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

• Published in: Clinical breast cancer Vol. 16; no. 2; pp. 139 - 144.e3
• Main Authors: Sawyer, Michael B., Pituskin, Edith, Damaraju, Sambasivarao, Bies, Robert R., Vos, Larissa J., Prado, Carla. M.M., Kuzma, Michelle, Scarfe, Andrew G., Clemons, Mark, Tonkin, Katia, Au, Heather-Jane, Koski, Sheryl, Joy, Anil A., Smylie, Michael, King, Karen, Carandang, Diana, Damaraju, Vijaya L., Hanson, John, Cass, Carol E., Mackey, John R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2016
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cyclophosphamide - administration & dosage; Drug clearance; Epirubicin - administration & dosage; Female; Fluorouracil - administration & dosage; Follow-Up Studies; Genotype; Glucuronosyltransferase - genetics; Hematology, Oncology and Palliative Medicine; Humans; Immunoenzyme Techniques; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Obstetrics and Gynecology; Polymorphism, Single Nucleotide - genetics; Prognosis; Prospective Studies; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Single nucleotide polymorphisms; SNP; Survival Rate; Toxicity; UGT2B7; Single nucleotide polymorphisms; SNP; Toxicity; Drug clearance; UGT2B7
• ISSN: 1526-8209; 1938-0666
• DOI: 10.1016/j.clbc.2015.09.006

An epirubicin dose of 100 mg/m2 is well tolerated by most patients; however, a subset will experience dose-limiting toxicity. We observed statistically significant effects with a genetic variation in the enzyme uridine glucuronosyltransferase 2B7 (UGT2B7) on the clinical outcomes, epirubicin clearance, and rates of leukopenia. UGT2B7 genotyping could allow epirubicin dosing optimization to maximize efficacy and minimize toxicity. 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/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) 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; χ2 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.