title: Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer.
abstract: BACKGROUND
  BR.21 is a double-blind, placebo-controlled trial of second-/third-line erlotinib in stage IIIB/IV non-small cell lung cancer patients. Predictive and prognostic analyses of epidermal growth factor receptor (EGFR), ABCG2, and AKT1 genetic polymorphisms were performed.
  
  
  METHODS
  Two hundred forty-two patients were genotyped for EGFR-216G>T (EGFR216), EGFR-191C>A (EGFR191), EGFR intron 1 CA-dinucleotide-repeat (CADR), ABCG2+421C>A (ABCG2), and AKT1-SNP4G>A (AKT1). Cox proportional hazard and logistic regression models compared genotypes with overall survival (OS), progression-free survival (PFS), and presence/absence of skin toxicity.
  
  
  RESULTS
  Prognostic evaluation was based on the placebo arm: patients carrying at least one CADR long allele (>16 repeats) had a trend toward worse PFS: the adjusted hazard ratio was 1.7 (95% confidence interval [CI]: 1.0-3.0; p = 0.07). EGFR216, EGFR191, ABCG2, and AKT1 were not prognostic. Polymorphisms were not predictive for erlotinib effect (OS/PFS): no treatment-polymorphism interactions were demonstrated. Individuals carrying the rare T/T genotype of EGFR216 had an adjusted odds ratio of 8.8 (95% CI: 1.1-72; p = 0.04) of developing skin toxicity; no other significant polymorphic relationships with skin toxicity were found.
  
  
  CONCLUSIONS
  In contrast to previous publications, carrying shorter alleles of the EGFR CADR polymorphism was not predictive of OS or PFS. EGFR216 homozygous variants were associated with greater skin toxicity from erlotinib.
authors.affiliation: Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital-University Health Network and University of Toronto, Toronto, Canada. Geoffrey.Liu@uhn.on.ca
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Cheng
authors.forename: K
authors.initials: K
authors.lastname: Ding
authors.forename: A
authors.initials: A
authors.lastname: Le Maitre
authors.forename: N
authors.initials: N
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Patel
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.forename: F A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: M S
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt