Impact of UGT1A4, UGT2B7, and UGT2B15 pharmacogenetics on tamoxifen (TAM) metabolism.

Abstract

2588 Background: The aims were to characterize the genetic profiles of UGT1A4, UGT2B7 and UGT2B15in Asian healthy populations (Chinese, Malay, Indians, N=80 each) and investigate the effects of these SNPs on the disposition of TAM in Asian breast cancer patients (N=202). Methods: Healthy Asian subjects and Asian breast cancer patients were genotyped for UGT1A4, UGT2B7 and UGT2B15 SNPs. Plasma levels of tamoxifen and its metabolites in Asian patients were determined via LC-MS/MS analysis. Genotypic-phenotypic differences were examined using non-parametric tests. Haplotypic effects were examined using haplotype-specific generalized linear model. Results: Screening of the 5′ upstream, exonic, exonic-intronic junctions and 3′ downstream regions identified 61, 77 and 47 SNPs in UGT1A4, UGT2B7 and UGT2B15respectively. A total of 16, 14 and 20 tag-SNPs were identified in these genes respectively and genotyped in patients. Haplotypic analysis revealed associations between LD block 1 (-1548A>G, -1531C>T, -419G>A, -219C>T, -163G>A, 142T>G, 448T>C, 804G>A, IVS1+196T>C, IVS1+346T>G, IVS1+414A>G, IVS2+307A>G) and higher plasma Tam-N-Gluc level and MRTAM-N-Gluc/TAM after adjustment for significant covariates. The median (range) MRTAM-N-Gluc/TAM was 2.1- and 1.9-fold higher among patients carrying one and two copies of H2 (GCATAGCACTGG), respectively, compared to patients who carried two copies of H1 haplotype (ACGCGTTGTTAA) [H1/H1 vs H1/H2 vs H2/H2: 0.35 (0.11 - 2.09) vs 0.74 (0.19 - 3.60) vs 0.66 (0.52 - 1.66), P < 0.0001]. Similar association was observed between H2 and Tam-N-Gluc level [H1/H1 vs H1/H2 vs H2/H2: 0.75 (0.15 - 4.45) vs 1.29 (0.19 - 9.20) vs 1.66 (0.62 - 2.83) ng/ml, P= 0.004]. UGT2B15 LD block 3 (1568A>C, *168C>T, *186A>T, *+630C>G and *+888A>G) was associated with modest decrease and increase in (E)-END and MRZ-NDM-4-O-GLUC/E-END, respectively. UGT2B7haplotypes were not associated with O-glucuronidations of 4-OHT and END. Conclusions: This study highlights the involvement of UGT1A4 haplotypes in the variability in TAM N-glucuronidation while UGT2B7 and UGT2B15 variants played limited role in the variabilities of O-glucuronidations of 4-OHT and END in Asian breast cancer patients. Clinical trial information: 0822570P.