Correlation of aldo‐ketoreductase (AKR) 1C3 genetic variant with doxorubicin pharmacodynamics in Asian breast cancer patients

Abstract

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 × 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. 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.

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

“…Three ABCB1 SNPs that are in relatively strong linkage disequilibrium (r 2 >0.8) were included in this analysis. These SNPs have been reported to increase systemic doxorubicin clearance [22], potentially explaining the decreased risk of systolic dysfunction in patients. Alternatively, cardiomyocytes are known to express P-gp [23] and cardiac tissue samples of ABCB1 variant carriers have greater P-gp expression [24], suggesting that enhanced doxorubicin efflux within cardiomyocytes may provide the cardioprotective effect.…”

11β-Prostaglandin F2α, a bioactive metabolite catalyzed by AKR1C3, stimulates prostaglandin F receptor and induces slug expression in breast cancer

“…Recently AKR1C3 has been demonstrated to contribute to the acquisition of chemoresistance and radioresistance of carcinoma cells in various human malignancies (Matsunaga et al, 2013;Voon et al, 2013;Veitch et al, 2009;Xie et al, 2013) however the underlying mechanism is not fully elucidated. As AKR1C3 has been recently suggested as a new therapeutic target of castration resistant prostate cancer (Hamid et al, 2012), and development of AKR1C3 inhibitors and clinical studies have been ongoing (Loriot et al, 2014), an understanding of the underlying mechanism may be indispensable in making therapeutic choices.…”

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

“…Finally, SLC22A16, a solute carrier active in anthracyclines transportation, is another proposed contributor in anthracyclines-induced hemato-toxicity (Voon et al, 2013;Faraji et al, 2016). However, this association was not supported by any statistically significant evidence.…”

“…association between ABCB1 variants and hematological toxicity induced by any cytotoxic regimen except for four studies (Kim et al, 2012;Chaturvedi et al, 2013;Voon et al, 2013;Angelini et al, 2017). However, the association found in these studies resulted from the univariate analysis where other genetic or nongenetic variants were not considered.…”

“…CBR1 and CBR3, which encode essential enzymes (i.e., carbonyl reductases) in the metabolic pathway of anthracyclines, have been studied in association with anthracycline cardiotoxicity as shown previously. As hematological toxicity is another significant dose-limiting toxicity for anthracyclines, both genes were also evaluated for association with this adverse event (Fan et al, 2008;Voon et al, 2013). Only one association was detected between CBR3 rs8133052, and low blood counts reported early in the anthracycline course (Fan et al, 2008).…”