KARISMA2 is a randomized, double-blinded, six-armed placebo controlled study to identify a low dose of tamoxifen, with less side-effects and a density reduction non-inferior to the standard dose of 20 mg.

This is a dose determination study aiming to identify the optimal tamoxifen dose for reducing the risk of breast cancer. The change in mammographic density is a very good marker of therapy response. Investigators will test if 1 mg, 2.5 mg, 5 mg and 10 mg reduce the mammographic density to the same extent as 20 mg.

1440 healthy women 40-74 yrs were included when adhering the national Swedish mammography screening program between 2016- 2019. Women were randomized and treated daily for 6 months. Mammograms were taken at baseline and at end of treatment and side effects were measured throughout the study trough schedueled questionnaires and spontaneous AE-reporting.

Inclusion Criteria:

• Attending the national mammography screening program, i.e. aged 40-74 and has performed a screening mammogram maximum 3 months prior to study inclusion
• Having a measurable mammographic density, i.e. ≥4.5 % density (volumetric) measured by Volpara
• Informed consent must be signed before any study specific assessments have been performed

Exclusion Criteria:

• Pregnancy at start, during time of study medication and up to 3 months after quitting study medication
• Breast feeding at start, during time of study medication and up to 3 months after quitting study medication
• Any previous or current diagnosis of breast cancer (including carcinoma in situ)
• Mammographic BI-RADS code 3 or above at baseline mammography, or at a diagnostic mammography during time of treatment (the first 6 months of the study)
• Any previous diagnosis of cancer with the exception of non-melanoma skin cancer and in situ cancer of the cervix
• Currently using oral oestrogen and progesterone based hormone replacement therapy
• Current use of hormone contraceptive with hormones, e.g. hormonal contraceptive pills, or progesterone implants. Hormonal intrauterine devices are accepted.
• A history of thrombo-embolic disease such as embolies, deep vein thrombosis, stroke, TIA or cardiac arrest.
• Known APC (Activated protein C )- resistance, an inherited hemostatic disorder
• A history of major surgery of the breast, e.g. reduction or enlargement, which might affect density measurements
• Women who have an increased risk of venous thrombosis due to immobilization, e.g. using wheelchair
• Known uncontrolled diabetes
• Hypertension at baseline, defined as systolic pressure higher than 140 mm Hg and diastolic higher than 90 mm Hg
• Use of drugs that interfere with CYP2D6 expression such as Seroxat (paroxetine), Fontex (fluoxetin) and Zyban / Voxra (bupropion)
• Use of Waran (warfarin)
• Non-medical approved drugs against hot-flashes including phytooestrogen
• Not able to understand study information and/or informed consent

Female mammography screening population in Sweden age 40-74

From baseline (start of treatment) to end of study (6 months or early termination)

Adverse events where collected through an app, by phone or email. Participants where urged to report when events occurred.