Uridine glucuronosyltransferase 2B7 polymorphism based pharmacogenetic dosing of epirubicin in FEC chemotherapy for early-stage breast cancer

Abstract Background Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in UGT2B7’s -161 promoter polymorphism have lower clearance and significantly higher rates of leucopenia 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 scheduled to receive at least 3 cycles of FE100C in the (neo)adjuvant setting. Patients received standard dose FE100C during the first 21 day cycle. Based on genotype, epirubicin dose was escalated in the 2nd and 3rd cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the 3 genotypes. Results Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in cycle one. Twelve and ten TT patients were dose escalated at cycle 2 and 3, respectively; 16 CT patients were dose escalated at cycle 2 and 3. Leucopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, cycle 3 leucopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. Conclusion Pharmacogenetically-guided epirubicin dosing is well tolerated and permitted dose escalation without increased toxicity. MicroAbstract Clinical outcomes for early-stage breast cancer patients have been improved by increased doses of epirubicin chemotherapy although hematological and cardiac toxicity limit the dose that can be administered. In this study we explored epirubicin dosing based upon 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 FEC regimen and there were no differences in clinical outcomes or toxicity rates indicating pharmacogenetic dosing is feasible and well tolerated.