Prospective evaluation of the drug-metabolizing enzyme polymorphisms and toxicity profile of docetaxel in Korean patients with operable lymph node-positive breast cancer receiving adjuvant chemotherapy

Cancer Chemother Pharmacol. 2012 May;69(5):1221-7. doi: 10.1007/s00280-011-1816-4. Epub 2012 Jan 20.

Abstract

Background: Inter-individual variability of pharmacokinetics may account for unpredictable toxicities of docetaxel.

Methods: From March 2007 to June 2008, female patients with operable lymph node-positive breast cancer receiving docetaxel-containing adjuvant chemotherapy were included in this study. The 4 cycles of planned dose of docetaxel (100 mg/m(2)) was performed as adjuvant chemotherapy, following 4 cycles of adriamycin and cyclophosphamide. We evaluated toxicity profile of docetaxel and single nucleotide polymorphisms (SNPs) of CYP3A5 gene, ABCB1 gene, ABCC2 gene and SCLO1B3 gene. Toxicities during treatment of docetaxel were evaluated and defined according to the NCI CTCAE version 3.0.

Results: Pharmacogenetic analysis was performed in 218 Korean women who had received the uniformly planned chemotherapy. With regard to ABCB1 3435 C>T, ABCB1 3435 T/T had significantly higher risks of neutropenia (P = 0.015). Meanwhile, allele frequencies for CYP3A5 6986 G and ABCB1 3435 T revealed a trend for neutropenia (P = 0.107 and 0.068). We could not find any other association between genotypes and other toxicities.

Discussion: Although ABCB1 3435 T/T was significantly associated with docetaxel-related neutropenia in our study population, polymorphism of pharmacogenetic genes related to docetaxel metabolism did not appear to be evidently associated with docetaxel-related adverse events.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • Adult
  • Aged
  • Alleles
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Chemotherapy, Adjuvant / methods
  • Cohort Studies
  • Cyclophosphamide / administration & dosage
  • Cytochrome P-450 CYP3A / genetics
  • Docetaxel
  • Doxorubicin / administration & dosage
  • Female
  • Humans
  • Lymphatic Metastasis
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics
  • Neutropenia / chemically induced*
  • Neutropenia / epidemiology
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Republic of Korea
  • Retrospective Studies
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids / administration & dosage

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Taxoids
  • Docetaxel
  • multidrug resistance-associated protein 2
  • Doxorubicin
  • Cyclophosphamide
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A