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Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women
Authors:Marike Gabrielson  Mattias Hammarström  Magnus Bäcklund  Jenny Bergqvist  Kristina Lång  Ann H Rosendahl  Signe Borgquist  Roxanna Hellgren  Kamila Czene  Per Hall
Affiliation:1. Department of Medical Epidemiology and Biostatics, Karolinska Institutet, Stockholm, Sweden;2. Department of Medical Epidemiology and Biostatics, Karolinska Institutet, Stockholm, Sweden

Breast Centre, Department of Surgery, Capio St Görans Hospital, Stockholm, Sweden;3. Department of Translational Medicine, Diagnostic Radiology, Lund University, Lund, Sweden;4. Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden;5. Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden

Department of Oncology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark;6. Department of Radiology, Södersjukhuset, Stockholm, Sweden;7. Department of Medical Epidemiology and Biostatics, Karolinska Institutet, Stockholm, Sweden

Department of Oncology, Södersjukhuset, Stockholm, Sweden

Abstract:Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.
Keywords:breast cancer  mammographic breast density  primary prevention  tamoxifen
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