Background: Metals have emerged as a viable therapeutic target for a new generation of anti-cancer and anti-metastatic agents. Copper, an essential trace element, serves as an important catalytic cofactor in several biological functions and has emerged as an essential factor in carcinogenesis. Among other elements, bone marrow derived VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key elements in tumor progression. We hypothesized tetrathiomolybdate (TM)-associated copper depletion (CD) inhibits tumor metastases by reducing the number of EPCs and other copper dependent processes in the pre-metastatic niche. These results are an update of our previously reported study (Chan N, Willis A, Kornhauser N et al. Influencing the Tumor Microenvironment: Phase 2 Study of Copper Depletion with Tetrathiomolybdate in High Risk Breast Cancer and Preclinical Models of Lung Metastases. Clin Cancer Res. October 21, 2016) with longer follow-up.

Methods: A single arm phase II study of breast cancer (BC) patients (pts) at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. TM was given to maintain ceruloplasmin (Cp) levels between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was a change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels.

Results: Seventy-five pts received 2778 cycles of TM on the primary and extension study. The primary study treatment duration was 24 cycles (each cycle is 28 days) plus an extension phase. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. Forty-eight percent of pts are TNBC and 40% of pts are stage 4 NED. Median Cp levels were monitored with each cycle. A decrease from 28 to 16 (p<0.0001) was seen after one cycle. Interestingly, TNBC pts seemed to have a greater decrease from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (2.3%), febrile neutropenia (0.04%), fatigue (0.2%). Five-year analysis showed a decrease in EPC's (p=0.004) and LOXL-2 (p<0.001). At a median follow-up of 7.1 years, the EFS for 75 pts is 71.4%. The EFS for 36 pts with TNBC is 71.7%. EFS for stage 2/3 TNBC is 83% and for stage IV TNBC is 59.3%.

Conclusions: TM is safe, well tolerated and appears to affect multiple components of the tumor microenvironment that have been identified in pre-clinical models as important for progression. Ongoing studies in banked specimens are underway to further delineate its effect on copper dependent processes necessary for metastases. Randomized trials are warranted, especially in patients who are at high risk for relapse such as those with TNBC.

Citation Format: Sahota S, Willis A, Kornhauser N, Ward M, Cobham M, Cigler T, Moore A, Andreopoulou E, Fitzpatrick V, Schneider S, Prima N, Wiener A, Ko D, De Laurentiis A, Warren JD, Rubinchik A, Mittal V, Vahdat LT. A phase II study of copper-depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence: Updated results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-02.