Purpose Monitoring metabolites of tamoxifen, such as endoxifen, has been suggested as a strategy to ascertain therapeutic effect of tamoxifen therapy but clinical guidelines are missing. Herein we aim to investigate the outcome of endoxifen concentrations of low dose tamoxifen, using change in mammographic breast density (MBD) as a proxy for therapy response. Material and Methods In the randomized KARISMA trial, including five doses of tamoxifen, measurements of plasma endoxifen concentrations, determination of CYP2D6 metabolizer status and MBD change over the trial period, were carried out. Association between endoxifen concentrations and relative MBD change after 6 months treatment was analysed using linear regression in a spline model. Results A total of 824 women (335 premenopausal, 489 postmenopausal) were included. In analyses of premenopausal women, a spline model described a MBD decrease, equivalent to the mean (-18.5%) seen in women exposed to 20 mg tamoxifen, at endoxifen concentrations of 2–3 ng/mL. The MBD decrease reached a nadir at endoxifen levels of 3 ng/mL and did not decrease further at higher endoxifen concentrations. Most intermediate and normal tamoxifen-metabolizers (≈ 90% of all participants) reached an endoxifen concentration of > 2 ng/mL at tamoxifen doses of 5 and 10 mg. No MBD decrease was seen in the postmenopausal group. Conclusion We have identified a possible window of effect on MBD at endoxifen concentrations of 2–3 ng/mL in premenopausal women, which corresponds to the doses of 5 and 10 mg tamoxifen. Since MBD change was used as a surrogate marker for therapy response, results should be confirmed using clinically established outcomes measures. Trial Registration ClinicalTrials.gov ID: NCT03346200

中文翻译：

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Endoxifen 对乳腺 X 线摄影密度的影响——KARISMA 试验的结果


目的 监测他莫昔芬的代谢物，如内多昔芬，已被建议作为确定他莫昔芬治疗效果的一种策略，但缺乏临床指南。在此，我们旨在研究低剂量他莫昔芬的 endoxifen 浓度的结果，使用乳房 X 光检查乳房密度 （MBD） 的变化作为治疗反应的代表。材料和方法 在随机 KARISMA 试验中，包括 5 剂他莫昔芬，测量血浆 endoxifen 浓度，测定 CYP2D6 代谢物状态和试验期间的 MBD 变化。使用样条模型中的线性回归分析治疗 6 个月后 endoxifen 浓度与相对 MBD 变化之间的关联。结果 共纳入 824 例女性 （绝经前 335 例，绝经后 489 例）。在对绝经前妇女的分析中，样条模型描述了 MBD 降低，相当于在内昔芬浓度为 2-3 ng/mL 时暴露于 20 毫克他莫昔芬的妇女的平均值 （-18.5%）。MBD 降低在 3 ng/mL 的 endoxifen 水平达到最低点，并且在较高的 endoxifen 浓度下没有进一步降低。大多数中间和正常他莫昔芬代谢者 （≈ 90% 的参与者） 在他莫昔芬剂量为 5 和 10 mg 时达到 > 2 ng/mL 的内昔芬浓度。绝经后组未见 MBD 降低。结论 我们已经确定了绝经前妇女中 2-3 ng/mL 的 endoxifen 浓度对 MBD 的可能影响窗口，这对应于 5 和 10 mg 他莫昔芬的剂量。由于 MBD 变化被用作治疗反应的替代标志物，因此应使用临床确定的结局指标来确认结果。试验注册 ClinicalTrials.gov ID： NCT03346200