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The Oncologist, Vol. 10, No. 2, 104-111, February 2005; doi:10.1634/theoncologist.10-2-104
© 2005 AlphaMed Press

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Cancer Pharmacogenomics: Powerful Tools in Cancer Chemotherapy and Drug Development

Wooin Lee, A. Craig Lockhart, Richard B. Kim, Mace L. Rothenberg

Department of Medicine, Divisions of Medical Oncology and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Correspondence: Wooin Lee, Ph.D., 542 RRB, 23rd Avenue at Pierce Avenue, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA. Telephone: 615-343-3512; Fax: 615-322-4707; e-mail: wooin.lee{at}vanderbilt.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Explain how genetic factors contribute to variability in drug response.
  2. Apply this understanding to clinical outcomes in patients treated with specific chemotherapy agents.
  3. Describe approaches for improving clinical cancer therapy and cancer drug development.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
 References
 
Interindividual differences in tumor response and normal tissue toxicities are consistently observed with most chemotherapeutic agents or regimens. While many clinical variables have been associated with drug responses (e.g., age, gender, diet, drug-drug interactions), inherited variations in drug disposition (metabolism and transport) genes and drug target genes also likely contribute to the observed variability in cancer treatment outcome. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use such genetic information to predict the safety, toxicity, and/or efficacy of drugs. There exist several clinically relevant examples of the utility of pharmacogenomics that associate specific genetic polymorphisms in drug metabolizing enzymes (e.g., TPMT, UGT1A1, DPD), drug transporters (MDR1), and drug target enzymes (TS) with clinical outcomes in patients treated with commonly prescribed chemotherapy drugs, such as 5-fluorouracil and irinotecan (Camptosar®; Pfizer Pharmaceuticals; New York, NY http://www.pfizer.com). Techniques to discover and evaluate the functional significance of these polymorphisms have evolved in recent years and may soon be applied to clinical practice and clinical trials of currently prescribed anticancer drugs as well as new therapeutic agents. This review discusses the current and future applications of pharmacogenomics in clinical cancer therapy and cancer drug development.

Key Words. Cancer pharmacogenomics • Genetic variations • Cancer therapy • Cancer drug development


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
 References
 
Pharmacogenomics is a rapidly growing field that aims to elucidate the genetic basis for interindividual differences in drug response and to use such genetic information to predict the safety, toxicity, and/or efficacy of drugs in individual patients or groups of patients. While drug-drug interactions and environmental factors significantly contribute to interindividual variability in drug response, genetic factors (e.g., inherited variability of drug targets, drug metabolizing enzymes, and/or drug transporters) also appear to have a major impact on drug response and disposition (Fig. 1Go). Considering the significant heterogeneity associated with patient responses to chemotherapeutic agents and their narrow therapeutic indices, pharmacogenomics has the potential to offer individualized cancer treatment regimens [1–3]. Clearly, a better understanding of the genetic determinants of chemotherapeutic response will enable prospective identification of patients at risk for severe toxicity or those most likely to benefit from a particular treatment regimen. Such studies can be translated to clinical practice via molecular diagnostics (genotyping) in order to guide selection of the optimal drug combination and dosage for the individual patient. A number of detailed reviews on cancer pharmacogenomics have been published recently [1–6]. This article focuses on the current and future applications of pharmacogenomics in clinical cancer therapy and cancer drug development.



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  		Figure 1. Multiple factors contributing to variations in drug responses.

 

   GENETIC VARIATIONS AFFECTING DRUG RESPONSE AND TOXICITY WITH CANCER CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Genetic Variations Affecting...
Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
 References
 
Pharmacogenomic approaches have been applied to many existing chemotherapy agents in an effort to identify relevant inherited variations that may better predict patient response to chemotherapy. Genetic variations include nucleotide repeats, insertions, deletions, and single nucleotide polymorphisms (SNPs), which can alter the amino acid sequence of the encoded proteins, RNA splicing, and gene transcription. Such genetic polymorphisms in drug-metabolizing enzymes, transporters, and molecular targets have been actively explored with regard to functional changes in phenotype (altered expression levels and/or activity of the encoded proteins) and their contribution to variable drug response. Recent studies also indicate that genetic variations vary substantially among different ethnic groups and that the evaluation of the haplotypes (combination of polymorphisms that are inherited together) can often result in better correlation with phenotypes than with individual polymorphisms. The following sections describe some clinically relevant examples of genetic polymorphisms to illustrate the relevance of cancer pharmacogenomics in optimizing chemotherapy as a way to enhance efficacy and safety (Table 1Go).


