Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil

Most adjuvant breast cancer treatment regimens include the combination of an anthracycline (epirubicin or doxorubicin) and the alkylating agent cyclophosphamide. This study sought to investigate the influence of pharmacogenetics on the pharmacokinetics and metabolism of these agents. Blood samples were taken from patients treated with cyclophosphamide (n = 51) and epirubicin (n = 35), with or without 5-fluorouracil (5-FU). The pharmacokinetics and metabolism of the three drugs were investigated, together with pharmacogenetic investigations for cyclophosphamide and epirubicin. Cyclophosphamide and its metabolites and also epirubicin and epirubicinol were measured in plasma. DNA was extracted from whole blood and genotyping performed using RT-PCR. Patients with at least one variant CYP2C19*17 allele had a longer CP half-life (p = 0.007), as did homozygous variants for the CYP2B6*6 allele. There was no significant effect of GSTP1, CYP2B6*2, CYP2B6*5 or CYP2C19*2 on any pharmacokinetic parameter of CP. An NQO2 exonic SNP was associated with a higher exposure to epirubicinol relative to epirubicin (p = 0.011). Other polymorphic variants of NQO1, carbonyl reductase, UGT enzymes and transporters had no influence on epirubicin or its metabolite. Overall, pharmacogenetic factors had only a minor influence on cyclophosphamide or anthracycline-based adjuvant therapy of breast cancer.