title: 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.
  
  
  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: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors: S
authors: S
authors: Jain
authors: J
authors: J
authors: Cohen
authors: M M
authors: MM
authors: Ward
authors: N
authors: N
authors: Kornhauser
authors: E
authors: E
authors: Chuang
authors: T
authors: T
authors: Cigler
authors: A
authors: A
authors: Moore
authors: D
authors: D
authors: Donovan
authors: C
authors: C
authors: Lam
authors: M V
authors: MV
authors: Cobham
authors: S
authors: S
authors: Schneider
authors: S M
authors: SM
authors: Hurtado Rúa
authors: S
authors: S
authors: Benkert
authors: C
authors: C
authors: Mathijsen Greenwood
authors: R
authors: R
authors: Zelkowitz
authors: J D
authors: JD
authors: Warren
authors: M E
authors: ME
authors: Lane
authors: V
authors: V
authors: Mittal
authors: S
authors: S
authors: Rafii
authors: L T
authors: LT
authors: Vahdat
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy; D002614:Chelating Agents / Q000627:therapeutic use; D003300:Copper / Q000097:blood*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D008982:Molybdenum / Q000494:pharmacology / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000517:prevention & control*; D012307:Risk Factors; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate
keywords: breast cancer; endothelial progenitor cells; tetrathiomolybdate