89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

Purpose: 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 Zr-89-trastuzumab PET (for HER2-positive breast cancer) or Zr-89-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. Experimental Design: 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[F-18] fluoro-2-deoxy-D-glucose (FDG), Zr-89-trastuzumab, or Zr-89-bevacizumab. Response evaluation was performed according to RECIST1.0. FDG, Zr-89-trastuzumab, and Zr-89-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. Results: 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 Zr-89-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 Zr-89-bevacizumab PET and FDG-PET was not correlated with CT response. Conclusions: NVP-AUY922 showed proof-of-concept clinical response in HER2-amplified metastatic breast cancer. Early change on Zr-89-trastuzumab PET was positively associated with change in size of individual lesions assessed by CT. (C) 2014 AACR.