de Vries Schultink A H M, Alexi X, van Werkhoven E, Madlensky L, Natarajan L, Flatt S W, Zwart W, Linn S C, Parker B A, Wu A H B, Pierce J P, Huitema A D R, Beijnen J H
Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Breast Cancer Res Treat. 2017 Feb;161(3):567-574. doi: 10.1007/s10549-016-4083-6. Epub 2016 Dec 22.
Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL.
The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices.
An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47-0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48-0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients.
Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.
在接受他莫昔芬治疗的患者中，内美通浓度与乳腺癌复发相关。然而，他莫昔芬本身及其他代谢产物也显示出抗雌激素抗肿瘤活性。因此，本研究的目的是开发一种综合抗雌激素活性评分（AAS），该评分考虑了他莫昔芬及其三种代谢产物的浓度和抗雌激素活性。研究了AAS与无复发生存率之间的关联，并与先前公布的内美通浓度阈值5.97 ng/mL进行比较。
在细胞增殖试验中测定他莫昔芬、（Z）-内美通、（Z）-4-羟基他莫昔芬和N-去甲基他莫昔芬的抗雌激素活性。AAS通过计算每种代谢产物浓度乘以相对于他莫昔芬的IC比值之和来确定。对1370例雌激素受体α（ERα）阳性乳腺癌患者计算AAS。使用Cox回归研究AAS与复发之间的关联，并使用一致性指数与5.97 ng/mL的内美通阈值进行比较。
AAS阈值为1798与无复发生存率相关，危险比（HR）为0.67（95%置信区间（CI）0.47 - 0.96），自举后偏差校正HR为0.69（95%CI 0.48 - 0.99）。AAS和内美通的一致性指数无显著差异；然而，使用AAS阈值而非内美通导致5.2%的患者有不同的剂量建议。
内美通浓度可作为他莫昔芬及其代谢产物抗雌激素作用的替代指标。然而，对于由综合算法定义的他莫昔芬及其三种代谢产物的总体效应，可见治疗改善趋势，而且与乳腺癌复发显著相关。
