Copper Depletion Therapy Shown to Suppress High-Risk Triple-Negative Breast Cancer

An anticopper compound that disarms the ability of bone marrow cells from establishing a “home base” in organs to receive and nourish migrating cancer tumor cells has shown unexpected benefits in one of the most difficult-to-treat forms of cancer—high-risk triple-negative breast cancer.

The average survival for metastatic triple-negative breast cancer patients is typically nine months. However, results of a new phase II clinical trial conducted by researchers from Weill Cornell Medical College (New York, NY, USA) reported in the March 2013 issue of the journal Annals of Oncology, demonstrated that if patients at high-risk of relapse with no current visible breast cancer are copper depleted, it results in a prolonged period of time with no cancer recurrence. Only two of 11 study participants with a history of advanced triple-negative breast cancer, in fact, relapsed within 10 months after using the anticopper drug, tetrathiomolybdate (TM).

Dr. Linda Vahdat, director of the Breast Cancer Research Program, chief of the Solid Tumor Service and professor of medicine at Weill Cornell Medical College reported that four of the study participants with a history of metastatic triple-negative breast cancer have had long-term benefit, remaining disease free for between three and five and a half years. “The anticopper compound appears to be keeping tumors that want to spread in a dormant state,” reported Dr. Vahdat. “We believe one of the important ways it works is by affecting the tumor microenvironment, specifically the bone marrow-derived cells that are critical for metastasis progression.”

Furthermore, study participants with other forms of high-risk for relapse breast cancers--either stage 3 or stage 4—without evidence of disease after treatment have also fared well. The progression-free survival rate among these 29 patients in the study has been 85%, up to now. Dr. Vahdat expects to initiate a phase III randomized clinical trial in the near future.

New findings in the science of metastasis and study of the body’s use of copper to enhance cancer metastasis led to this clinical trial. Weill Cornell investigators have contributed to the recent determination of the role bone marrow cells play in promoting metastasis. They earlier discovered that an assortment of bone marrow-derived cells, which include VEGFR [vascular endothelial growth factor]1+ hematopoietic progenitor cells (HPCs), prepare a site in distant organs to accept cancer cells. HPCs also recruit endothelial progenitor cells (EPCs), among others, to trigger an “angiogenic switch” that creates blood vessels at the site to feed newly migrated cancer cells.

Breast cancer research studies conducted at Weill Cornell have also found that immediately before the cancer relapse, levels of EPCs and HPCs increase substantially further, suggesting that the EPC target of the copper depletion approach is one that makes sense.

Copper is key to mobilizing these cells. Copper is essential to the metastatic process. It is a key component of enzymes that help turn on angiogenesis in the tumor microenvironment, and it also appears to play a role in directing cancer cell migration and invasion, according to researchers. TM is a copper chelation compound utilized to treat Wilson’s disease, a hereditary copper metabolism disorder, and has been studied in phase I and phase II clinical trials for a number of disorders. Animal studies have demonstrated that depleting copper decreases proliferation of EPCs, as well as blood vessel formation and tumor growth.

Dr. Vahdat’s study is the first human clinical trial to utilize a copper depletion strategy to modulate EPCs in breast cancer patients with an extraordinarily high risk of relapse from hidden residual disease. Most of the studies in other solid tumors with visible advanced disease have been disappointing, say researchers. In spite of recent enhancements in breast cancer therapy, there is a considerable risk of relapse in a high-risk subset of patients. The risk of relapse in stage 3 patients is 50%–75% over five years, and patients with stage 4 breast cancer always recur. Triple-negative breast cancer patients have a poorer prognosis even when diagnosed in early disease stages.

In the study, researchers found that 75% of patients achieved the copper depletion target using TM after one month of therapy, and that copper depletion was most effective (91%) in patients with triple-negative tumors, compared to other tumor types (41%). In copper-depleted patients only, there was a considerable decrease in EPCs, and the 10-month relapse-free survival was 85%. Furthermore, TM was found to be safe and well tolerated in patients.

The study’s findings revealed that copper depletion appears to suppress the production, release, and mobilization of EPCs from the bone marrow, leading to a suppressed angiogenic switch and tumor dormancy.

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