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Red clover and lifestyle changes to contrast menopausal symptoms in premenopausal patients with hormone-sensitive breast cancer receiving tamoxifen

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Abstract

Purpose

To determine whether a red clover preparation plus dietary intervention administered to premenopausal women with breast cancer (BC), improves menopausal symptoms due to anti-oestrogen treatment, and hence promotes compliance with tamoxifen, prevents weight gain and is safe.

Methods

Surgically-treated premenopausal women with oestrogen receptor (ER) positive disease taking tamoxifen were recruited to a prospective double-blind randomized trial (NCT03844685). The red clover group (N = 42) received one oral tablet/day (Promensil® Forte) containing 80 mg red clover extract for 24 months. The placebo group (N = 39) received one oral tablet/day without active ingredient. All women were encouraged to follow a Mediterranean-type diet and keep active. Outcomes were Menopausal Rating Score (MRS), body mass index (BMI), waist and hip girth, insulin resistance, and levels of cholesterol, triglycerides, and sex hormones. As safety indicators, endometrial thickness, breast density, and effects of patient serum on ER-positive BC cell lines were investigated.

Results

MRS reduced significantly (p < 0.0001) with no between-group difference (p = 0.69). The red clover group had significantly greater reductions in BMI and waist circumference (p < 0.0001 both cases). HDL cholesterol increased significantly in both groups (p = 0.01). Hormone levels and insulin resistance changed little. Endometrial thickness remained constant (p = 0.93). Breast density decreased significantly in both groups (p < 0.0001). Proliferation and oestrogen-regulated gene expression didn’t differ in cell lines treated with serum from each group.

Conclusions

This is the first trial to assess red clover in BC patients on tamoxifen. The preparation proved safe clinically and in vitro, and was associated with reduced BMI and waist circumference, but the diet-lifestyle intervention probably improved the menopausal symptoms.

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Acknowledgements

Dr Cristina Ferraris thanks Dr Marco Greco for allowing a specific clinic to follow the patients of this study. All authors thank Don Ward for help with the English.

Funding

Dr Barbara Ballestra received a study fellowship from Named S.p.A (Lesmo, MB, Italia), to carry out this study. PharmaCare Laboratories Pty Ltd (Warriewood, NSW, Australia), provided to the institute’s pharmacy the Red Clover extract and the placebo pill for this study and provided fundings for in vitro experiments.

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Authors and Affiliations

  1. Breast Unit, Fondazione IRCCS, Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Cristina Ferraris, Barbara Ballestra, Chiara Listorti, Secondo Folli & Gabriele Martelli

  2. Biomarker Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Vera Cappelletti & Carolina Reduzzi

  3. Breast Radiology, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Gianfranco P. Scaperrotta

  4. Clinical Studies Scientific Director’s Office, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Iolanda Pulice

  5. Pharmacy and Experimental Clinical Studies, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Eleonora G. A. Ferrari

  6. Department of Clinical Epidemiology and Trials Organization, Fondazione IRCCS Istituto Nazionale Dei Tumori Di Milano, Via Venezian 1, 20133, Milano, Italy

    Luigi Mariani

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  1. Cristina Ferraris
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  2. Barbara Ballestra
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Correspondence to Chiara Listorti.

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All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Ferraris, C., Ballestra, B., Listorti, C. et al. Red clover and lifestyle changes to contrast menopausal symptoms in premenopausal patients with hormone-sensitive breast cancer receiving tamoxifen. Breast Cancer Res Treat 180, 157–165 (2020). https://doi.org/10.1007/s10549-020-05534-4

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