title: Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases.
abstract: Bone marrow-derived progenitor cells, including VEGFR2+endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.
  
  
  
  Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition.
  
  
  
  Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012).
  
  
  
  Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. ©2016 AACR.
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Nancy
authors: N
authors: Chan
authors: Department of Statistical Science, Cornell University, Ithaca, New York.
authors: Amy
authors: A
authors: Willis
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Naomi
authors: N
authors: Kornhauser
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Maureen M
authors: MM
authors: Ward
authors: Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York.
authors: Sharrell B
authors: SB
authors: Lee
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Eleni
authors: E
authors: Nackos
authors: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Bo Ri
authors: BR
authors: Seo
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Ellen
authors: E
authors: Chuang
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Tessa
authors: T
authors: Cigler
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Anne
authors: A
authors: Moore
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Diana
authors: D
authors: Donovan
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Marta
authors: M
authors: Vallee Cobham
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Veronica
authors: V
authors: Fitzpatrick
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Sarah
authors: S
authors: Schneider
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Alysia
authors: A
authors: Wiener
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Jessica
authors: J
authors: Guillaume-Abraham
authors: Investigational Pharmacy, New York Presbyterian Hospital, New York, New York.
authors: Elnaz
authors: E
authors: Aljom
authors: Department of Medicine, Norwalk Hospital, Norwalk, Connecticut.
authors: Richard
authors: R
authors: Zelkowitz
authors: Department of Biochemistry, Weill Cornell Medicine, New York, New York.
authors: J David
authors: JD
authors: Warren
authors: Department of Medicine, Weill Cornell Medicine, New York, New York.
authors: Maureen E
authors: ME
authors: Lane
authors: Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.
authors: Claudia
authors: C
authors: Fischbach
authors: Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York. ltv2001@med.cornell.edu vim2010@med.cornell.edu.
authors: Vivek
authors: V
authors: Mittal
authors: Department of Medicine, Weill Cornell Medicine, New York, New York. ltv2001@med.cornell.edu vim2010@med.cornell.edu.
authors: Linda
authors: L
authors: Vahdat
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000517:prevention & control / Q000556:secondary*; D000594:Amino Acid Oxidoreductases / Q000097:blood; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002570:Ceruloplasmin / Q000032:analysis; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D066026:Endothelial Progenitor Cells / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D016513:Mice, SCID; D008982:Molybdenum / Q000494:pharmacology / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000097:blood; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control; D009503:Neutropenia / Q000139:chemically induced; D012306:Risk; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002614:Chelating Agents; D009363:Neoplasm Proteins; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human