Early trial findings suggest that copper depletion may promote tumor dormancy in patients at high risk for recurrent breast cancer.
The phase II study indicates that treatment with the anti-angiogenic copper chelator tetrathiomolybdate (TM) reduced the number of bone marrow-derived endothelial progenitor cells (EPCs) in women with triple-negative breast cancer, and thus halted recurrence.
EPCs are essential for activation of the angiogenic switch that enables progression from micrometastases to macrometastases, explain Linda Vahdat (Weill Cornell Medical College, New York, USA) and co-authors in the Annals of Oncology.
The team enrolled patients with stage 3 or 4 breast cancer with no evidence of disease (NED; n=28) or stage 2/3 triple-negative disease (n=12), all of whom had a 60% or greater 10-year risk for recurrence. Patients were given TM 100 mg/day to achieve a level of the copper-carrying enzyme ceruloplasmin (Cp) below 17 mg/dL for 2 years or until relapse.
Overall, 75% of patients achieved copper depletion within 1 month of treatment, but success differed between patients with luminal breast cancer subtype and triple-negative patients (41 vs 91%).
Patients with triple-negative, HER2-positive, or stage 4 NED had significantly higher EPC value at baseline than luminal stage 3 patients.
From an average baseline EPC level of 39 cells/mL, copper-depleted patients achieved a significant 27-EPC/mL reduction, whereas average EPC/mL increased by 61 in nondepleted patients. Decrease in EPC from baseline was strongest in triple-negative patients, and was significantly associated with Cp level, TM dosage, and use of non-tamoxifen hormone therapy and proton pump inhibitors.
EPC levels increased in patients with rising Cp, Vahdat et al emphasize.
Six (15%) patients relapsed in the first 12 months of TM treatment. This included three patients with stage 3 disease, one of whom had triple-negative disease, and three stage 4 NED patients, including one triple-negative, one HER2-positive, and one luminal cancer patient.
Therefore, just two of the 11 triple-negative patients relapsed during the study, one of whom did not achieve copper depletion. The remaining patient experienced recurrence within 2 months of treatment, "suggesting that active neoangiogenesis was occurring at the time of enrollment, which could not be halted due to delayed effects of copper depletion," the researchers say.
"We are cautiously optimistic about the low incidence of relapse and have extended the study to 6 years in selected patients."
They add that two patients with stage 4 NED triple-negative disease have remained free from recurrence at 49 and 65 months of TM treatment, which the team says is "encouraging given the dismal median survival of 9 months in metastatic triple-negative patients."
Commenting in a press release, Vahdat hoped to begin a phase III trial shortly: "As good as these interim findings look to us, we cannot talk about significant benefit until we compare TM treatment to other therapies."
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