title: Correlation of aldo-ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients.
abstract: OBJECTIVE
  Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.
  
  
  METHODS
  We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics.
  
  
  RESULTS
  Two previously reported AKR1C3 intronic variants, IVS4-212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4-212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 10(9) vs. 3.85 ± 3.42 × 10(9) l(-1) , P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 10(9) vs. 1.56 ± 2.80 × 10(9) l(-1) , P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2-55.8) vs. 31.0 (95% confidence interval 20.7-41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3-70.5) vs. 46.3 (95% confidence interval 35.1-57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4-212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration-time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4-212 C<G genotype remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators.
  
  
  CONCLUSIONS
  The AKR1C3 IVS4-212 GG genotype was associated with greater haematological toxicity and longer progression-free survival and overall survival after doxorubicin-based therapy, suggesting potential interaction of this variant with doxorubicin metabolism.
authors.affiliation: Department of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
authors.forename: Pei Jye
authors.initials: PJ
authors.lastname: Voon
authors.forename: Hui Ling
authors.initials: HL
authors.lastname: Yap
authors.forename: Cho-Yee-Thu
authors.initials: CY
authors.lastname: Ma
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.forename: Andrea L A
authors.initials: AL
authors.lastname: Wong
authors.forename: Nur Sabrina
authors.initials: NS
authors.lastname: Sapari
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.forename: Thomas I P
authors.initials: TI
authors.lastname: Soh
authors.forename: Boon-Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: How-Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000493:pharmacokinetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D027701:Organic Cation Transport Proteins / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D027701:Organic Cation Transport Proteins; C467737:SLC22A16 protein, human; D004317:Doxorubicin; D015096:3-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; D006911:Hydroxyprostaglandin Dehydrogenases; C531130:CBR3 protein, human; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3