364PD - Head & neck cancer pharmacogenetics: case control study on 5- fluorouracil and cisplatin adjuvant treatment outcome

Date 16 December 2016
Event ESMO Asia 2016 Congress
Session Head and neck cancer
Topics Cytotoxic agents
Pharmacology
Head and Neck Cancers
Presenter Sunishtha Bhatia
Citation Annals of Oncology (2016) 27 (suppl_9): ix112-ix122. 10.1093/annonc/mdw587
Authors S.S.Y. Bhatia1, D. Parmar2
  • 1Biosciences, Amity Institute of Biotechnology, 201303 - Noida/IN
  • 2Developmental Toxicology Division, IITR, 211017 - Lucknow/IN

Abstract

Background

Pharmacogenetics is the study of variability in drug responses due to heredity. It attempts to identify specific genes that are associated with specific diseases and that may be targets for new drugs. Cytochrome P4502D6 (CYP2D6) is of great pharmacogenetic interest due to its involvement in the biotransformation of several anticancer compounds to the active metabolites. And therefore, variations in the activity of CYP2D6 enzyme due to genetic polymorphisms may alter activity directly affecting the concentrations of active metabolites. CYP2D6*4 (G1934A), located on intron 3 and exon 4 junction, and CYP2D6*10 allele (C100T at exon 1), results in decreased catalytic activity of the enzyme and may lead to inappropriate metabolism of the anticancer drug thus, leading to variation in treatment outcome. The present study was undertaken to investigate the association of variant genotypes of CYP2D6 with the treatment response (personalized medicine approach) in head & neck cancer cases receiving adjuvant 5-fluorouracil and cisplatin.

Methods

300 patients suffering from head & neck cancer and equal number of age matched controls were included in the study. Genomic DNA was isolated from the blood samples and CYP2D6 genotypes were determined in genomic DNA by PCR based RFLP. Follow-up carried out to correlate the association (if any) in between variants and treatment outcome. Chi-square test and logistic regression models were used to determine associations between genotype, use of concomitant CYP2D6 inhibitors and disease relapse rate.

Results

The frequency of variant alleles of CYP2D6 (CYP2D6*4 & *10) was found to be significantly higher in the cases when compared with the controls. The variant genotypes have lower benefit of 5-fluorouracil and cisplatin adjuvant treatment and tend to have a higher risk of disease relapse.

Conclusions

This study suggests that the presence of the inactive CYP2D6*4 & *10 causes a reduction in the metabolic activation of anticancer agents, thereby lowering the risk of toxicity but worsening the therapeutic response.

Clinical trial indentification

N/A

Legal entity responsible for the study

Council for Scientific & Industrial Research

Funding

Council for Scientific & Industrial Research

Disclosure

All authors have declared no conflicts of interest.