Supplementation of Tamoxifen with Low-Dose Endoxifen in Patients with Breast Cancer with Impaired Tamoxifen Metabolism (TAMENDOX): A Randomized Controlled Phase I/II Trial.

We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in patients with breast cancer with compromised tamoxifen bioactivation.

我们测试了在雌激素生物激活受损的乳腺癌患者中，以低剂量(Z)-endoxifen补充标准他莫昔芬治疗的可行性和安全性。

patients_and_methods

:We conducted a prospective, interventional, three group randomized trial including 235 patients with hormone receptor-positive breast cancer who received standard tamoxifen therapy (20 mg/day).

我们进行了一项前瞻性、干预性、三组随机试验，包括235名接受标准他莫昔芬治疗（每天20毫克）的激素受体阳性乳腺癌患者。

Patients were stratified by CYP2D6 genotype (n = 78), defining poor, intermediate, and normal metabolizers, or by baseline (Z)-endoxifen plasma concentration (n = 78), defining ≤15, 15 to 25, and ≥25 nmol/L.

患者根据CYP2D6基因型（n = 78）进行分层，定义为代谢不良、中等和正常代谢者，或根据基线(Z)-endoxifen血浆浓度（n = 78）进行分层，定义为≤15、15至25和≥25 nmol/L。

Co-treatment with (Z)-endoxifen 3 and 1.5 mg/day or placebo was performed, respectively.

分别进行了(Z)-endoxifen 3 mg/天和1.5 mg/天或安慰剂的联合治疗。

A control group (n = 79) received placebo regardless of metabolizer phenotype.

对照组（n = 79）无论代谢表型如何均接受安慰剂治疗。

The primary endpoint was the number of patients with (Z)-endoxifen levels >32 nmol/L after 6 weeks of treatment.

主要终点是治疗6周后，(Z)-endoxifen水平大于32纳摩尔/升的患者数量。

Adverse events were continuously monitored.

不良事件被持续监测。

Results

A higher proportion of patients in both intervention groups achieved target concentrations >32 nmol/L compared with control (P < 0.0001).

在两个干预组中，达到目标浓度>32纳摩尔/升的患者比例均高于对照组(P < 0.0001)。

At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 poor metabolizer patients and all patients with baseline (Z)-endoxifen ≤15 nmol/L achieved the target concentration.

在补充3毫克(Z)-endoxifen的情况下，92.3%的CYP2D6弱代谢患者和所有基线(Z)-endoxifen ≤15纳摩尔/升的患者达到了目标浓度。

At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 intermediate metabolizer patients and 95% of patients with 15 to 25 nmol/L baseline (Z)-endoxifen levels achieved the target concentration.

在接受1.5 mg (Z)-endoxifen补充治疗的情况下，88%的CYP2D6中代谢者患者和95%基线(Z)-endoxifen水平在15至25 nmol/L的患者达到了目标浓度。

Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced grade 3 adverse events.

接受(Z)-endoxifen治疗的患者（6/80，7.5%）和接受安慰剂的患者（8/155，5.2%）经历3级不良事件的比例相似。

Conclusions

Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized antiestrogen treatment for patients with low endoxifen plasma levels.

在标准他莫昔芬治疗中添加低剂量(Z)-恩多昔芬是安全的，并为低恩多昔芬血浆水平的患者提供了一种新的个性化抗雌激素治疗方案。