A Uridine Glucuronosyltransferase 2B7 Polymorphism Predicts Epirubicin Clearance and Outcomes in Early-Stage Breast Cancer

• DOI: 10.1016/j.clbc.2015.09.006
• Publication Date: 2015-09-25T21:51:40Z
• Authors: Michael B. Sawyer; Edith Pituskin; Sambasivarao Dama...; Robert R. Bies; Larissa J. Vos; Carla. M.M. Prado; Michelle Kuzma; Andrew G. Scarfe; Mark Clemons; Katia Tonkin; Heather-Jane Au; Sheryl Koski; Anil A. Joy; Michael Smylie; Karen King; Diana Carandang; Vijaya L. Damaraju; John Hanson; Carol E. Cass; John R. Mackey
• Keywords: Adult; Genotype; Breast Neoplasms; Middle Aged; Polymorphism, Single Nucleotide; 3. Good health; Immunoenzyme Techniques; 03 medical and health sciences; 0302 clinical medicine; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Female; Neoplasm Invasiveness; Fluorouracil; Glucuronosyltransferase; Neoplasm Grading; Neoplasm Recurrence, Local; Cyclophosphamide; Aged; Epirubicin; Follow-Up Studies; Neoplasm Staging

Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), an enzyme rich in single nucleotide polymorphisms (SNPs). We studied whether the -161 C > T germline SNP in UGT2B7 was related to epirubicin metabolism and whether differences exist in the toxicity and efficacy of epirubicin-based chemotherapy among patients who were TT homozygotes, CT heterozygotes, and CC homozygotes.A total of 132 women with non-metastatic breast cancer receiving FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) were prospectively enrolled. Toxicity was assessed in cycle 1 using the National Cancer Institute Common Toxicity Criteria, version 2.0.The sequence at -161 was studied in 132 subjects; 37 were TT homozygotes, 63 were CT heterozygotes, 26 were CC homozygotes, and 6 could not be genotyped. The CC genotype patients had decreased epirubicin clearance (median, 103.3 L/hr) compared with the CT/TT genotype patients (median, 134.0 L/hr; P = .002). The CC homozygous patients had an increased risk of grade 3 to 4 leukopenia compared with the TT homozygotes or heterozygotes (P = .038 and P = .032, respectively). TT homozygotes or heterozygotes had an increased risk of early recurrence (P = .039; χ(2) test).The results of the present prospective pharmacogenetic study suggest that the UGT2B7 -161 C > T SNP correlate with drug metabolism, toxicity, and efficacy in patients receiving epirubicin chemotherapy. Further studies of this UGT2B7 SNP as a predictor of epirubicin toxicity and efficacy are warranted.