Uridine Glucuronosyltransferase 2B7 Polymorphism-Based Pharmacogenetic Dosing of Epirubicin in FEC Chemotherapy for Early-Stage Breast Cancer

Clinical outcomes for early-stage breast cancer patients have been improved by increased doses of epirubicin chemotherapy, although hematological and cardiac toxicity limits the dose that can be administered. In this study, we explored epirubicin dosing based on a single nucleotide polymorphism in the enzyme that metabolizes epirubicin. Patients with CT and TT genotypes metabolize epirubicin more quickly than those with the CC genotype, and we proposed that they could safely receive higher doses. Forty-five early-stage breast cancer patients were treated with standard or dose-escalated epirubicin in the fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen, and there were no differences in clinical outcomes or toxicity rates, indicating that pharmacogenetic dosing is feasible and well tolerated. Background: Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. Patients and Methods: We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m(2) or to 120 and 140 mg/m(2) for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. Results: Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m(2) of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. Conclusion: Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.