Results from an early phase single-arm trial suggest that targeting the tumor microenvironment with a copper-depleting agent, tetrathiomolybdate, creates an inhospitable environment for tumor progression in patients with breast cancer, with the effect most striking in those with triple-negative disease.
The results (abstract 11008) were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2 in Chicago.
“Copper alters the tumor microenvironment, and [tetrathiomolybdate] depletes this microenvironment of factors that are critical for tumor progression,” study author Linda T. Vahdat, MD, of the Weill Cornell Breast Center in New York, told Cancer Network.
Tetrathiomolybdate has been shown in previous studies to suppress angiogenesis.
The phase II clinical trial enrolled 75 patients (median age = 51) with moderate- to high-risk stage II breast cancer with at least four positive lymph nodes (n = 45), or patients with stage III or IV breast cancer with no evidence of disease (n = 30). Patients took tetrathiomolybdate pills for 2 years to test whether the drug could help prevent recurrence—24 cycles (28 days each). The investigators used tetrathiomolybdate to maintain levels of the copper-carrying protein ceruloplasmin between 5–17 mg/dl. After 1 cycle, the median level of ceruloplasmin decreased from 28 at baseline to 16 (P < .0001).
After a median follow-up of 5.6 years, the progression-free survival was 81% for all patients, and 94% for patients with stage II/III triple-negative disease. Copper depletion was most efficient in patients with triple-negative breast cancer, who comprised 48% of the study group.
Tetrathiomolybdate was well tolerated, with grade 3/4 toxicities of neutropenia (2.5%) and anemia (0.04%) that were both reversible. Copper depletion was associated with a significant decrease in endothelial progenitor cells (P < .001) and lysyl oxidase (P < .001) in the 2-year analysis. Patients in the trial continue to be followed.
“This trial is a fantastic approach and the beginning of the next phase of clinical trials we should be doing with this medication,” said Sofia D. Merajver, MD, PhD, scientific director of the breast cancer program at the University of Michigan Comprehensive Cancer Center. Dr. Merajver first studied tetrathiomolybdate to prevent metastasis in breast and other solid tumors.
Study investigators are currently developing a phase III randomized study of tetrathiomolybdate in breast cancer patients.
Parts of the tumor microenvironment—including endothelial and inflammatory cells, and stromal fibroblasts—have been shown to affect tumor progression and metastasis. Preclinical cancer studies and breast cancer patient samples have also shown that endothelial progenitor cells that express VEGFR2 from the bone marrow are increased prior to detection of macrometastases, suggesting that these cells play a role in remodeling the tumor microenvironment, increasing vasculature and facilitating a switch from micrometastasis to disseminated macrometastasis.
Depleting copper may prevent breast cancer relapse by disrupting the function of endothelial progenitor cells within the tumor microenvironment needed to convert micrometastases to macrometastases. A side effect of low copper levels is mild anemia, which can be used as an inexpensive biomarker for this type of treatment, said Merajver.
Although copper is a necessary element, treatment with tetrathiomolybdate does not affect the function of normal cells. “Decreasing copper by 80% turns out to be fine to maintain the normal, housekeeping functions of normal cells,” Merajver told Cancer Network. “But this level is not enough for very active angiogenesis required by tumors. The new blood vessel growth required for tumor progression is inhibited when copper is within this low level. This is the window of opportunity that this copper chelation affords.”