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The protocol involves low doses of (Z)-endoxifen, a metabolite of the well-known drug tamoxifen<\/a>. <\/p>\n<\/div>\n The study, known as the KARISMA Endoxifen trial, tested the effects of two daily doses of (Z)-endoxifen on mammographic breast density<\/a>, a known marker of breast cancer risk and treatment response. <\/p>\n<\/div>\n Researchers examined whether (Z)-endoxifen could reduce breast density safely and with fewer side effects than tamoxifen, potentially offering a new option for breast cancer prevention. Here\u2019s what they found.<\/p>\n<\/div>\n<\/div>\n The KARISMA Endoxifen trial was a double-blind, randomized, placebo-controlled phase II study that enrolled premenopausal women ages 40 to 55. <\/p>\n<\/div>\n Researchers recruited 240 healthy participants from Sweden\u2019s national breast cancer screening program between December 2021 and November 2023.<\/p>\n<\/div>\n To be eligible, participants needed to have regular menstrual cycles or confirm premenopausal status<\/a> via blood tests, and to have a baseline mammogram<\/a> showing measurable breast density. Women taking medications that could interfere with endoxifen metabolism were excluded.<\/p>\n<\/div>\n Participants were randomly assigned to one of three groups receiving daily oral capsules for six months: a placebo, 1 milligram (mg) of (Z)-endoxifen, or 2 mg of (Z)-endoxifen. <\/p>\n<\/div>\n The study was \u201cdouble-blinded,\u201d meaning neither the participants nor the researchers knew who was receiving which treatment until the trial was completed, ensuring unbiased results.<\/p>\n<\/div>\n Mammographic breast density was measured from full-field digital mammograms obtained at the start, 3 months, 6 months, or upon early discontinuation. A specialized automated method, STRATUS, assessed breast density area in square centimeters, and images were aligned to reduce measurement errors.<\/p>\n<\/div>\n Safety and tolerability were evaluated throughout the study by monitoring vital signs and blood chemistry, and by assessing participant-reported side effects via a digital application and questionnaires. <\/p>\n<\/div>\n Tolerability was assessed using the Breast Cancer Prevention Trial Eight Symptom Scale (BESS Plus), a validated symptom questionnaire, supplemented with questions specific to tamoxifen-related symptoms based on previous research.<\/p>\n<\/div>\n The trial\u2019s main goal was to determine whether either dose of (Z)-endoxifen was better than placebo at reducing mammographic breast density, a proxy for breast cancer risk reduction. <\/p>\n<\/div>\n Statistical analysis focused on relative changes in breast density adjusted for baseline values and compared the results between placebo and active treatment groups.<\/p>\n<\/div>\n <\/div>\n Of the over 126,000 females invited to participate, 240 were enrolled and randomly assigned to the three treatment groups, with 75 females in each group completing baseline and end-of-treatment mammograms for analysis. <\/p>\n<\/div>\n