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
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 IV NED 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. Clin Cancer Res; 23(3) 666 76. (c)2016 AACR.
Clinical Cancer Research