title: Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib.
abstract: OBJECTIVE
  To investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib.
  
  
  METHODS
  Gefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included -191C>A, -216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment.
  
  
  RESULTS
  The analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the -216 GG (n=51), GT (n=41) and TT (n=16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p=0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p=0.004, dominant model). The -191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR -216 and -191 polymorphisms were in linkage disequilibrium (D'=0.66, p=0.01). The haplotype (-191C, -216T) was associated with increased risk for rash (p=0.049), but was not more predictive of rash than the single -216 polymorphism.
  
  
  CONCLUSIONS
  These findings indicate that EGFR -216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.
authors.affiliation: Department of Clinical Pharmacy, University of Tennessee, Memphis, TN, United States.
authors.forename: Trevor
authors.initials: T
authors.lastname: McKibbin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Michael
authors.initials: M
authors.lastname: Tagen
authors.forename: Najat C
authors.initials: NC
authors.lastname: Daw
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGregor
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Allen
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003967:Diarrhea / Q000139:chemically induced; D003875:Drug Eruptions / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005076:Exanthema / Q000139:chemically induced; D000077156:Gefitinib; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000009:adverse effects*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib