title: Monitoring afatinib treatment in HER2-positive gastric cancer with 18F-FDG and 89Zr-trastuzumab PET.
abstract: We evaluated the ability of the PET imaging agent (89)Zr-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib.
  
  
  METHODS
  Using (89)Zr-trastuzumab, (18)F-FDG, or 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using (89)Zr-trastuzumab and (18)F-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies.
  
  
  RESULTS
  Although (18)F-FDG uptake in NCI-N87 tumors did not change, a decrease in (89)Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 ± 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 ± 3.4 %ID/g, respectively; P < 0.05). (89)Zr-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment.
  
  
  CONCLUSIONS
  Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. (89)Zr-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib.
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. janjigiy@mskcc.org
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.forename: Nerissa
authors.initials: N
authors.lastname: Viola-Villegas
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.forename: Vadim
authors.initials: V
authors.lastname: Divilov
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.forename: Erica M
authors.initials: EM
authors.lastname: Gomes-DaGama
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Gregory
authors.initials: G
authors.lastname: Carbonetti
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000077716:Afatinib; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019788:Fluorodeoxyglucose F18; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011854:Radiochemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D061067:Antibodies, Monoclonal, Humanized; D019788:Fluorodeoxyglucose F18; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C571668:zirconium-89-trastuzumab; C508053:ERBB2 protein, human
keywords: 18F-FDG; 89Zr-trastuzumab; HER2; afatinib; gastric cancer