A155

Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. Breast cancer patients treated with TAM for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up, and in the occurrence of contralateral breast cancer. The major hydroxylated metabolites, 4-hydroxy (OH)-TAM and 4-OH-N-desmethylTAM (endoxifen), exhibit up to 100 times the anti-estrogenic activity of TAM itself. In patients treated with TAM, there is substantial inter-individual variability in cancer response, development of resistance to TAM therapy, and in the incidence of TAM-induced adverse events, including deep vein thrombosis, hot flashes, and the development of endometrial cancer. A major mode of metabolism of TAM, 4-OH-TAM, and endoxifen is by glucuronidation via the UDP glucuronosyltransferase (UGT) family of enzymes. Polymorphisms in the UGT enzymes responsible for the glucuronidation of TAM and its metabolites play an important role in inter-individual differences in TAM metabolism, and may potentially play an important role in inter-individual variability in patient response to TAM. Previous studies have shown UGT2B7 to be the most active hepatic UGT against 4-OH-TAM and endoxifen in vitro and the UGT2B7268Tyr variant results in lower activity against these substrates as compared to its wild-type UGT2B7268His counterpart. The present study examined the correlation between UGT2B7 codon 268 genotypes and liver microsomal activities against trans-4-OH-TAM and trans-endoxifen. Seventy-two human liver microsomes, prepared from adjacent normal liver specimens obtained during surgery from individual patients undergoing resection for hepatocellular carcinoma, were screened for glucuronidation activity against trans-4-OH-TAM and trans-endoxifen and analyzed by ultra-pressure liquid chromatography. The corresponding genomic DNA from each individual was analyzed by restriction fragment length polymorphism analysis for the UGT2B7 codon 268 polymorphism. The rate of O-glucuronidation was 31% and 27% lower, respectively, in individuals homozygous for the UGT2B7 (Tyr/Tyr) genotype for trans-4-OH-TAM and trans-endoxifen, respectively, as compared to subjects with the UGT2B7 (His/His) genotype (p-value <0.001 and 0.01, respectively). There was a significant trend of decreased O-glucuronidation activity against both trans-4-OH-TAM (p-value=0.0003) and trans-endoxifen (p-value=0.009) with increasing numbers of the UGT2B7268Tyr allele, as determined by trend test. These results suggest that women taking TAM who have one or more UGT2B7268Tyr polymorphic alleles metabolize trans-4-OH-TAM and trans-endoxifen at a significantly slower rate than those women with only the wild-type alleles. Therefore, the UGT2B7 codon 268 polymorphisms may significantly contribute to inter-individual variability in response to TAM therapy.

Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA