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Copper depletion may reduce breast cancer relapse in patients at high risk

Wednesday, April 20, 2016

This article first appeared on MDLinx. Read the original, with video interview, here.

Photo of Linda Vahdat, M.D.Linda Vahdat, M.D. Tetrathiomolybdate (TM), an anti-angiogenic copper chelator, is safe and well tolerated, and may work on the tumor microenvironment via a number of copper-dependent biologic processes that are possibly important for tumor progression, in patients with breast cancer, particularly in those with triple-negative breast cancer (TNBC), according to results from a late-breaking study presented here at the American Association for Cancer Research Annual Meeting 2016.

“Copper is an interesting element. It’s involved in multiple biologic processes, which are important for tumor progression both within the tumor itself and within the tumor microenvironment. In the tumor microenvironment, it facilitates tumors doing their bad things,” explained lead author Linda T. Vahdat, MD, MBA, professor of medicine, Weill Cornell Medicine and NewYork-Presbyterian, and director of the Breast Cancer Research Program and co-leader of the Breast Cancer Program, Meyer Cancer Center, New York, NY.

“Copper is important for a lot of different enzymes, which condition the pre-metastatic niche. We also know that when tumors spread, they have to land on a landing pad that is collagen based. When you pull copper out of the system, that landing pad, that collagen scaffolding gets totally messed up, too,” she added.

Dr. Vahdat and colleagues at Weill Cornell Medicine conducted this study to assess whether the depletion of copper could affect the tumor microenvironment in patients with breast cancer who are at a high risk of relapse, as well as assess this in triple-negative preclinical models.

For years years or until relapse, patients with stage II TNBC and those with stage III/IV breast cancer with no evidence of disease (NED) were treated with oral TM to maintain ceruloplasmin (CP) at levels between 8-17 mg/dL. Study endpoints included changes in endothelial progenitor cells (EPC), safety, disease-free survival (DFS), overall survival (OS), and effects on biomarkers. The dose of TM they used was 180 mg/d given over the course of 4 weeks to rapidly copper depleted patients, which was then titrated down to 100 mg to maintain copper depletion.

During the primary study as well as extension studies, a total of 75 patients (median age: 51 years) received over 2,400 cycles of TM. After one cycle, median CP levels decreased to 15.5, from 28 at baseline (P < 0.0001). Neutropenia (2.3%), anemia (0.04%), leukopenia (1.2%), and fatigue (0.09%) comprised the grade 3/4 toxicities.

Dr. Vahdat and colleagues found that copper depletion was associated with a significant decrease in EPCs (P=0.0014) and serum lysyl oxidase (LOXL2) (P < 0.001). After a median follow-up of 5.9 years, progression-free survival (PFS) in all patients was 72%, including a PFS of 90% for all stage II/III patients with TNBC. OS was 84%, and relapse after two years was rare.

For their laboratory studies, Dr. Vahdat and colleagues implanted MDA-LM2-luciferase cells into CB17-SCID mice that were treated with TM or water. They quantified tumor progression via bioluminescence imaging (BLI), measured CD status by Cp oxidase levels and LOXL2 activity via ELISA. Finally, they assessed collagen deposition using Picrosirius Red staining and second harmonic generation (SHG) imaging.

In the pre-clinical models, researchers found that TM had no effect on the primary tumor, but did affect decreases in secondary lung metastases (P=0.04), as demonstrated on bioluminescence imaging. In addition, decreased LOX was observed in pre-metastatic lungs compared with controls (P=0.03), as demonstrated by Western blot. Collagen cross-linking was also reduced per immunohistochemistry (IHC) by image J (P=001). Reductions in collagen fiber length were also observed upon SHG analysis.

Currently, 33 patients are still enrolled in extension studies for further study of copper depletion, explained Dr. Vahdat.

“If we really want to move the needle on curing patients with breast cancer, especially TNBC—where I think this might have its greatest value—sometimes you need to take a chance, but it needs to be grounded in science. We have followed the scientific trail on this whole concept from the very beginning,” she concluded. “It’s really precision medicine, but from the microenvironment perspective.”