Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Ann Oncol. 2013 Jun;24(6):1491-8. doi: 10.1093/annonc/mds654. Epub 2013 Feb 13.
Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence.
This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs.
Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%).
TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
骨髓来源的内皮祖细胞（EPCs）对于转移进展至关重要。本研究探讨了四硫钼酸盐（TM），一种抗血管生成的铜螯合剂，对高乳腺癌复发风险患者的 EPCs 的影响。
这项 2 期研究纳入了无疾病证据的 3 期和 4 期乳腺癌患者（NED），以及如果是三阴性的 2 期患者。TM 100mg 口服给药，以维持铜蓝蛋白<17mg/dl 达 2 年或直至复发。主要终点是 EPCs 的变化。
40 名患者（28 名 2/3 期，12 名 4 期 NED）入组。75%的患者在 1 个月内达到铜耗竭目标。91%的三阴性患者铜耗竭，而 luminal 亚型为 41%。仅在铜耗竭的患者中，EPCs/ml 显著减少了 27%（P=0.04）。6 名患者在研究期间复发，其中只有 1 名患者的 EPCs 维持在基线以下。10 个月无复发生存率为 85.0%（95%CI 74.6%-96.8%）。只有 3/4 级毒性是血液学毒性：中性粒细胞减少（3.1%的周期）、发热性中性粒细胞减少（0.2%）和贫血（0.2%）。
TM 是安全的，似乎能维持铜耗竭患者的 EPCs 低于基线。TM 可能促进肿瘤休眠，最终预防复发。
