Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach.
Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene-gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (Pcorr=0.0465, Pcorr=0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (Pcorr=0.0465). Haplotype analysis further revealed ACYP3A4-ACYP3A5 haplotype to be significantly associated with responders (Pcorr=0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with 'grade 1 or no leucopenia' (Pcorr=0.0465, Pcorr=0.048). On evaluating higher order gene-gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2-4 anemia and dose delay/reduction due to neutropenia (P=0.024, P=0.004, P=0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Sonam
S
Tulsyan
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Pankaj
P
Chaturvedi
Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Abhishek Kumar
AK
Singh
Department of Endocrine & 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 Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Sushma
S
Agrawal
Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India.
Rama Devi
RD
Mittal
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 / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D043823:Taxoids
ABCB1; Clinical response; Cytochrome P450; Myelosuppression; Polymorphisms