title: Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study.
abstract: OBJECTIVE
  This phase II trial assessed the activity and tolerability of a daily oral dose of 500 mg gefitinib (ZD1839, Iressa) in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma, and explored the clinical value of determining the status of the epidermal growth factor receptor (EGFR).
  
  
  METHODS
  Primary measure of efficacy was progression-free survival at 6 months. Mutations in exons 18 to 21 of EGFR and/or immunohistochemical expression of EGFR were evaluated in tumor specimens from patients enrolled in this trial as well as from patients not treated with gefitinib.
  
  
  RESULTS
  Twenty-seven of 30 (90%) patients were eligible and evaluable for analysis of gefitinib efficacy and toxicity. Of these, four survived progression-free >6 months with one objective response (4%). The most commonly observed grade 3 toxicities were dermatologic (15%, 4 of 27) and diarrhea (30%, 8 of 27). Specimens from 26 of 26 or 25 of 26 patients were evaluable for immunohistochemical or mutation analysis, respectively. The response rate for patients with EGFR-positive tumors was 9% (1 of 11). EGFR expression was associated with longer progression-free survival (P = 0.008) and possibly longer survival (P = 0.082). The patient with the only objective response had a mutation in the catalytic domain of the tumor's EGFR (P = 0.04). Among 32 invasive tumors from patients not treated with gefitinib, one exhibited a catalytic domain mutation.
  
  
  CONCLUSIONS
  Gefitinib was well tolerated but had minimal activity in unscreened patients with recurrent ovarian or primary peritoneal carcinoma. Prescreening patients for activating mutations in EGFR may improve response rate to gefitinib. This report is the first to document activating mutations in catalytic domain of EGFR in 3.5% (2 of 57) of ovarian cancers.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. russell.schilder@fccc.edu
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Schilder
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sill
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Darcy
authors.forename: Steven L
authors.initials: SL
authors.lastname: Decesare
authors.forename: George
authors.initials: G
authors.lastname: Lewandowski
authors.forename: Roger B
authors.initials: RB
authors.lastname: Lee
authors.forename: Cletus A
authors.initials: CA
authors.lastname: Arciero
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics*; D005091:Exons; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib