title: Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3.
abstract: BACKGROUND
  National Cancer Institute of Canada Clinical Trials Group PA.3 (NCIC CTG PA.3) was a phase 3 study (n = 569) that demonstrated benefits for overall survival and progression-free survival with the addition of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib to gemcitabine in patients with advanced pancreatic carcinoma (APC). Mutation status of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and EGFR gene copy number (GCN) were evaluated as predictive markers in 26% of patients who had tumor samples available for analysis.
  
  
  METHODS
  KRAS mutation status was evaluated by direct sequencing of exon 2, and EGFR GCN was determined by fluorescence in situ hybridization (FISH) analysis. The results were correlated with survival, which was the primary endpoint of the trial.
  
  
  RESULTS
  KRAS analysis was successful in 117 patients, and EGFR FISH analysis was successful in 107 patients. KRAS mutations were identified in 92 patients (78.6%), and EGFR amplification or high polysomy (FISH-positive results) was identified in 50 patients (46.7%). The hazard ratio of death between gemcitabine/erlotinib and gemcitabine/placebo was 0.66 (95% confidence interval [CI], 0.28-1.57) for patients with wild-type KRAS and 1.07 (95% CI, 0.68-1.66) for patients with mutant KRAS (P value for interaction = .38), and the hazard ratio was 0.6 (95% CI, 0.34-1.07) for FISH-negative patients and 0.90 (95% CI, 0.49-1.65) for FISH-positive patients (P value for interaction = .32).
  
  
  CONCLUSIONS
  In a molecular subset analysis of patients from NCIC CTG PA.3, EGFR GCN and KRAS mutation status were not identified as markers predictive of a survival benefit from the combination of erlotinib with gemcitabine for the first-line treatment of APC.
authors.affiliation: Department of Pathology, University Health Network, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Gilda
authors.initials: G
authors.lastname: da Cunha Santos
authors.forename: Neesha
authors.initials: N
authors.lastname: Dhani
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Kayu
authors.initials: K
authors.lastname: Chin
authors.forename: Olga
authors.initials: O
authors.lastname: Ludkovski
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Wendy
authors.initials: W
authors.lastname: Parulekar
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
authors.forename: Ming Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000032:analysis*; D002170:Canada; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D018628:Gene Dosage; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage*; D016896:Treatment Outcome; D018631:ras Proteins / Q000032:analysis / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000093542:Gemcitabine