title: Genetic Variations of Drug Transporters Can Influence on Drug Response in Patients Treated with Docetaxel Chemotherapy.
abstract: OBJECTIVE
  Dose-limiting toxicities of docetaxel are widely considered to be neutropenia, anemia, skin toxicity, and nausea. One of the factors that limit the use of docetaxel is its unpredictability of inter-individual variation in toxicity.
  
  
  METHODS
  In order to identify the genetic factors that affect the risk of docetaxel-induced toxicities, we recruited patients who received docetaxel chemotherapy. We genotyped 92 patients with single-nucleotide polymorphisms (SNPs) in 5 genes: CYP3A4 (CYP3A4(*)1B, CYP3A4(*)18, and CYP3A4(*)3), CYP3A5 (CYP3A5(*)2 and CYP3A5(*)3), ABCB1 (C1236T, G2677G/T, and C3435T), SLCO1B3 (rs11045585), and ABCC2 (rs12762549).
  
  
  RESULTS
  Out of 92 patients, 70 had grade 3 or 4 neutropenia; 4 had grade 1 or 2; and 18 had no toxicity (76.1%, 4.3%, and 19.6%, respectively). The findings of the SNP analysis showed that patients with TT genotype of ABCB1 3435C>T polymorphism showed significantly higher risk of neutropenia and anemia (p=0.029 and p=0.044, respectively). There were significant associations between docetaxel-induced leucopenia and 2677G/T of ABCB1 and rs12762549 of ABCC2 (p=0.025 and p=0.028, respectively). In a multivariate analysis, we observed that patients carrying 2677G>T in ABCB1might be associated with higher risk of chemo-resistance when treated with docetaxel (odds ratio [OR], 6.48; confidence interval, 1.92 to 21.94; p=0.003). In a subgroup analysis of non-small cell lung cancer patients, a significant association of tumor response with G2677T/A (OR, 4.54) in ABCB1 and SLCO1B3 (OR, 9.44) was observed.
  
  
  CONCLUSIONS
  Our data suggest that ABCB1 (2677G/T) and SLCO1B3 (rs11055585) might be major genetic predictors of docetaxel-related toxicities in patients receiving docetaxel chemotherapy.
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.
authors: Jung Ran
authors: JR
authors: Choi
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.
authors: Jeong-Oh
authors: JO
authors: Kim
authors: Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea.
authors: Dae Ryong
authors: DR
authors: Kang
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.
authors: Jung-Young
authors: JY
authors: Shin
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.
authors: Xiang Hua
authors: XH
authors: Zhang
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.
authors: Ji Eun
authors: JE
authors: Oh
authors: Department of Clinical Pharmacology and Toxicology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
authors: Ji-Young
authors: JY
authors: Park
authors: Department of Clinical Pharmacology and Toxicology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
authors: Kyoung-Ah
authors: KA
authors: Kim
authors: Laboratory of Medical Oncology, Research Institutes of Medical Oncology, The Catholic University of Korea, Seoul, Korea.|Department of Medical Oncology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors: Jin-Hyoung
authors: JH
authors: Kang
keywords: Docetaxel; Genetic predictor; Single nucleotide polymorphism; Tumor response
references: Pharmacogenetics. 1998 Oct;8(5):391-401
references: 9825831
references: Clin Cancer Res. 2006 Oct 1;12(19):5786-93
references: 17020985
references: Adv Drug Deliv Rev. 2002 Nov 18;54(10):1271-94
references: 12406645
references: Clin Pharmacol Ther. 2009 Feb;85(2):155-63
references: 18509327
references: Lung Cancer. 2011 Dec;74(3):364-8
references: 21893363
references: Oncologist. 2014 Apr;19(4):352-3
references: 24682465
references: Clin Pharmacol Ther. 2006 Jun;79(6):570-80
references: 16765145
references: Clin Chim Acta. 2007 Aug;383(1-2):172-4
references: 17582393
references: Int J Cancer. 2002 Jan 1;97(1):129-32
references: 11774254
references: J Hum Genet. 2009 Oct;54(10):564-71
references: 19696793
references: Pharmacogenetics. 2001 Mar;11(2):175-84
references: 11266082
references: Clin Cancer Res. 2000 Jul;6(7):2598-603
references: 10914699
references: J Clin Invest. 1998 Sep 1;102(5):1016-23
references: 9727070
references: Drug Resist Updat. 2008 Jun;11(3):77-98
references: 18486526
references: Pharmacol Ther. 2006 Nov;112(2):457-73
references: 16766035
references: Cancer Biol Ther. 2005 Aug;4(8):815-8
references: 16210916
references: OMICS. 2013 Jul;17(7):353-67
references: 23758476
references: Cancer Chemother Pharmacol. 2011 Jun;67(6):1471-8
references: 21468756
references: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8
references: 10716719
references: Cancer Sci. 2008 May;99(5):967-72
references: 18294295
references: Br J Clin Pharmacol. 2012 Apr;73(4):606-18
references: 21995462
references: Cancer Lett. 2006 Mar 8;234(1):40-50
references: 16377077
references: Adv Ther. 2012 Jan;29(1):71-7
references: 22161550
references: N Engl J Med. 2003 Feb 6;348(6):538-49
references: 12571262