Discussion
It can be calculated from the Finnish Cancer Registry databases that approximately 11 000 postmenopausal women with a history of breast cancer were living in the area served by our outpatient department in the period 1993 -1998 (Finnish Cancer Register), yet only 131 of them (1%) were admitted to our department. The low rate can be explained by several factors and insufficient spread of information on our policy could be one explanation. However, we feel that the most important cause of refusal to register at our clinic is the severe fear of ERT among these patients. Further, it is likely that such reservations about the use of ERT concern not only patients, but also their physicians. Nevertheless we managed to recruit a representative number of patients, but out of the 131 patients registered only 108 (82.4%) turned out to have solid indications for using ERT. Even of this population, 20 (18.5%) refused to start using ERT, which left 88 patients to start ERT. We studied our patients carefully at recruitment to ensure that none of them had any recurrence before being included in our study. In addition, the patients starting ERT were also thoroughly examined during the ERT to detect any recurrence as soon as possible. Because a history of breast cancer denotes an increased risk of endometrial cancer [26], we also carefully monitored endometrial health. ERT was given either orally or transdermally, at doses commonly used in otherwise healthy women, and, as expected, all climacteric symptoms were alleviated and their quality of life improved. As regards protection against cardiovascular diseases and osteoporosis by ERT, we acknowledge that the follow-up time was far too short and the number of patients too limited to provide any reliable data; however, it was conspicuous that none of these postmenopausal patients using ERT developed ischemic heart disease or became hypertensive during the trial.
Large prospective, preferably placebo-controlled trials would be necessary to assess the final safety of ERT in healthy women, not to mention patients with a history of breast cancer. In practice such a study would be difficult to perform, and perhaps even unethical, because one cannot offer a placebo for a symptomatic climacteric patient wishing to receive ERT. Moreover, due to the good present prognosis of breast cancer patients [1 -3], thousands of such patients would be needed if the end point of the trial were to be a recurrence of the cancer. Nevertheless, we feel that our trial, although limited in patient number and duration, is valuable. The strength of our study was increased because we carefully excluded any recurrence in our patients before and during ERT, which has not been the case in some previous surveys dealing with the same topic [18 - 25].
The overall risk of recurrence or contralateral breast cancer was similar in patients with ERT (3%) or without ERT (4%). Thus our data may indicate that ERT as given for 2-3 years did not increase the risk of recurrence, or a new cancer of the contralateral breast. Moreover, our data obtained in a prospective set-up are in harmony with the published recurrence rate (1 - 5%) of breast cancer in women using ERT (Table 3). We admit all the limitations, such as a lack of randomisation or potential differences between study group and controls in our study, but even smaller, nonrandomised series on this controversial topic are valuable.
Table 3. Previous, non-comparative data on the use of ERT following breast cancer as compared with the present data on patients using (ERT + ) or not using (ERT-) ERT
The role of progestin on the development of breast cancer is still unclear. The data from Sweden and United States have shown that adding progestin to estrogen replacement increases the risk of breast cancer by 14-40% in healthy women [27 -29], whereas a progestin addition does not affect the risk of cancer recurrence in women with a history of breast cancer who are using estrogen replacement [21,23,25]. Progestins are also of importance for endometrial protection, because breast cancer per se indicates an increased risk of endometrial cancer [26]. In our study, ERT did not lead to endometrial cancer, although our progestin regimen was not so rigorous as sometimes recommended [30]. However, a word of caution is needed. The duration of exposure to ERT may need to exceed 5 -10 years in healthy women before the risks of breast and endometrial cancer become evident [9], and therefore we will continue the follow-up of our patients.
Previous retrospective reports on ERT in breast cancer patients are based on study populations of 25 -90 patients who have used ERT for a mean of 1.5-2.5 years (Table 3). We treated our patients in a prospective setting. The recurrence rate during ERT was rather similar to that in previous surveys [18 - 24] (Table 3). This finding may suggest that previous retrospective data [18 - 24] is rather accurate. Yet we readily admit that a much larger number of patients with breast cancer using or not using ERT must be followed before ERT can be routinely prescribed to breast cancer patients. In addition, the need for ERT in these patients can be questionable, because selective estrogen receptor modulators, such as raloxifene, decrease the risk of breast cancer and provide several health benefits, but unfortunately increase vasomotor symptoms [31].
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