Abstract PD9-07: A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with high risk breast cancer (BC): Role of collagen processing and tumor microenvironment
Authors: Liu YL , Bager CL , Willumsen N , Kornhauser N , Cobham M , Andreopoulou E , Cigler T , Moore A , LaPolla D , Fitzpatrick V , Ward M , Warren JD , Mittal V , Vahdat LT 
Published: May 2019

Abstract
Background: Copper is an important catalytic cofactor in several biological functions and is essential for lysyl oxidase (LOX), a key enzyme in cross-linking collagen, which may play a role in tumor metastasis. We hypothesized that tetrathiomolybdate (TM)-associated copper depletion (CD) would inhibit tumor metastases by altering copper dependent collagen remodeling in the pre-metastatic niche. These results are an update of our previously reported clinical outcomes with longer follow-up and translational outcomes implicating the tumor microenvironment in metastatic transformation of BC. Methods: Pts at high risk for recurrence, node+ triple negative (TNBC) or stage 3/4 BC with no evidence of disease (NED), were enrolled on a phase II study of CD with TM. TM was given to maintain ceruloplasmin (Cp) levels between 8-16 mg/dl for two years (yrs) with an extension phase or until relapse. Median Cp levels were monitored with each cycle. Clinical endpoints included safety/tolerability and progression of disease (POD)/death. Event-free (EFS) and overall survival (OS) were calculated using Kaplan Meier survival analyses. Translational endpoints included markers of collagen cross-linking (LOXL-2), formation (PRO-C3), and degradation (C1M and C6M). Results: Seventy-five pts received 2993 cycles of TM on the primary (24 cycles, 28 days per cycle) and extension study. Median age was 51 yrs (range 29-66). Forty-five pts had stage 2/3 BC, and 30 pts were stage 4 NED. At a median follow-up of 8.4 yrs, the overall EFS was 71.4% and OS was 78.8%. The EFS and OS for the 36 pts with TNBC were 71.7% and 81%, and the EFS and OS for the 39 pts with Luminal/HER2+ BC were 71.2% and 78.6% respectively. TM was well tolerated with grade 3/4 toxicities including: neutropenia (1.9%), febrile neutropenia (0.03%), and fatigue (0.2%). LOXL2 levels were significantly decreased at 12 and 24 cycles compared with baseline (p&lt;0.01) in those who were NED but not in those who had progressive disease (POD). LOXL2 levels were significantly correlated with C1M levels (spearman coefficient -0.34, p=0.02). C1M levels were significantly increased at 5, 11 and 24 cycles as compared with baseline (p&lt;0.01) in those who were NED and were significantly higher as compared to levels in those experiencing POD/death, p&lt;0.05. This difference may be more pronounced in those not achieving adequate CD (&lt;50%) and in luminal/HER2+ BC. Interestingly, the ratio of C1M/PRO-C3 was significantly more elevated over time in those NED as compared to those experiencing POD/death. No associations were found with other collagen markers (PRO-C3 and C6M). Conclusions: TM is safe, well-tolerated and associated with decreased LOXL-2 and increased C1M levels over time in NED pts. This suggests that copper depletion may result in decreased collagen crosslinking and increased collagen degradation over formation, potentially “normalizing” the collagen microenvironment to create an inhospitable environment for tumor metastases. Larger randomized trials in high risk populations with translational outcomes are needed to further investigate the role of collagen processing in the tumor microenvironment and its potential as a biomarker of response.
Citation Format: Liu YL, Bager CL, Willumsen N, Kornhauser N, Cobham M, Andreopoulou E, Cigler T, Moore A, LaPolla D, Fitzpatrick V, Ward M, Warren JD, Mittal V, Vahdat LT. A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with high risk breast cancer (BC): Role of collagen processing and tumor microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-07.