Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse

S. Jain, J. Cohen, M. M. Ward, N. Kornhauser, E. Chuang, T. Cigler, A. Moore, D. Donovan, C. Lam, M. V. Cobham, S. Schneider, S. M. Hurtado Rúa, S. Benkert, C. Mathijsen Greenwood, R. Zelkowitz, J. D. Warren, M. E. Lane, V. Mittal, S. Rafii, L. T. Vahdat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Background: 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. Patients and methods: 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. Results: 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%). Conclusions: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Original languageEnglish (US)
Pages (from-to)1491-1498
Number of pages8
JournalAnnals of Oncology
Volume24
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Breast cancer
  • Endothelial progenitor cells
  • Tetrathiomolybdate

ASJC Scopus subject areas

  • Hematology
  • Oncology

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