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

Autor: Veronica Fitzpatrick, Linda T. Vahdat, Naomi Kornhauser, Anne Moore, Cecilie L. Bager, JD Warren, Eleni Andreopoulou, Tessa Cigler, Maureen M. Ward, YL Liu, M Cobham, D. Lapolla, Nicholas Willumsen, Vivek Mittal
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research. 79:PD9-07
ISSN: 1538-7445
0008-5472
Popis: 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 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.
Databáze: OpenAIRE
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