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Polymorphisms of Genes Encoding Drug Transporters Or Cytochrome P450 Enzymes and Association with Clinical Response in Cancer Patients: a Systematic Review

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Polymorphisms of Genes Encoding Drug Transporters Or Cytochrome P450 Enzymes and Association with Clinical Response in Cancer Patients: a Systematic Review Cancer Chemotherapy and Pharmacology (2019) 84:959–975 https://doi.org/10.1007/s00280-019-03932-0 REVIEW ARTICLE Polymorphisms of genes encoding drug transporters or cytochrome P450 enzymes and association with clinical response in cancer patients: a systematic review Inthuorn Kulma1,2 · Kanyarat Boonprasert1,2 · Kesara Na‑Bangchang1,2,3 Received: 6 May 2019 / Accepted: 20 August 2019 / Published online: 4 September 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Purpose Not all patients respond well to cancer chemotherapy. One of the most important factors contributing to treatment response (efcacy 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 fulflled the inclusion criteria and had none of the exclusion criteria were included in the analysis. Results Various studies reported conficting 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 (efcacy 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 diference in populations studied, sample size, tumor sites and stages, chemotherapeutic drug regimens, and evaluation parameters for efcacy 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 Drug transporter · Cytochrome P-450 · Polymorphism · Treatment outcome · Response · Systematic review Introduction Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0028 0-019-03932 -0) contains Cancer is one of the leading causes of mortality worldwide. supplementary material, which is available to authorized users. Surgery is the primary treatment for managing early-stage and locally advanced stage disease. Nevertheless, complete * Kesara Na-Bangchang [email protected] tumor removal is not successful in several types of cancer. Resistance of most tumors to available anticancer drugs also 1 Graduate Program in Bioclinical Sciences, Chulabhorn further aggravates poor prognosis [1]. International College of Medicine, Thammasat University The ATP-binding cassette (ABC) transporter encodes the (Rangsit Campus), Pathumtani 12121, Thailand 2 multidrug efux pump P-glycoprotein (P-gp) and is involved Center of Excellence in Pharmacology and Molecular in pumping intracellular drugs out of the cells. This protein Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumtani 12121, Thailand family acts as a resistance factor to anticancer drugs [2]. The solute carrier (SLC) family on the other hand facilitates drug 3 Drug Discovery and Development Center, Ofce of Advanced Science and Technology, Thammasat University entry into cells. This protein family encodes membrane-bound (Rangsit Campus), Pathumtani 12121, Thailand transporters [3]. For example, SLCO1B1 or solute carrier Vol.:(0123456789)1 3 960 Cancer Chemotherapy and Pharmacology (2019) 84:959–975 organic anion transporter family member 1B1 is a major with regard to the association between pharmacogenetics in infux transporter expressed on the basolateral membrane of pharmacokinetics and chemotherapeutic response in can- human hepatocytes which mediated the active metabolite of cer patients. The following combination keywords were irinotecan [4]. Various members of the ABCB, ABCC, and applied: cancer AND pharmacogenetics/polymorphism/ ABCG subfamilies, i.e., ABCB1 (multidrug resistance-1: genetic variation/single nucleotide polymorphisms, AND MDR1), ABCG2 (breast cancer resistance protein: BCRP) or drug transporters/cytochrome P450/CYP, AND anticancer ABCC2 (multidrug resistance-associated protein-2: MRP2) drug/chemotherapeutic drug response/outcome. Both free play important roles in conferring multidrug resistance in can- text and MeSH search for keywords were used. The search cer cells, as well as alteration of clearance of chemotherapy was restricted to human studies. Two independent review- drugs with enhanced toxicity [2]. This likely results in poor ers were responsible for completing the title search, title, prognosis of response to chemotherapy. abstract, full text screening, and full-text extraction. There is an increasing interest factors contributing to inter- individual variability in drug efcacy and toxicity leading Inclusion and exclusion criteria to variability in clinical responses [5]. This is of particular concern in cancer chemotherapy as most anticancer agents The inclusion criteria of this systematic review were as fol- exhibit low selectivity against cancer cells and narrow thera- lows: (1) full-text research articles published in English, and peutic index. A small increase in plasma drug concentrations (2) articles related to studies of association between poly- may lead to toxicity, while a small decrease in plasma con- morphisms of drug transporters and CYP genes and chemo- centrations may reduce clinical efcacy [6]. Investigation of therapeutic drug response in all type’s cancer patients. The factors associated with variability in chemotherapeutic out- exclusion criteria were: (1) comments, reviews, editorials, comes and improving strategies to personalized medicine to and conference abstracts, (2) articles with insufcient data, maximize efcacy and minimize toxicity is currently of great and (3) articles with duplication of previous publications. research interest [7]. One of the most important factors is pol- ymorphisms of genes involved in the pharmacokinetic pro- Data extraction cesses (absorption, distribution, metabolism, and excretion). The majority of drug metabolism reactions are catalyzed by Both independent authors were extracted the data from the cytochrome P450 (CYP) enzymes [6]. Polymorphisms all included publications using predefned tables which of genes that encode drug metabolizing enzymes and drug included items as follows: frst author, publication year, transporters can markedly afect drug efcacy and toxicity [8]. type of cancer, sample size, chemotherapeutic regimens, Single-nucleotide polymorphisms (SNPs) in genes involved genotyping method, name of genes, and clinical outcomes in metabolism and transport of chemotherapeutic drugs (tumor response, survival time, toxicity, and others). have been shown to signifcantly afect response to therapy Tumor response was defned as treatment response deter- and critically predict clinical outcomes [9]. For example, the mined according to (1) extent of tumor necrosis; patients rs3212986 variant of CYP2A6 gene has been associated with with < 90% necrosis were classifed as poor responders and good clinical response to cisplatin/S-1 combination therapy those with ≥ 90% as good responders, (2) Response Evalua- with prolonged overall survival time. Additionally, the poly- tion Criteria in Solid Tumors (RECIST) and WHO criteria morphism of the transporter gene ABCC2-24C>T has been [11, 12], (3) percentage of tumor lesion, (4) reduction of shown to improve response to platinum-based chemotherapy BCR/ABL fusion gene transcripts, (5) percentage of blast in non-small cell lung cancer [10]. Nevertheless, association cells in the bone marrow aspirates and biopsy including studies of the polymorphisms of these genes in cancer patients absolute neutrophil and platelets count, (6) Becker’s Criteria and response to chemotherapeutic drugs remain conficting [13], (7) Sokal score [14], (8) percentage of prostate-specifc and controversial with inconclusive results. The present study antigen, or (9) reduction of serum PSA from baselines. Sur- aims to provide a thorough and systematic review of current vival time was defned as (1) overall survival (OS: the time information on association between polymorphisms of drug from diagnosis until death from any cause or last known transporters or CYP enzymes and chemotherapeutic response. date alive or the time from the frst cycle of chemotherapy to death or last follow-up day or the date of surgery to the date of death or the cut-of date of follow-up, (2) progression-free Methods survival (PFS: the time interval between start of chemo- therapy or surgery until the date of disease progression, (3) Search strategy event-free survival (EFS: the interval from the date of treat- ment to the date of a confrmed relapse, persistence of the The electronic databases PubMed and ScienceDirect
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