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  		Table 1. Examples of genetic variations associated with changes in patient responses to chemotherapy agents
 
Polymorphisms in Drug-Metabolizing Enzymes

Thiopurine methyltransferase and 6-Mercaptopurine
6-Mercaptopurine (6-MP) is a purine antimetabolite used in the treatment of leukemia. The antitumor activity of 6-MP is via the inhibition of the formation of nucleotides necessary for DNA and RNA synthesis. Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of 6-MP to form inactive metabolites. Genetic variations in the TPMT gene have profound effects on the bioavailability and toxicity of 6-MP. It has been demonstrated that about 1 in 300 individuals inherit TPMT deficiency as an autosomal recessive trait. Patients who carry TPMT polymorphisms are at risk for severe hematologic toxicities when treated with 6-MP because these polymorphisms lead to a decrease in the rate of 6-MP metabolism [7, 8].

The molecular basis for polymorphic TPMT activity has been well defined. Three particular TPMT alleles, designated as TPMT*2, TMPT*3A, and TPMT*3C, have been shown to account for nearly 95% of the observed cases of TPMT deficiency [9]. Each of these mutant alleles encodes TPMT proteins that undergo rapid degradation, leading to enzyme deficiency [10]. The types and frequencies of TPMT alleles have been reported to differ among ethnic groups [11, 12]. A recent trial estimated that 71% of patients with bone marrow intolerance to 6-MP were phenotypically TPMT deficient and that these patients were more likely to be hospitalized, receive platelet transfusions, and miss scheduled doses of chemotherapy [13]. Appropriate 6-MP dose reductions for TPMT-deficient patients have allowed for similar toxicity and survival outcomes as patients with normal TPMT levels [14, 15]. Genotyping methods have been established for the molecular diagnosis of TPMT deficiency and can assist with determining a safe starting dose for 6-MP therapy [16]. Clinical studies have established the importance of 6-MP dose intensity as a significant predictor of event-free survival in children with acute lymphatic leukemia (ALL). Reductions in 6-MP dose intensity tend to occur as a result of missed weeks of therapy, highlighting the potential utility of pretreatment genotyping for TPMT mutation [14]. TPMT testing is now being used for dose optimization in children with ALL before 6-MP therapy is initiated.

UDP-glucuronosyltransferase 1A1 and Irinotecan
Irinotecan (Camptosar®; Pfizer Pharmaceuticals; New York, NY, http://www.pfizer.com) is a semisynthetic analogue of camptothecin and requires metabolic activation by carboxylesterase to form the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which in turn inhibits topoisomerase-I [17]. SN-38 is further detoxified via formation of SN-38 glucuronide (SN38G). Irinotecan has potent antitumor activity against a wide range of tumors, and it is one of the most commonly prescribed chemotherapy agents. Diarrhea and myelosuppression are, however, the dose-limiting toxicities of irinotecan and interfere with optimal utilization of this important drug. Such toxicities of irinotecan have often been associated with increased levels of SN-38. Studies of the clinical pharmacogenetics of irinotecan have been mainly focused on polymorphisms in UDP-glucuronosyltransferase 1A1 (UGT1A1), the enzyme responsible for glucuronidation of SN-38 to form the less toxic, inactive metabolite SN38G [18].

A prominent role for genetic variations in UGT1A1 is suggested by the observed marked interpatient variability in SN38G formation [19]. Variations in UGT1A1 activity most commonly arise from polymorphisms in the UGT1A1 promoter region that contains several repeating TA elements. The presence of seven TA repeats (referred to as UGT1A1*28), instead of the wild-type number of six, results in reduced UGT1A1 expression and activity [20]. Accordingly, UGT1A1*28 has been shown to be associated with reduced glucuronidation of SN-38, increased exposure to SN-38, and increased clinical toxicity for patients treated with irinotecan [21–25]. The frequencies of UGT1A1*28 alleles vary significantly among different ethnic groups: UGT1A1*28 alleles are present in approximately 35% of Caucasians and African Americans while their frequency is much lower in Asians [26, 27]. In addition, common UGT1A1 promoter variants are in linkage disequilibrium, and the haplotype structure of the promoter appears to differ among ethnic groups [27]. A recent prospective study by Innocenti et al. [25] demonstrated, with sufficient statistical power, that patients with a UGT1A1*28 allele are at higher risk of grade 4 neutropenia. While that study clearly illustrates the importance of UGT1A1 pharmacogenetics as a molecular predictor of irinotecan toxicity, clinical guidelines have yet to be developed with regard to dosage adjustment or selection of alternative nonirinotecan-containing regimens. Clinical trials are ongoing or planned to address the impact of dose on irinotecan safety in patients with different UGT1A1*28 genotypes [6, 28].

