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


METHODS
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.


RESULTS
Haplotype analysis revealed significant association of G(rs10509681)-*1(rs1799853)-*3(rs1057910)-G(rs4244285) 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).


CONCLUSIONS
Multi-analytical approaches may provide a better clinical prediction of pharmacogenetic based treatment outcomes in breast cancer patients.
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Sonam
S
Tulsyan
Department of Endocrine and Breast Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Gaurav
G
Agarwal
Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Punita
P
Lal
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India. Electronic address: bml_pgi@yahoo.com.
Balraj
B
Mittal
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System
cyclophosphamide; cytochrome P450; gene–gene interactions; myelo-toxicity; pharmacogenetics; single nucleotide polymorphisms