title: 89Zr-trastuzumab and 89Zr-bevacizumab PET to evaluate the effect of the HSP90 inhibitor NVP-AUY922 in metastatic breast cancer patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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 (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Medical Oncology.
authors.forename: Sietske B M
authors.initials: SB
authors.lastname: Gaykema
authors.affiliation: Departments of Medical Oncology, c.p.schroder@umcg.nl.
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
authors.affiliation: Section of Medicine, UK and Drug Development Unit, The Institute of Cancer Research, The Royal Marsden Hospital, Sutton, United Kingdom; and.
authors.forename: Joanna
authors.initials: J
authors.lastname: Vitfell-Rasmussen
authors.affiliation: Section of Medicine, UK and Drug Development Unit, The Institute of Cancer Research, The Royal Marsden Hospital, Sutton, United Kingdom; and.
authors.forename: Sue
authors.initials: S
authors.lastname: Chua
authors.affiliation: Departments of Medical Oncology.
authors.forename: Thijs H
authors.initials: TH
authors.lastname: Oude Munnink
authors.affiliation: Nuclear Medicine and Molecular Imaging.
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Brouwers
authors.affiliation: Radiology and.
authors.forename: Alfons H H
authors.initials: AH
authors.lastname: Bongaerts
authors.affiliation: Novartis Pharma AG, Basel, Switzerland and Novartis Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Akimov
authors.affiliation: Novartis Pharma AG, Basel, Switzerland and Novartis Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fernandez-Ibarra
authors.affiliation: Nuclear Medicine and Molecular Imaging, Hospital and Clinical Pharmacy, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.affiliation: Departments of Medical Oncology.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Section of Medicine, UK and Drug Development Unit, The Institute of Cancer Research, The Royal Marsden Hospital, Sutton, United Kingdom; and.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.affiliation: Section of Medicine, UK and Drug Development Unit, The Institute of Cancer Research, The Royal Marsden Hospital, Sutton, United Kingdom; and.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography / Q000379:methods*; D011379:Prognosis; D011868:Radioisotopes; D012118:Resorcinols / Q000494:pharmacology*; D015040:Zirconium
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D061067:Antibodies, Monoclonal, Humanized; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D011868:Radioisotopes; D012118:Resorcinols; C571668:zirconium-89-trastuzumab; D000068258:Bevacizumab; C580636:89Zr-bevacizumab; D015040:Zirconium