Copper depletion could inhibit tumor progression, especially TN

Adequate copper is required for normal iron metabolism and blood cell formation. However, high circulating levels of copper have been linked to increased breast cancer risk. Copper concentrations tend to be elevated in breast cancer patients. Inducing copper deficiency has been shown to reduce tumor development and angiogenesis in mouse models of HER2 overexpressing (HER2+) and inflammatory breast cancer (IBC).

A 2013 study reported that treating breast cancer patients at high risk of recurrence with tetrathiomolybdate, a copper chelator (a drug that removes copper from the body), appeared to promote tumor dormancy and help prevent relapse, especially among women with triple negative (ER-/PR-/HER2-) breast cancer.

Now a report presented at the 2015 American Society for Clinical Oncology (ASCO) Annual Meeting in June has concluded that copper depletion could result in an inhospitable environment for tumor progression, especially for triple negative disease.

One study found that circulating levels of copper and the copper/zinc ratio were significantly higher in breast cancer patients compared to controls, suggesting that zinc might mitigate the cancer-promoting effects of too much copper. Women with breast cancer should not exceed the RDA (recommended dietary allowance) of approximately 0.9 mg of copper. Note that women with low iron stores are at risk of anemia if they do not have adequate copper intake.

The report referenced at the beginning of this news story describes preliminary results of a Phase II clinical trial of copper depletion (using the copper chelator tetrathiomolybdate) in women with high-risk breast cancer who showed no evidence of disease progression at enrollment. Bone marrow-derived endothelial progenitor cells (EPCs) and copper-dependent pathways have been shown to be important in remodeling the tumor microenvironment and generating the pre-metastatic niche. The authors hypothesized that copper depletion would reduce EPCs and inhibit copper-dependent processes in breast cancer patients at high risk for breast cancer progression.

The study included 75 breast cancer patients at high risk of relapse, which was defined as having either (1) lymph node positive triple negative disease (48% of participants); or (2) stage III or IV breast cancer with no evidence of disease at enrollment. Median age was 51. Tetrathiomolybdate dosage was calibrated to maintain ceruloplasmin (a copper-carrying protein in the blood) levels of five to 17 mg/dl until the end of treatment or breast cancer recurrence. The primary study endpoint was change in EPCs during treatment with tetrathiomolybdate. Secondary endpoints included the tolerability and safety of tetrathiomolybdate, as well as its effects on other relevant markers. Treatment lasted for a maximum of 24 cycles of 28 days each. Participant have received more than 2,021 cycles to date.

After a median follow-up period of 5.6 years, the progression-free survival rate for all 75 participants from the beginning of tetrathiomolybdate treatment is 81%; the rate for all stage II or III women with triple negative disease is 94%. Treatment with tetrathiomolybdate was effective in reducing the median ceruloplasmin level from 28 at baseline to 16 after one cycle. However, copper depletion was greatest in women with triple negative disease. Tetrathiomolybdate was well tolerated; the only serious toxicities were reversible neutropenia (2.5%) and anemia (0.04%). Copper depletion was associated with a significant decrease in EPCs and another marker (LOX: lysyl oxidase) in the two-year analysis; the five-year analysis is ongoing. The authors conclude that tetrathiomolybdate is safe and well tolerated and appears to affect multiple components of the tumor microenvironment, resulting in an inhospitable environment for tumor progression. This effect is especially striking in triple negative breast cancer. Further phase III trials are warranted, according to the authors.