Background 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 as a proxy for therapy response. Methods In the randomized KARISMA-Tam (Karolinska Mammography project for risk prediction of breast cancer -Intervention Study with Tamoxifen) trial, including 5 doses of tamoxifen, measurements of plasma endoxifen concentrations, determination of CYP2D6 metabolizer status, and mammographic breast density change over the trial period were carried out. Association between endoxifen concentrations and relative mammographic breast density change after 6 months treatment was analyzed 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 mammographic breast density decrease, equivalent to the mean (−18.5%) seen in women exposed to 20 mg tamoxifen, at endoxifen concentrations of 2-3 ng/mL. The mammographic breast density 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 (about 90% of all participants) reached an endoxifen concentration of more than 2 ng/mL at tamoxifen doses of 5 and 10 mg. No mammographic breast density decrease was seen in the postmenopausal group. Conclusions We have identified a possible window of effect on mammographic breast density at endoxifen concentrations of 2-3 ng/mL in premenopausal women, which corresponds to the doses of 5 and 10 mg tamoxifen. Because mammographic breast density change was used as a surrogate marker for therapy response, results should be confirmed using clinically established outcomes measures.

中文翻译：

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Endoxifen 对乳腺 X 线摄影密度的影响：KARISMA-Tam 试验结果


背景 监测他莫昔芬的代谢物，如恩多昔芬，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 光检查乳房密度的变化作为治疗反应的代表。方法 在随机 KARISMA-Tam （Karolinska 乳腺 X 光检查项目乳腺癌风险预测 - 他莫昔芬干预研究） 试验中，包括 5 剂他莫昔芬，测量血浆内昔芬浓度，测定 CYP2D6 代谢物状态，以及试验期间乳房 X 光检查乳腺密度变化。使用样条模型中的线性回归分析治疗 6 个月后 endoxifen 浓度与相对乳腺 X 线摄影乳腺密度变化之间的关联。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，样条模型描述了乳房 X 光检查乳房密度降低，相当于在内昔芬浓度为 2-3 ng/mL 时暴露于 20 mg 他莫昔芬的女性中观察到的平均值 （-18.5%）。乳腺 X 线摄影乳腺密度降低在 Endoxifen 水平为 3 ng/mL 时达到最低点，并且在较高 endoxifen 浓度下没有进一步降低。大多数中间和正常的他莫昔芬代谢者（约占所有参与者的 90%）在他莫昔芬剂量为 5 和 10 mg 时达到超过 2 ng/mL 的内诺昔芬浓度。绝经后组未见乳腺 X 线摄影乳腺密度降低。 结论 我们已经确定了绝经前妇女 endoxifen 浓度为 2-3 ng/mL 时对乳房 X 光检查乳腺密度的可能影响窗口，这对应于 5 和 10 mg 他莫昔芬的剂量。由于乳腺 X 线摄影乳腺密度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测量来确认结果。