Correlation of aldo-ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients
Article first published online: 20 MAY 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 6, pages 1497–1505, June 2013
How to Cite
Voon, P. J., Yap, H. L., Ma, C.-Y.-T., Lu, F., Wong, A. L. A., Sapari, N. S., Soong, R., Soh, T. I. P., Goh, B.-C., Lee, H.-S. and Lee, S.-C. (2013), Correlation of aldo-ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients. British Journal of Clinical Pharmacology, 75: 1497–1505. doi: 10.1111/bcp.12021
- Issue published online: 20 MAY 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 1 NOV 2012 06:40AM EST
- Manuscript Accepted: 26 OCT 2012
- Manuscript Received: 22 JUL 2012
- National Medical Research Council, Singapore. Grant Numbers: NMRC/CSI/0009/2006, NMRC/CSI/0015/2009, NMRC/CG/NCIS/2010
- Cancer Science Institute Singapore. Grant Number: R-713-001-011–271
- ClinicalTrials.gov. Grant Numbers: NCT00212082, NCT00669773
- aldo-ketoreductase (AKR)1C3;
- ATP-binding cassette (ABCB)1;
- carbonyl reductase (CBR)3;
- solute carrier family (SLC)22A16
Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.
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.
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 × 109 vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109 vs. 1.56 ± 2.80 × 109 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.
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.