Gaykema, S. B. M., Schroder, C. P., Vitfell-Rasmussen, J., Chua, S., Munnink, T. H. O., Brouwers, A. H., Bongaerts, A. H. H., Akimov, M., Fernandez-Ibarra, C., Lub-de Hooge, M. N., de Vries, E. G. E., Swanton, C., Banerji, U. (2014) Zr-89-trastuzumab and Zr-89-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients. CLINICAL CANCER RESEARCH, 20 (15). pp. 3945-3954. ISSN 1078-0432

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Abstract

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.

Item Type:	Article
Authors (ICR Faculty only):	Banerji, udai
All Authors:	Gaykema, S. B. M., Schroder, C. P., Vitfell-Rasmussen, J., Chua, S., Munnink, T. H. O., Brouwers, A. H., Bongaerts, A. H. H., Akimov, M., Fernandez-Ibarra, C., Lub-de Hooge, M. N., de Vries, E. G. E., Swanton, C., Banerji, U.
Additional Information:	ISI Document Delivery No.: AM9DF Times Cited: 0 Cited Reference Count: 41 Gaykema, Sietske B. M. Schroder, Carolien P. Vitfell-Rasmussen, Joanna Chua, Sue Munnink, Thijs H. Oude Brouwers, Adrienne H. Bongaerts, Alfons H. H. Akimov, Mikhail Fernandez-Ibarra, Cristina Lub-de Hooge, Marjolijn N. de Vries, Elisabeth G. E. Swanton, Charles Banerji, Udai Novartis; American Women's Club of the Hague [KP565404]; Dutch Cancer Society [RUG 2007-3739, RUG 2009-4273]; Institute of Cancer Research/The Royal Marsden NHS Foundation Trust; Breast Cancer Research Foundation; Experimental Cancer Medicine Centre grants [C51/A7401/C12540/A15573]; Cancer Research UK grants [C309/A8274/A309/A11566, C51/A6883]; NIHR Biomedical Research Centre This work was supported by Novartis, The American Women's Club of the Hague KP565404 (2008), and grants RUG 2007-3739 and RUG 2009-4273 of the Dutch Cancer Society. The UK investigators acknowledge infrastructural grants, including NIHR grants to The Institute of Cancer Research/The Royal Marsden NHS Foundation Trust, the Breast Cancer Research Foundation, Experimental Cancer Medicine Centre grants (C51/A7401/C12540/A15573), infrastructural grant support of Cancer Research UK grants (C309/A8274/A309/A11566; C51/A6883), and NIHR Biomedical Research Centre funding. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	in-situ hybridization tumor response solid tumors fdg-pet therapy growth heat-shock-protein-90 xenograft heterogeneity trastuzumab
Research teams:	ICR divisions > Cancer Therapeutics > Medicine (Banerji Drug Evaluation PD Group) ICR divisions > Clinical Studies > Medicine (Banerji Drug Evaluation PD Group)
Depositing User:	Alexander Smithson
Date Deposited:	08 Sep 2014 14:10
Last Modified:	08 Sep 2014 14:10
URI:	http://publications.icr.ac.uk/id/eprint/13488

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