TY - JOUR
T1 - Influencing the tumor microenvironment
T2 - 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
AU - Chan, Nancy
AU - Willis, Amy
AU - Kornhauser, Naomi
AU - Mward, Maureen
AU - Lee, Sharrell B.
AU - Nackos, Eleni
AU - Seo, Bo Ri
AU - Chuang, Ellen
AU - Cigler, Tessa
AU - Moore, Anne
AU - Donovan, Diana
AU - Cobham, Marta Vallee
AU - Fitzpatrick, Veronica
AU - Schneider, Sarah
AU - Wiener, Alysia
AU - Guillaume-Abraham, Jessica
AU - Aljom, Elnaz
AU - Zelkowitz, Richard
AU - Warren, J. David
AU - Lane, Maureen E.
AU - Fischbach, Claudia
AU - Mittal, Vivek
AU - Vahdat, Linda
N1 - Funding Information:
This work was supported by the Anne Moore Breast Cancer Research Fund (all authors), Stephen and Madeline Anbinder Foundation (all authors), Susan G Komen for the Cure (to L. Vahdat), New York Community Trust (to L. Vahdat), Manhasset Women Against Breast Cancer (to L. Vahdat, V. Mittal), Breast Cancer Alliance of Greenwich (to L. Vahdat) Cancer Research and Treatment Fund (to L. Vahdat), and Berman Fund (to L. Vahdat), Keith Miller Foundation (to L. Vahdat), Anonymous (to L. Vahdat, V.Mittal), and Lefkofsky Foundation (to L. Vahdat, V. Mittal). Laboratory specimens were supported by The National Center for Advancing Translational Science of the NIH award number UL1TR000457.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Purpose: 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. Experimental Design: 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. Results: 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 IVNED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (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). Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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. Results: 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 IVNED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 50% (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). Conclusions: 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.
KW - Department of medicine
KW - New York
KW - Weill cornell medicine
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UR - http://www.scopus.com/inward/citedby.url?scp=85012865407&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-1326
DO - 10.1158/1078-0432.CCR-16-1326
M3 - Article
C2 - 27769988
AN - SCOPUS:85012865407
SN - 1078-0432
VL - 23
SP - 666
EP - 676
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -