title: ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression.
abstract: We investigated the correlation between metabolic response by (18)F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy.
  
  
  METHODS
  (18)F-FDG PET was performed at baseline, 1-7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery.
  
  
  RESULTS
  (18)F-FDG PET showed high baseline tumor glycolytic activity (mean SUV(max), 14.2; range, 1.3-53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, -0.5-47.7, P < 0.001, n = 44), and again before surgery (mean, 3.0; range, -0.5-36.1, P < 0.001, n = 40). At week 1, there were 3 patients with complete metabolic response (CMR), 33 with partial metabolic response (PMR), 6 with stable metabolic disease (SMD), and 2 with progressive metabolic disease (PMD). Before surgery, there were 3 with CMR, 33 with PMR, 4 with SMD, and none with PMD. The best response according to RECIST was 2 with partial response, 36 with stable disease, and 1 with progressive disease (n = 39). Of the patients with a posttreatment decrease in GLUT4 expression, 1 had CMR, 15 had PMR, 2 had SMD, and 1 had PMD at week 1, whereas before surgery 1 patient had CMR, 16 had PMR, 2 had SMD, and none had PMD. Among 27 patients with KIT exon 11 mutations, 1 had CMR, 22 had PMR, 3 had SMD, and 1 had PMD at week 1, whereas 1 had CMR, 22 had PMR, 2 had SMD, and 2 were unknown before surgery; among 4 patients with a wild-type genotype, 2 had PMR and 2 SMD at week 1, whereas 1 had CMR, 2 had PMR, and 1 had SMD before surgery.
  
  
  CONCLUSIONS
  After imatinib mesylate initiation, metabolic response by (18)F-FDG PET was documented earlier (1-7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in (18)F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1-7 in patients with exon 11 mutations.
authors.affiliation: Department of Imaging, Dana-Farber Cancer Institute, Boston, MA 02115, USA. abbeele@dfci.harvard.edu
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Constantine
authors.initials: C
authors.lastname: Gatsonis
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: de Vries
authors.forename: Yulia
authors.initials: Y
authors.lastname: Melenevsky
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szot-Barnes
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Lori
authors.initials: L
authors.lastname: Rink
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Meridith
authors.initials: M
authors.lastname: Blevins
authors.forename: Jorean
authors.initials: J
authors.lastname: Sicks
authors.forename: Burton
authors.initials: B
authors.lastname: Eisenberg
authors.forename: Barry A
authors.initials: BA
authors.lastname: Siegel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D001692:Biological Transport; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D046152:Gastrointestinal Stromal Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000379:methods*; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D051275:Glucose Transporter Type 4; D010879:Piperazines; D011743:Pyrimidines; D019788:Fluorodeoxyglucose F18; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit