Copper Depletion As A Strategy To Affect The Tumor Microenvironment In Breast Cancer Patients At High Risk Of Relapse And In Triple Negative Preclinical Models Of Breast Cancer: Updated Results Of A Phase Ii Study Of Tetrathiomolybdate (Tm) In Breast Cancer (Bc) Patients (Pts) At High Risk For Recurrence

Background: The pre-metastatic niche mobilizes copper to assist in conditioning the tumor microenvironment facilitating tumor progression. This includes bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX). We hypothesized that TM-associated CD would reduce EPCs and other copper dependent processes in the pre-metastatic niche in BC pts. Methods: Stage 2 triple negative BC, Stage 3 and stage 4 without any evidence of disease, (NED) BC pts, received oral TM to maintain ceruloplasmin (Cp) between 8-17mg/dL for 2 years or until relapse. Endpoints included change in EPCs, safety, disease-free (DFS) and overall survival (OS) and effect on biomarkers. Laboratory studies: MDA-LM2-luciferase cells were implanted into CB17-SCID mice, and treated with TM or water. Tumor progression was quantified by bioluminescence imaging (BLI), CD status by Cp oxidase levels, lysyl oxidase (LOXL2) activity by ELISA, and collagen deposition by Picrosirius Red staining and Second Harmonic Generation (SHG) imaging analysis. Results: 75 pts (45 stage 2/3 BC, 30 stage 4 NED) received over 2400 cycles of TM on the primary and extension studies. Median age: 51 yrs (range 29-66). Of the 75 pts, 48% had TNBC, 40% were stage 4 NED. Median Cp level decreased from 28 at baseline to 15.5 (p Conclusions: TM is safe, well tolerated and appears to affect multiple copper dependent biologic processes in the tumor microenvironment known to be important for tumor progression, most striking in TNBC. Randomized trials in a high risk for relapse population are warranted. Citation Format: Eleni Nackos, Sharrell Lee, Amy Willis, Naomi Kornhauser, Maureen Ward, Marta Cobham, Tessa Cigler, Anne Moore, Veronica Fitzpatrick, Sarah Schneider, Alysia Wiener, Jessica Guillaume-Abraham, Bo Ri Seo, J David Warren, Anna Rubinchik, Claudia Fischbach, Vivek Mittal, Linda Vahdat. Copper depletion as a strategy to affect the tumor microenvironment in breast cancer patients at high risk of relapse and in triple negative preclinical models of breast cancer: Updated results of a phase II study of tetrathiomolybdate (TM) in breast cancer (BC) patients (pts) at high risk for recurrence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-349.