Polymorphisms of genes encoding drug transporters or cytochrome P450 enzymes and association with clinical response in cancer patients: a systematic review

Abstract

Purpose: Not all patients respond well to cancer chemotherapy. One of the most important factors contributing to treatment response (efficacy and toxicity) is genetic determinant. The current systematic review aims to provide current status of the information on the genetic contribution of genes encoding drug transport proteins and drug metabolizing enzyme, cytochrome P450 (CYP), and relationship with clinical outcomes of cancer chemotherapy.

Methods: The literature search was performed through PubMed and ScienceDirect databases. One hundred and four research articles that fulfilled the inclusion criteria and had none of the exclusion criteria were included in the analysis.

Results: Various studies reported conflicting results for the polymorphisms of the major genes and association with treatment outcomes in patients with various types of cancer. Nevertheless, among the investigated gene polymorphisms, it appears that the 1236C>T, 3435C>T and 2677 G>T/A SNPs of the drug transporter gene ABCB1 were the most promising determinants of clinical outcomes. Although both 1236C>T and 3435C>T polymorphism are synonymous SNPs, several studies have demonstrated that not all synonymous SNPs are silent. Therefore, using the haplotype (1236C>T, 2677G>T, and 3435C>T) analysis rather than a single SNP may be a more useful approach for phenotype prediction. Some of the patients with variants of CYP genes were associated with unsatisfactory treatment response (efficacy and toxicity), suggesting that these variants may be associated with either reduction or absence of CYP enzyme activity.

Conclusions: The controversial results may be due to several factors including difference in populations studied, sample size, tumor sites and stages, chemotherapeutic drug regimens, and evaluation parameters for efficacy and/or toxicity. Before the information can be successfully applied to individualized cancer chemotherapy, further studies should be focused on these promising genetic markers and their association with clinical outcomes using standardized protocols.

Keywords: Cytochrome P-450; Drug transporter; Polymorphism; Response; Systematic review; Treatment outcome.