Abstract
2015 Background: Anthracyclines are widely used for the treatment of breast cancer. Unlike doxorubicin, the major mechanism of epirubicin inactivation is metabolism to inactive glucuronides by uridine glucuronosyltransferase (UGT) 2B7. A polymorphism has been discovered at position -161 T to C in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We have carried out a prospective pharmacogenetic study of epirubicin metabolism in M0 breast cancer patients treated with adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m2, Epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 weeks. Patients did not receive prophylactic G-CSF. Drug levels were drawn at 1 and 24 hours. Patients were followed during cycle 1 for toxicity, graded according to the NCIC CTC criteria. To date 102 patients have been enrolled to date out of a planned sample of 120. Patient characteristics-median (range): age 50 (28 - 67), sex 101 F/ 1 M, baseline AST 22 U/L (13–66), ALT 21 U/L (5–90), bilirubin 7 μmol/L (2–24), creatinine 73 μmol/L (51 - 126). Results: 24 patients were TT homozygotes, 55 were CT heterozygotes, and 23 were CC homozygotes. There was no relationship between nausea, vomiting or mucositis and UGT2B7 genotype. The mean neutrophil survival fraction was 14%, 11% and 8% for TT, CT, and CC genotypes (p=0.3, ANOVA test). There was a trend for increased grade 3/4neutropenia in patients having at least one deficient allele (i.e. CT or CC) vs. wild type homozygous (TT) (p=0.1, Chi square test). Patients with a deficient allele (CT or CC) were at increased risk for grade 3/4 leucopenia compared to TT homozygotes (p=0.01, Chi square test). Conclusions: The preliminary analysis of this prospective pharmacogenetic study suggested that the UGT2B7 -161 C/T SNP predicts for grade 3/4 leucopenia in women treated with FEC100. Studies of this UGT2B7 polymorphism as a predictor of epirubicin toxicity and efficacy are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
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