Abstract P3-02-02: Targeting the tumor microenvironment: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence
Authors: E Nackos, A Willis, N Kornhauser, M Ward, E Andreopoulou, T Cigler, A Moore, V Fitzpatrick, M Cobham, S Schneider, A Wiener, J Guillaume-Abraham, JD Warren, A Rubinchik, M Lane, V Mittal, L Vahdat
Journal: Cancer Research (2016)

Abstract Background: Bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, including lysyl oxidase (LOX), are critical components to remodeling the tumor microenvironment and establishing the pre-metastatic niche. In preclinical models, it has been well established that copper depletion (CD) inhibits tumor progression. We hypothesized that TM-associated CD would reduce EPCs and other copper dependent processes in the pre-metastatic niche in BC pts at high risk for relapse. We investigated the relationship between CD and its effect on EPCs and other components of the tumor microenvironment including LOX, an enzyme critical for cross-linkage of collagen and priming the pre-metastatic niche. Methods: In this single arm, phase II study, BC pts at high risk for recurrence, defined as node+ triple negative (TN), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Pts received oral TM to maintain ceruloplasmin (Cp) between 5-17 mg/dl for 2 years on the primary study. The primary endpoint was change in EPCs measured by flow cytometry before and during treatment with TM. Secondary endpoints included tolerability, safety and effect of copper depletion on other markers including LOX, quantified by ELISA. Results: We enrolled 75 pts. The study treatment duration was 24 cycles (each cycle is 28 days). Over 2200 cycles have been administered. The median age is 51 (range 29-66). 45 pts have Stage 2/3 BC and 30 are Stage 4 NED. TNBC pts represent 48%, and 40% of pts are Stage 4 NED. Median Cp level decreased from 28 at baseline to 15.5 (p&amp;lt;0.0001) after one cycle. Copper depletion was most efficient in TNBC, with 91% achieving a target CP within 4 weeks. TM was well tolerated and the only grade 3/4 toxicities were reversible neutropenia (3.2%) and anemia (0.0005%). CD was associated with a significant decrease in EPCs (p=0.0014) and LOX (p&amp;lt;0.001). At a median follow-up of 5.4 years, the PFS for all 75 pts from the start of TM treatment was 71%, including a PFS of 90% for all stage 2/3 pts with TNBC. The overall survival of all patients enrolled in the trial is 86%. Relapse after two years is a rare event. 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. This seems to be most striking in TNBC. We believe, further phase III trials in a high risk for relapse population are warranted. Citation Format: Nackos E, Willis A, Kornhauser N, Ward M, Andreopoulou E, Cigler T, Moore A, Fitzpatrick V, Cobham M, Schneider S, Wiener A, Guillaume-Abraham J, Warren JD, Rubinchik A, Lane M, Mittal V, Vahdat L. Targeting the tumor microenvironment: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-02-02.