title: Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor.
abstract: OBJECTIVE
  Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients.
  
  
  METHODS
  A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes.
  
  
  RESULTS
  With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance.
  
  
  CONCLUSIONS
  The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.
authors.affiliation: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
authors.forename: Dong-Hoe
authors.initials: DH
authors.lastname: Koo
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Ryu
authors.forename: Baek-Yeol
authors.initials: BY
authors.lastname: Ryoo
authors.forename: Mo Youl
authors.initials: MY
authors.lastname: Beck
authors.forename: Young-Soon
authors.initials: YS
authors.lastname: Na
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Sang Seop
authors.initials: SS
authors.lastname: Lee
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D056910:Republic of Korea; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate