Background: Breast cancer incidence is increasing throughout the world. Despite remarkable risk reducing effects demonstrated in preventive randomised endocrine trials; primary preventive strategies are scarcely part of clinical routine. Putative reasons for reluctance may be inadequate tools for identification of women at high risk of breast cancer and reluctance to prescribe pharmaceuticals with considerable side effects in the preventive setting.

Trial Design: A randomized, double blinded, six-armed placebo controlled dose determination study to investigate the optimal dose of tamoxifen with the most favorable side effect spectra. To reduce the number of participants, costs and to shorten the trial period; change in mammographic density will be used as clinical outcome. After randomization and baseline mammography, women will be treated with placebo, 1mg, 2.5mg, 5mg, 10mg or 20mg of tamoxifen for six months where after a subsequent mammogram is performed.

Eligibility criteria: 1) Attending the national Swedish mammography screening program, 2) Having a measurable mammographic density, i.e. ≥4.5 % density (volumetric) measured by Volpara.

Specific aims: The primary aim is to identify the minimum dose of tamoxifen non-inferior in its ability to reduce mammographic density and with fewer side effects compared to 20 mg of tamoxifen. Secondarily, to study the associations between different doses of tamoxifen and changes in circulating levels of a number of proteins, lipids, hormones, and tamoxifen metabolites, including the impact of polymorphisms in the CYP2D6 gene. A translational aim is to study molecular changes in the healthy breast tissue as a result of tamoxifen exposure.

Statistical Methods: Previous studies have shown that ∼ 50% of women treated with 20mg of tamoxifen have a reduction in density and respond to therapy. We therefore use the median density decrease in women treated with 20mg tamoxifen as the predefined response threshold. The primary efficacy endpoint is thus the proportion of responders that reaches this threshold. We will test for non-inferiority after treatment with placebo, 1mg, 2.5mg, 5mg, and 10mg compared to the group of women treated with 20mg tamoxifen. Per definition 50% of the women in the 20mg group are responders. The non-inferiority margin is defined to be 16.7 percentage points; that is the fraction of responders is not less than one third of the treated individuals (50% minus 16.7% = 33.3%).The null hypothesis is thus that the proportion of responders in women treated with placebo, 1mg, 2.5mg, 5mg, and 10mg is 33.3% or higher. Power calculations have determined a need of 1200 participants corresponding to 200 participants in each treatment arm.

Present accrual and target accrual: The trial will start recruiting as of September 2016. Eligible women are identified from the Swedish mammographic screening cohort, i.e. women age 40-74 years invited for biennial screening.

Contact information for people with a specific interest in the trial:

Signe.Borgquist@med.lu.se & Per.Hall@ki.se.

Citation Format: Borgquist S, Eriksson M, Czene K, Hall P. KARISMA, The karma intervention study. - A tamoxifen dose determination trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-06-01.