A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer

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Abstract

Menopausal symptoms are a major survivorship issue for patients treated for breast cancer. There are increasing concerns over the use of hormone replacement therapy (HRT) in this setting and a growing consumer interest in “natural” therapies. It had been suggested that soy phyto-oestrogens might be beneficial in the treatment of menopausal symptoms. Seventy-two patients with a histologically confirmed pre-existing diagnosis of breast cancer who were having menopausal symptoms were randomised between 12 weeks of treatment with soy capsules or placebo. Quality of life and menopausal symptom scores were assessed at baseline, 4, 8 and 12 weeks. There was no statistical difference in menopausal symptom scores or quality of life between the two arms of the study.

Introduction

Menopausal symptoms are a major survivorship issue for patients previously treated for breast cancer – both as a result of adjuvant therapies and for those patients who naturally progress through the menopause [1]. The use of hormone replacement therapy (HRT) in this setting had been widespread, but increasing concerns over the safety of HRT both for women without a previous diagnosis of breast cancer [2] and breast cancer survivors [3] have led to a search for alternatives. The pathophysiology of hot flushes (or flashes) is poorly understood, but may be caused by dysfunction of central thermoregulatory centres in the hypothalamus triggered by changes in oestrogen levels [4]. It is postulated that increases in the level of oestrogen or serotonin may improve symptoms.

There has been considerable interest in the use of phyto-oestrogens, both in the lay and the medical press. Phyto-oestrogens are plant-derived substances which mimic or modulate the action of endogenous oestrogens usually by binding to oestrogen receptors. Soy is a rich source of phyto-oestrogens called isoflavones which have a chemical structure very similar to oestradiol.

Epidemiological data from Japan suggest that the incidence of hot flushes is inversely related to the dietary soy intake [5]. Observational studies have suggested that soy supplementation may result in an improvement in menopausal symptoms, particularly vasomotor symptoms such as flushing, in patients with no history of breast cancer [6]. A randomised double-blind trial of soy and wheat flour supplementation showed no difference between the two groups [7], but another trial showed that soy protein was superior to casein placebo [8].

It has been suggested that a diet rich in soy products may be a causative factor in the much lower incidence of breast cancer seen in Asian populations [9], [10], [11], but the epidemiological evidence is inconclusive.

Genistein (4′,5,7-trihydroxyflavone) is the most abundant isoflavone in soy products, with smaller quantities of daizein and glycitein also being found. Genistein primarily functions as an oestrogen agonist but also has some mixed agonist/antagonist properties [12]. Isoflavones inhibit aromatase (although the concentrations needed for this are quite high) and the enzymes that convert oestrone to the more potent oestradiol [13]. Genistein is known to be a protein tyrosine kinase inhibitor [14] and may inhibit angiogenesis.

In vitro, genistein inhibits the growth of a number of cancer cells lines, including hormone-dependent and hormone-independent breast cancer cell lines [12], [15], [16]. The interaction of genistein and tamoxifen is not entirely clear. In vitro data has shown both inhibition of the effects of tamoxifen and an apparent synergy [12]. However, two animal studies have suggested that the combination of tamoxifen and soy had an inhibitory effect on tumour growth [17], [18].

Overall, the evidence suggests that phyto-oestrogens are unlikely to be detrimental to women who are being treated for breast cancer, or have had breast cancer in the past.

We therefore designed a randomised trial of soy isoflavines for the treatment of menopausal symptoms in patients previously treated for breast cancer. Since this trial was initiated, two others have reported on a similar group of patients [19], [20] and one in patients without cancer [21]. However, the trial reported here differs from these studies in the methods of assessment, the soy product used, “Phytosoya” TM, that is widely available as an over-the-counter medication in Europe, and has a different duration of therapy.

Section snippets

Patient population

Participants in the trial were women over 18 years of age with a histologically confirmed pre-existing diagnosis of breast cancer who were having menopausal symptoms, defined as menopausal score of >1 (scoring system described in Fig. 1). Patients were excluded if they had advanced or metastatic disease, were already taking soy products, were currently taking other therapy for menopausal symptoms, had a severe concurrent non-malignant illness or were unable to give informed consent. Any

Results

A total of 72 participants were randomised between 1999 and 2002. A trial flow diagram is show in Fig. 2. The baseline patient characteristics are shown in Table 1, Table 2 illustrating the two study arms were well balanced other than for time since definitive surgery (P = 0.029). There was a trend towards duration of menopausal symptoms being longer in the Soy arm, but this was non-significant (P = 0.96). In particular, the baseline vasomotor symptom score was well balanced. Reasons for stopping

Discussion

This trial differs from previous reports in two or more of the three following aspects: the soy preparation used, the duration of therapy and the methods of assessment. The results of this randomised, double-blind controlled trial do not support the use of soy supplements for the treatment of menopausal symptoms in this population. There have been three other similar trials reported since the inception of our trial and the results of both of these are consistent with our findings. Quella et al.

Conflict of interest statement

None of the authors has any financial or personal relationships that could inappropriately influence or bias this work.

Active drug and placebo tablets were supplied free of charge by Arkopharma Laboratories, Carros, France.

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