title: Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib.
abstract: BACKGROUND
  The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide.
  
  
  METHODS
  Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran-Mantel-Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided.
  
  
  RESULTS
  Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P < .001). The level of phosphorylated PKB/Akt was also associated with time to progression (P < .001).
  
  
  CONCLUSIONS
  Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.
authors.affiliation: Department of Neurosurgery, Brain Tumor Research Center, University of California-San Francisco, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143, USA. hkogan@radonc17.ucsf.edu
authors.forename: Daphne A
authors.initials: DA
authors.lastname: Haas-Kogan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.forename: Nannette
authors.initials: N
authors.lastname: Jelluma
authors.forename: Nils D
authors.initials: ND
authors.lastname: Arvold
authors.forename: Rachel
authors.initials: R
authors.lastname: Baumber
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: Ami
authors.initials: A
authors.lastname: Kapadia
authors.forename: Mary
authors.initials: M
authors.lastname: Malec
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000077204:Temozolomide