title: Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy.
abstract: BACKGROUND
  In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy.
  
  
  METHODS
  Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib.
  
  
  CONCLUSIONS
  In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.
authors.affiliation: Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyndespierre@gmail.com.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Despierre
authors.affiliation: Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Anderson
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Corneel
authors.initials: C
authors.lastname: Coens
authors.affiliation: Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Università di Torino, Turin, Italy.
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.|Vesalius Research Center (VRC), VIB, Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Academic Division of Gynecological Oncology, Mauriziano Hospital, Turin, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ferrero
authors.affiliation: Département d'Oncologie Médicale Adulte, Centre Leon Bérard, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
authors.affiliation: Hospital Universitario Clínico San Carlos, Servicio de Oncologia Medica, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Casado
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.|Vesalius Research Center (VRC), VIB, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D011494:Protein Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors