title: Pharmacogenetic analysis of advanced non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin chemotherapy.
abstract: BACKGROUND
  Genetic polymorphisms contribute toward interindividual variations in drug response. We investigated the effects of genetic polymorphisms on the clinical outcome of advanced non-small-cell lung cancer patients with first-line paclitaxel and carboplatin.
  
  
  METHODS
  A total of 194 non-small-cell lung cancer patients were prospectively enrolled from January 2010 to January 2013. We genotyped 11 polymorphisms in seven genes involved in the glycolysis pathway and the related pharmacokinetic/pharmacodynamic pathway. Genetic associations with PET-SUV, survival outcome, and toxicity were analyzed, and in-vitro drug transport activity was measured in the oocyte system.
  
  
  RESULTS
  Patients with the c.334 T>G and c.699 G>A homozygous variant in SLCO1B3 showed a higher incidence of grade 3/4 anemia (P=0.002). Transport activities of oocyte that overexpress the SLCO1B3 c.699 G>A variant showed a significantly decreased uptake of paclitaxel compared with the wild-type expressing oocytes. In addition, patients with GG/GA/AA genotypes of ABCB1, c.2677 T>G/A locus showed inferior progression-free survival (hazard ratio=1.49, P=0.017) compared with other genotypes. The GA genotype of HIF1A, c.1834 G>A locus was associated with inferior progression-free survival compared with the GG genotype (hazard ratio=2.47, P=0.008).
  
  
  CONCLUSIONS
  This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin.
authors.affiliation: aDepartment of Pharmacology and Brain Korea 21 Plus Project for Medical Sciences bDepartment of Internal Medicine, Division of Medical Oncology cDepartment of Nuclear Medicine, College of Medicine, Yonsei University, Seoul dDepartment of Internal Medicine, Division of Medical Oncology, CHA University Bundang Medical Center, Seongnam eDepartment of Pharmacology and PharmacoGenomics Research Center, College of Medicine, Inje University, Busan, Korea.
authors.forename: Hyung Soon
authors.initials: HS
authors.lastname: Park
authors.forename: Sun Min
authors.initials: SM
authors.lastname: Lim
authors.forename: Ho Jung
authors.initials: HJ
authors.lastname: Shin
authors.forename: Arthur
authors.initials: A
authors.lastname: Cho
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016019:Survival Analysis
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016190:Carboplatin; D017239:Paclitaxel