COPPER DEPLETION MAY SLOW CANCER PROGRESSION 

Copper-depleting treatment in patients with a high risk for breast cancer relapse could slow metastasis and promote tumor dormancy, according to a phase-2 single-group study of tetrathiomolybdate (TM), an oral copper chelator.

The results were published online February 13 in the Annals of Oncology.

"Though a randomized clinical trial is necessary to assess survival, efficacy measures were promising," report the researchers, led by Sarika Jain, MD, from the Department of Medicine at Weill Cornell Medical College in New York City.

"We are cautiously optimistic about the low incidence of relapse," they write. Two patients who had stage IV triple-negative breast cancer remain disease-free at 65 and 49 months, which "is encouraging given the dismal median survival of 9 months in metastatic triple-negative patients," they note.

Peter Ravdin, MD, director of the breast health center at the University of Texas Health Science Center in San Antonio, thinks this study is "a promising, very interesting result."

"It is looking at a way of blocking the establishment of metastasis, and that's rather different than most of the other things that we do," he told Medscape Medical News.

"There might be agents that work against the establishment of metastasis but don't work very well against established metastasis.... In this case...they're trying to prevent the metastasis from becoming established in the first place. That's a unique mechanism of action, compared with most of the rest of what is done, and I think it has really interesting implications," he explained.

Although TM looks interesting in animal models, Dr. Ravdin cautioned that "all we have at this point is this modest-size phase 2 study."

Patients at High Risk for Relapse

Copper is an important factor in tumor angiogenesis. Previous studies have shown decreased endothelial cell proliferation, blood vessel formation, and tumor growth with copper depletion, Dr. Jain and colleagues note.

Their open-label single-group study involved 40 women with "an extraordinarily high risk of relapse from occult residual disease," including histologically confirmed stage III disease, stage IV breast cancer with no evidence of disease (NED), and stage II triple-negative breast cancer.

More than 6 weeks after their previous chemotherapy, the patients (median age, 50 years) had no radiographic, biochemical, or physical evidence of recurrence.

Two phases of TM were administered. The first was to induce a target level of serum ceruloplasmin (Cp), a surrogate marker of copper availability; the second was to maintain that level.

During the induction phase, TM 180 mg daily was administered until Cp levels reached a target range of 5 to 16 mg/dL. Serum was tested every 2 weeks for the first month and weekly thereafter until the target was reached.

During the maintenance phase, TM 100 mg daily was administered to maintain the Cp level below 17 mg/dL for 2 years or until relapse. Dosing was reduced or increased in 20 mg increments to control toxic effects, and patients were taken off the study drug if they experienced unacceptable toxicity.

The primary outcome measure was change in the number of endothelial progenitor cells (EPC). Preclinical models of metastatic breast cancer have shown that EPCs mediate an angiogenic switch that changes avascularized micrometastases to vascularized macrometastases, the researchers explain.

Secondary outcome measures were safety, relapse-free survival, change in the number of hematopoietic progenitor cells (HPCs), and levels of plasma angiogenic factors and cytokines.

One of the 40 patients withdrew before the first dose of TM; the remaining 39 completed a total of 426 cycles of therapy (defined as 28 days) in the first year (mean, 10.7 cycles per patient).

There were 12 discontinuations: 6 related to relapse, 3 to toxic events, 2 to patient preference, and 1 was lost to follow-up.

The intention-to-treat analysis showed that 75% of patients reached the target copper-depletion level by 1 month; mean Cp level decreased to 14.2 mg/dL from a baseline level of 29.7 m/dL (P < .0001).

For the primary outcome, "we observed a significant, sustained reduction in EPCs with copper depletion. EPCs did not significantly change in patients unable to achieve or maintain the Cp target," the researchers report.

Specifically, in copper-depleted patients, the mean number of EPCs/mL decreased by 27 from baseline (P =.04); in patients not copper-depleted, the mean number of EPCs/mL increased by 61 EPCs/mL (P = .95).

"Copper depletion may inhibit the production, release, or mobilization of EPCs from the bone marrow, leading to a suppressed angiogenic switch and tumor dormancy," the researchers suggest.

The effect of copper depletion on HPCs and circulating markers of angiogenesis was not significant. However "our previous studies showed that HPCs predicted relapse and progression of disease," the researchers write, suggesting that these cells are important, but perhaps earlier in the metastatic cascade.

Overall, TM therapy was well tolerated; the only grade 3 or 4 toxic effects were hematologic (9 women experienced grade 3/4 neutropenia, 5 experienced grade 3 leukopenia, 1 experienced grade 3 anemia, and 1 experienced febrile neutropenia).

The overall 10-month relapse-free survival rate was 85%; however, there were differences between patient subgroups. In particular, the 10-month relapse-free survival was lower in stage IV NED patients than in stage II and III patients (75.0% vs 89.3%), and was lower in triple-negative patients than in luminal patients (81.8% vs 85.7%).

In addition, more triple-negative patients than luminal patients reached target Cp levels (91% vs 41%). "Though the test for interaction was not significant, this study was not powered to show these differential effects," the researchers write.

The association between decreases in Cp and decreases in the number of EPCs was stronger in triple-negative patients. "Angiogenesis-related genes are frequently overexpressed in triple-negative tumors, and antiangiogenic agents may be more effective in this subset," they note.

Only 2 of the 11 triple-negative patients relapsed, they report. "One patient did not adequately copper-deplete despite incremental dose increases. The other patient progressed within 2 months of TM therapy, suggesting that active neoangiogenesis was occurring at the time of enrolment, which could not be halted due to delayed effects of copper depletion," they explain.

The study has been extended to 6 years in selected patients and, "as the evidence accumulates in favor of copper depletion to prevent relapse, a large, randomized, multicenter trial enriched with triple-negative and stage 4 NED patients may be of utility," the researchers write.

The research was supported by the Anne Moore Breast Cancer Research Fund, the Stephen and Madeline Anbinder Foundation, the Rozaliya Kosmandel Research Fund, the Susan G. Komen for the Cure, the New York Community Trust, the Cancer Research and Treatment Fund, and the Berman Fund. Coauthor S.M. Hurtado Rúa, PhD, from Weill Cornell Medical College, was partially supported by the grant from the Clinical Translational Science Center. Dr. Ravdin have disclosed no relevant financial relationships.

Ann Oncol. Published online February 13, 2013. Abstract