title: Impact of ABCG2 polymorphisms on the clinical outcome and toxicity of gefitinib in non-small-cell lung cancer patients.
abstract: OBJECTIVE
  The current study investigates whether or not functional polymorphisms in the ATP-binding cassette transporter gene ABCG2 might affect gefitinib activity and/or toxicity in non-small-cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Towards this end, ABCG2 polymorphisms and expression were assessed in DNA and tumors from 94 NSCLC patients treated with gefitinib, whereas their associations with toxicity/response and time-to-progression/overall survival were evaluated using Pearson-χ(2) and log-rank-test, respectively.
  
  
  RESULTS
  Patients carrying an ABCG2 -15622T/T genotype or harboring at least one TT copy in the ABCG2 (1143C/T, -15622C/T) haplotype developed significantly more grade 2/3 diarrhea (p < 0.01). No associations were found between polymorphisms and outcome. Consistently, ABCG2 protein levels in tumors were not significantly different between patients harboring different ABCG2 variants.
  
  
  CONCLUSIONS
  The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a gefitinib-dependent, moderate-to-severe diarrhea suggesting that these pharmacogenetic markers should be considered to optimize NSCLC treatment.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
authors.forename: Clara
authors.initials: C
authors.lastname: Lemos
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Zucali
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Tahar
authors.initials: T
authors.lastname: van der Straaten
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced* / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D057285:Precision Medicine; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D000077156:Gefitinib