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

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.

• Authors: 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
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 24 Issue 6 Pg. 1491-8 (Jun 2013) ISSN: 1569-8041 [Electronic] England
• PMID: 23406736 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Copper
• Molybdenum
• tetrathiomolybdate

Topics

• Adult
• Aged
• Breast Neoplasms (blood, diagnosis, drug therapy)
• Chelating Agents (therapeutic use)
• Copper (blood)
• Endothelial Cells (drug effects, metabolism)
• Female
• Humans
• Middle Aged
• Molybdenum (pharmacology, therapeutic use)
• Neoplasm Recurrence, Local (blood, prevention & control)
• Risk Factors
• Stem Cells (drug effects, metabolism)