Role of cyclophosphamide metabolizing enzyme polymorphisms with treatment outcomes in breast cancer patients

Abstract

Cyclophosphamide (CP) based chemotherapy is the main treatment for women with breast cancer. Pharmacogenetic variability in drug metabolism is one possible mechanism which may influence its toxicity or efficacy. Activation of CP to 4-hydroxycyclophosphamide is catalyzed by the hepatic cytochrome P450 (CYP) isozymes. CYP3A5 and CYP2C9 are such drug metabolizing enzymes. We hypothesized that genetic variants of CYP3A5-CYP3A5null3 (rs776746), CYP2C9 - CYP2C9null2 (rs1799853) and CYP2C9null3 (rs1057910) may have an impact on the efficacy or toxicity of the cyclophosphamide therapy in the breast cancer treatment. Clinical outcome on survival, toxicity and recurrence in 101 breast cancer patients was followed in this pilot study. The patients were genotyped for CYP3A5null3 (6986A>G), CYP2C9null2 (432C>T) and CYP2C9null3 (1077A>T) polymorphism using PCR-RFLP. Chi square and logistic regression was carried out using SPSS ver.15.0 Out of 101 patients, there was dose delay or dose reduction in 5 patients due to toxicity (neutropenia/leucopenia) and therapeutic failure in terms of disease recurrence was noticed in 1 patient. One patient did not respond to the therapy. In patients with dose delay, all five had at least one variant allele of CYP3A5null3 and 2 patients were carriers of CYP2C9null3. The patient who did not respond to the treatment had variant alleles of CYP3A5null3 and CYP2C9null3. However, sample size was insufficient for statistical analysis. Therefore, larger sample size may be required to ascertain the role of cyclophosphamide metabolizing enzyme genetic variants with treatment outcomes.