The management of oestrogen deficiency symptoms in women with breast cancer is becoming an important part of their care, since many experience iatrogenic symptoms induced by their breast cancer therapy. These can include the anti-oestrogenic effects of tamoxifen, chemotherapy-induced ovarian suppression and chemical castration with gonadotrophin-releasing hormone agonists. Cross-sectional studies have demonstrated that at any one time oestrogen deficiency symptoms are the most common adverse effect of adjuvant therapy, occurring in up to 66% of patients aged less than 65 years, and that such symptoms are more bothersome and persist for longer in postmenopausal breast cancer survivors than in healthy postmenopausal women. It is anticipated that the prevalence of treatment-induced oestrogen-deficiency symptoms and the induction of a premature menopause are likely to increase with the more widespread use of adjuvant therapy following the clear survival benefits shown in the most recent worldwide overviews of early breast cancer therapy. In addition to the development of hot flushes and night sweats, loss of sexual interest is a frequently reported symptom accompanying endocrine breast cancer therapy. Chemical castration with chemotherapy and GHRHa can produce vaginal dryness, which, along with decreased emotional well-being, is an important predictor of sexual health in breast cancer survivors. Although vaginal dryness and dyspareunia are less frequent in women taking tamoxifen, problems with sexual interest, arousal and orgasm are reported with its use.
Concern that Hormone replacement therapy may increase the risk of developing recurrent breast cancer has led to considerable interest in the use of alternative therapies for the control of oestrogen-deficiency-related health problems in breast cancer survivors. As treatment options for the prevention of the long-term sequelae of oestrogen deficiency are to be discussed in detail by other authors in this volume, only alternatives for symptom management will be discussed here.
Alternatives to Hormone replacement therapy for symptom control have either not been evaluated in controlled prospective studies at all (i.e. all complementary therapies), or have not been shown to have any more than a placebo effect (i.e. evening primrose oil, vitamin E, clonidine, soy phytooestrogens). There have been anecdotal reports that serotonin-uptake inhibitors reduce hot flushes in breast cancer patients by 50% but there are no controlled clinical data to support this.81 Low-dose, slow-release topical oestrogen preparations are effective in the alleviation of distressing vaginal symptoms. Since they do not appear to be associated with any significant absorption across the vaginal epithelium, they probably do not exert any oestrogenic effect on the breast, but this requires confirmation.
Low-dose progestins and the synthetic gonadomimetic agent, tibolone, which has weak oestrogen-like, progestogen-like, and androgen-like activity, are hormonal preparations that are being prescribed increasingly to breast cancer patients as safe alternatives to Hormone replacement therapy. However, there is a complete lack of any controlled data on their safety and efficacy in breast cancer survivors. Although low-dose progestins have been shown to provide effective symptom relief in the short term (i.e. for 3 months), uncontrolled follow-up of 18 of the original breast cancer patients participating in this study for 3 years found that nearly 40% were still symptomatic on treatment and that troublesome side-effects, which included vaginal bleeding and depressive mood, were common. Tibolone (2.5 mg) appears to be as efficacious as standard dosages of Hormone replacement therapy for the control of vasomotor symptoms but there are no data on its use in women with breast cancer. Despite the hypothesis that tibolone may protect against breast cancer recurrence, since it inhibits the conversion of oestrone sulphate to oestradiol in MCF-7 and T-47D breast cancer cell lines, its relative oestrogenic and androgenic activities are reported to increase with the higher dosages that are sometimes required for symptom control, particularly in prematurely menopausal women.
Given the lack of a causal relationship between Hormone replacement therapy and breast cancer risk and the known benefits of Hormone replacement therapy in relieving menopausal symptoms, Hormone replacement therapy has increasingly been prescribed to individual breast cancer patients. Published data from a small number of observational trials of Hormone replacement therapy in breast cancer survivors with both early and advanced stage disease have, to date, not demonstrated any increase in disease progression or death from breast cancer, suggesting that Hormone replacement therapy may not adversely affect prognosis, even in those women whose tumours were Oestrogen receptor-positive. Although the ideal frequency for mammographic follow-up of women with breast cancer is not established and current practice is variable, there is no evidence to support such follow-up being performed more often than annually if patients are taking Hormone replacement therapy.
In the absence of data from randomized trials, reliable statements about the safety of Hormone replacement therapy in this clinical context cannot be made. A pilot study undertaken to ascertain the feasibility of conducting a national randomized trial of Hormone replacement therapy in symptomatic women with early stage breast cancer demonstrated high accrual (40%) and compliance (>80%) rates despite detailed, informed consent.This pilot study demonstrated that oestrogen-deficiency symptoms had a significant negative impact on patients’ quality of life. Three of the 100 women recruited into this study have developed recurrent breast cancer to date. Two were taking Hormone replacement therapy; one was randomized to receive opposed Hormone replacement therapy 38 months after diagnosis and developed recurrence after taking Hormone replacement therapy for 2 years. The second patient received unopposed Hormone replacement therapy 9 years after diagnosis and developed recurrent disease after six weeks’ treatment.
Following the successful implementation of this pilot study and patient feedback, which revealed that the management of oestrogen-deficiency symptoms is considered by breast cancer patients to be an important aspect of their care, a large randomized trial of Hormone replacement therapy has now been planned in the United Kingdom, and two smaller randomized trials have been established in Sweden. The United Kingdom trial aims to recruit a total of 3000 symptomatic women with stage I or stage II breast cancer, who will be randomized to Hormone replacement therapy for two years. It is anticipated that, in addition to providing reliable data on the effects of Hormone replacement therapy use on disease-free and overall survival, the question of potential antagonism between Hormone replacement therapy and tamoxifen will be answered.
Table Hormone replacement therapy after breast cancer — observational studies.
|Stage of Type of||Median time||Median duration||Median follow-up New cancer|
|Hormone replacement therapy
|from diagnosis of use in months in months (range) (range)||in months (range)||/recurrence|
|Unknown||l-ll||0+ Pc||Not stated||3-6||s= 24 months||0||0|
|25||l-IV||Not stated||26(0-180)*||35.2(6-78)*||Not stated||3||12|
|77||l-IV||0 and 0+ Ps||24 (0-324)||27 (1-233)||59 (10-425)||7||9.1|
|35||l-IV||0 and 0+ Ps||31 (0-215)||14.6 (1-44)||43||2||5.7|
|90||l-ll||P, 0 + Ps, and 0+ Pc||60 (0-300)||18 (3-144)||84 (4-360)||7||7.8|
|43||l-ll||Not stated||84 (0-286)||31 (24-142)||144 (46-342)||1||2.3|
|67||Unknown||0||Not known||94 (1-154)||94 (1-454)||0||0|
|61||l-lll||0 and 0+ P||44.4 (0-232.8)*||26.4 (0.48-198)*||Not stated||6||9.8|
|189||l-lll||Not stated||59 (2-392)||41+ (1-76+)||Not stated||12||6.3|
|120||l-IV||0 and 0+ P||96 (18.24-266.4)||28.8+ (12-127.2)||Not stated||5||4.2|