Significant role of CYP450 genetic variants in cyclophosphamide based breast cancer treatment outcomes: a multi-analytical strategy

• Published in: Clinica chimica acta 2014-07, Vol.434, p.21-28
• Main Authors: Tulsyan, Sonam, Agarwal, Gaurav, Lal, Punita, Mittal, Balraj
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; cyclophosphamide; Cyclophosphamide - adverse effects; Cyclophosphamide - therapeutic use; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Enzymologic; Genetic Variation; gene–gene interactions; Humans; Middle Aged; myelo-toxicity; pharmacogenetics; single nucleotide polymorphisms; Treatment Outcome
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/j.cca.2014.04.009

Cyclophosphamide (CP), an alkylating chemotherapeutic drug, is catalyzed by the Phase I cytochrome P450 (CYPs) isozymes — CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19. Hence this study aimed to elucidate the influence of genetic variants in CYP450 metabolizing enzymes on breast cancer treatment outcomes, using multi-analytical approaches. Treatment response was noticed in 111 patients whereas 234 patients were followed for myelo-toxicity. Eight known functional single nucleotide polymorphisms (SNPs) in six CYP450 genes were selected for the study on the basis of CP metabolizing enzyme polymorphisms. The possible functional effects of CYP450 polymorphisms were determined by online Web servers F-SNP. Multifactor dimensionality reductions (MDR), haplotype analysis were combined with logistic regression to characterize gene–gene interaction model with treatment outcomes. Haplotype analysis revealed significant association of Grs10509681-*1rs1799853-*3rs1057910-Grs4244285 on chromosome 10 with overall toxicity (P=0.024) and grade 2–4 leucopenia (P=0.03). On MDR analysis, CYP3A5*3, CYP2C19*2, CYP2B6*5 yielded the highest testing accuracy for treatment response (0.60) and CYP2C8*3, CYP2C9*2 for overall toxicity (0.50). Multi-analytical approaches may provide a better clinical prediction of pharmacogenetic based treatment outcomes in breast cancer patients. •Cyclophosphamide is catalyzed by the Phase I cytochrome P450 enzymes.•Variations in genes coding for metabolizing enzymes may affect its treatment outcome.•Haplotype combination showed significant association with grade 2–4 toxicity.•Haplotype combination showed significant association with grade 2–4 leucopenia.•Higher gene–gene interactions may be important in treatment outcomes of breast cancer therapy.