A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer
According to the authors, this may be the first study to describe an attempt to potentially alter the tumor microenvironment to remove critical components of the metastatic cascade necessary for tumor progression in patients with breast cancer at a high risk of relapse.
Patients with stage II triple-negative breast cancer, stage III and stage IV without any evidence of disease underwent copper depletion with oral tetrathiomolybdate for 2 years or until relapse. The entire cohort received standard chemotherapy either in the adjuvant or metastatic setting prior to enrolling in the study.
Of the 75 patients enrolled, 51 patients completed 2 years (1,396 cycles) of oral prevention. Two-year event-free survival rates for patients with stage II–III and stage IV without any evidence of disease were 91% and 67%, respectively. For patients with triple-negative breast cancer, event-free survival was 90% (in adjuvant patients) and 50% (in stage IV without any evidence of disease patients), at a median follow-up of 6.3 years, respectively.
The most common grade 3/4 toxicity was neutropenia (3.7%).
Overall, with a median follow-up of 6.3 years, the event-free survival and overall survival rates for the entire cohort were 72% and 84%, respectively. At 2 years, the event-free survival and overall survival for patients with stages II and III breast cancer were 91% and 96%, respectively. The event-free survival and overall survival for the patients with stage IV without any evidence of disease was 67% and 93%, respectively. Outcomes did not differ significantly between triple-negative and non–triple-negative patients. The time to relapse for patients with adjuvant triple-negative breast cancer was similar to those with non–triple-negative disease (P = .814). The 2-year event-free survival for stages II or III triple-negative breast cancer is 90% and 69% for those who have stage IV without any evidence of disease. With prolonged follow-up, recurrences are rare after 2 years.
Copper has emerged as an essential component of the metastatic process, and multiple preclinical studies have demonstrated that copper depletion decreases the proliferation, blood vessel formation, tumor growth, and motility. Infrastructure that is critical for tumor progression, perhaps most relevant in triple-negative breast cancer, appears to have been markedly reduced using a copper-depletion strategy that targets copper-dependent processes.
Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in patients at high risk for recurrent breast cancer are warranted. Translational studies are underway to understand these clinical observations and identify those patients who are potentially best suited to this strategy.