MedWire News: Genetic polymorphisms in the genes encoding cytochrome P450 2D6 (CYP2D6) and the adenosine triphosphate–binding cassette C2 (ABCC2) transporter may be important predictors for the clinical outcome of tamoxifen treatment for patients with breast cancer, researchers report.
“The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms,” explain Yusuke Nakamura (University of Tokyo, Japan) and colleagues.
In the present study, Nakamura and colleagues investigated the effects of allelic variants of CYP2D6 and single nucleotide polymorphisms (SNPs) of three ABC transporter genes (ABCB1, ABCC2, and ABCG2) on recurrence-free survival among 282 women with hormone receptor–positive, invasive breast cancer. All the women were receiving tamoxifen monotherapy.
The researchers report that patients with two variant alleles in CYP2D6 had a 9.5-fold higher rate of recurrence than patients without variant alleles. Similarly, patients with an AA genotype in the ABCC2 SNP rs3740065 had a 10.6-fold higher rate of recurrence than patients with the GG genotype at this location.
To analyze the effects of CYP2D6 and ABCC2 genotypes on the plasma concentrations of tamoxifen and its metabolites endoxifen and 4-hydroxytamoxifen, Nakamura and team assessed 98 patients with breast cancer taking tamoxifen 20 mg/day.
They found that patients with two CYP2D6 variants had a significantly lower median plasma concentration of endoxifen than patients with no variants, at 15.5 versus 35.4 ng/ml respectively. The differences in plasma 4-hydroxytamoxifen concentrations among CYP2D6 genotype groups were also statistically significant. However, no significant difference in the two metabolites was found among the ABCC2 genotype groups.
Writing in the Journal of Clinical Oncology, Nakamura and co-authors conclude: “These findings have the potential to improve the ability of physicians to select optimal hormonal therapy for the treatment of hormone receptor–positive breast cancer.”
In an accompanying editorial, Timothy Lash and Carol Rosenberg (both from Boston University School of Medicine, Massachusetts, USA) point out that if these variant CYP2D6 alleles increase the risk for recurrence to the extent reported, measurably poorer tamoxifen effectiveness would be expected in Asian populations, where the prevalence of such variants is high.
Since trial results show no evidence of reduced efficacy of tamoxifen in Asian patients, Lash and Rosenberg remark that: “This study’s results, while provocative, are not sufficiently compelling to change standard practice.”
They add: “Genotype-guided tamoxifen therapy may ultimately improve the potential for personalized therapy, but its routine use should await more reliable evidence from well-designed studies.”
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