Abstract
HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using (89)Zr-trastuzumab PET (for HER2-positive breast cancer) or (89)Zr-bevacizumab PET [for estrogen receptor (ER)-positive breast cancer] to determine in vivo degradation of client proteins caused by the novel HSP90 inhibitor NVP-AUY922. Of note, 70 mg/m(2) NVP-AUY922 was administered intravenously in a weekly schedule to patients with advanced HER2 or ER-positive breast cancer. Biomarker analysis consisted of serial PET imaging with 2[18F]fluoro-2-deoxy-D-glucose (FDG), (89)Zr-trastuzumab, or (89)Zr-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, (89)Zr-trastuzumab, and (89)Zr-bevacizumab distributions were scored visually and quantitatively by calculating the maximum standardized uptake values (SUVmax). In blood samples, serial HSP70 levels, extracellular form of HER2 (HER2-ECD), and pharmacokinetic and pharmacodynamic parameters were measured. Sixteen patients (ten HER2-positive and six ER-positive tumors) were included. One partial response was observed; seven patients showed stable disease. SUVmax change in individual tumor lesions on baseline versus 3 weeks (89)Zr-trastuzumab PET was heterogeneous and related to size change on CT after 8 weeks treatment (r(2) = 0.69; P = 0.006). Tumor response on (89)Zr-bevacizumab PET and FDG-PET was not correlated with CT response. NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on (89)Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT.
Highlights
Metastatic breast cancer remains an incurable disease in the majority of cases, despite advances in systemic treatment that have improved median survival [1, 2]
Change on 89Zr-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT
HSP90 client proteins playing a role in metastatic breast cancer include HER2, the hypoxia-inducible factor-1a (HIF1a), and the estrogen receptor (ER; refs. 4– 6)
Summary
Metastatic breast cancer remains an incurable disease in the majority of cases, despite advances in systemic treatment that have improved median survival [1, 2]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). HSP90 client proteins playing a role in metastatic breast cancer include HER2, the hypoxia-inducible factor-1a (HIF1a), and the estrogen receptor HER2 is a sensitive client protein of HSP90, which can be depleted by HSP90 inhibition with NVP-AUY922 in many different preclinical experiments including breast cancer models [7, 8]. HSP90 is overexpressed in metastatic breast cancer. There are many different reasons for evaluating HSP90 inhibitors in breast cancer. Several HSP90 inhibitors are currently in clinical development. Of the resorcinyclic pyrazole/isoaxazole amide analogues, HSP90 inhibitor NVP-AUY922 is the most potent [8]. NVP-AUY922 is active against HER2-positive as well as HER2-negative human breast cancer cells in vitro and www.aacrjournals.org
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