Article date: June 2013
By: Pei Jye Voon, Hui Ling Yap, Cho‐Yee‐Thu Ma, Fan Lu, Andrea L. A. Wong, Nur Sabrina Sapari, Richie Soong, Thomas I. P. Soh, Boon‐Cher Goh, How‐Sung Lee, Soo‐Chin Lee, in Volume 75, Issue 6, pages 1497-1505
Aims
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 × 109vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109vs. 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.
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.
DOI: 10.1111/bcp.12021
View this article