552 CYP3A5*3 (rs776746) is associated with docetaxel-specific toxicities during adjuvant breast cancer chemotherapy

Abstract

Background: Systemic therapy is a commonly administered treatment modality in cancer care. Adverse drug reactions (ADR) during chemotherapy affect quality of life and may hinder delivery of adequate doses in a suβ-population of patients, thereby limiting the therapeutic benefit. The heritable nature of CYP gene polymorphisms influencing drug metabolism and clearance are well characterized. In this study we investigated germ-line polymorphisms in several of CYP genes including CYP3A5 (CYP3A5∗3; G>A, rs776746); and drug efflux pump, MDR1 (C 3435 T, rs1045642) for their association with drug-induced toxicity phenotypes. Methods: DNA samples from breast cancer clinical trial patients (n= 184) receiving adjuvant poly-chemotherapy regimen with docetaxel (Taxotere), doxorubicin (Adriamycin) and cyclophosphamide in Edmonton, (Alberta, Canada) were selected for this study. All subjects signed an informed consent and the study was approved by institutional research ethics board. Following stringent data filtering criteria, a total of 147 cases were considered for association analysis. Patients with drug induced toxicity scores of 0-2 (n = 57) served as a reference (controls); these were compared with ≥ grade 3 toxicity groups: overall toxicity (group I, n = 90), docetaxel-specific (group II, n = 36) and non-docetaxel related (group III, n = 54). Hypersensitivity, fatigue, myalgia and neurotoxicity were classified docetaxel specific. Genotyping was performed using the Pyrosequencing technology platform. Associations between genotype and phenotype were analysed using unconditional logistic regression with SNPStats software. Results: We identified statistically significant associations only for CYP3A5 among several CYP gene polymorphisms tested. Group I (p-value 0.013; Odds Ratio (OR) 4.19 (CI: 1.17-15.03) and II (p-value 0.015; OR 5.14 (CI: 1.26-20.92)) results were consistent with the predictions that docetaxel-related toxicities are mediated predominantly by CYP3A5∗3 (heterozygote and variant genotypes) conferring risk. The MDR1 polymorphism was not associated with either overall or docetaxel-specific toxicity; however, CC genotype (wild type allele conferring higher expression, i.e., clearance of docetaxel) showed marginal protection (OR 0.30, p-value 0.037) in non-docetaxel related toxicity in group III. Conclusions: Pharmacogenetic screening helps stratify patients to (i) identify groups at risk for chemo-toxicity and (ii) customize therapies to improve treatment outcomes.