Dihydropyrimidine dehydrogenase and 5-FU
Based on its activity against a variety of tumors and synergistic interactions with other chemotherapy agents, 5-fluorouracil (5-FU) and its derivatives remain some of the most commonly prescribed chemotherapy agents [29]. Approximately 5% of administered 5-FU undergoes anabolism into cytotoxic nucleotides responsible for its antitumor activity, whereas the other 80%–95% undergoes catabolism into biologically inactive metabolites that are excreted in the urine and bile [30]. Dihydropyrimidine dehydrogenase (DPD) catalyzes the rate-limiting step in 5-FU catabolism; therefore, variability in this enzyme activity is one of the major factors that influences systemic exposure to fluorodeoxyuridine monophosphate (FdUMP) and the incidence of adverse effects to 5-FU [31]. DPD activity is completely or partially deficient in 0.1% and 3%–5% of individuals in the general population, respectively, and DPD deficiency has been associated with severe toxicity and fatal outcomes after 5-FU treatment [32–34].

DPD deficiency appears to be a genetic disorder arising from multiple polymorphisms in the DPYD gene resulting in decreased enzyme activity [35]. Analyses of the prevalence of the various mutations in the DPYD allele have shown that a guanidine to adenine point mutation in the invariant splice donor site (DPYD*2A) is by far the most common [36]. The molecular and genetic bases behind DPD deficiency and 5-FU toxicity have not been fully elucidated, as clinical findings are often not associated with a detectable mutation in the DPYD gene [36]. The clinical utility of examining variations in the DPYD gene should be further explored in combination with other markers for the prospective identification of high-risk patients for severe 5-FU toxicity.

Polymorphisms in Drug Transporters

MDR1 (P-glycoprotein, ABCB1)
P-glycoprotein (PGP), encoded by the MDR1 gene (ABCB1), is the best-characterized ATP-binding cassette (ABC) transporter. PGP was initially found to be overexpressed in multidrug resistant cancers [37]. PGP is involved in the transport of a large range of hydrophobic drugs, including cytotoxic chemotherapeutic agents (e.g., doxorubicin [Adriamycin®; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com], paclitaxel [Taxol®; Bristol-Myers Squibb; Princeton, NJ, http://www.bms.com]), hormones, and carcinogens as well as an array of structurally divergent drugs [38, 39]. This membrane efflux transporter is also found in normal tissues, such as the canalicular domain of hepatocytes, proximal tubules of the kidney, brush border of the small intestine, colon, adrenal glands, and capillary endothelium of the brain and testes [40–42]. In addition to its wide tissue distribution, PGP expression varies markedly among individuals. Genetic variations in the MDR1 gene have been correlated with drug exposure of some commonly prescribed drugs such as digoxin (Lanoxin®; GlaxoSmithKline; Research Triangle Park, NC, http://www.gsk.com) and fexofenadine (Allegra®; Aventis Pharmaceuticals Inc.; Bridgewater, NJ, http://www.aventis.com) [43, 44]. Multiple MDR1 polymorphisms have been described to occur in various allelic combinations. Grouping these polymorphisms into haplotypes may serve as a useful predictor of the functional consequences of MDR1 polymorphisms. The frequencies of variant MDR1 alleles differ, depending on racial background, raising the possibility of racial differences in chemotherapy pharmacokinetics and response [45, 46]. For example, the C3435T polymorphism (exon 26) has a frequency of 73%–84% in individuals of African origin and frequencies of 34%–59% in individuals of European and Asian origin [44]. A recent report also indicated that MDR1 polymorphisms may play a role in determining the pharmacokinetic and clinical toxicity profile of irinotecan [47]. Other studies evaluating the relationship between allelic variations in MDR1 and chemotherapy disposition and response are in progress.

Polymorphisms in Drug Targets

Thymidylate Synthase and 5-FU
One of the primary mechanisms of action of 5-FU is the inhibition of thymidylate synthase (TS) by FdUMP. TS is the critical enzyme in the de novo synthesis of thymidylate, an essential precursor of thymidine triphosphate, which is required for DNA synthesis and repair [48]. TS inhibition is, therefore, an important target for 5-FU as well as other folate-based antimetabolites, and clinical resistance to these TS-targeted agents has been linked to overexpression of TS in tumor [49–51]. TS expression levels in vivo appear to be regulated by the number of polymorphic tandem repeats in the TS enhancer region (TSER), where increases in TS expression and enzyme activity have been observed with increasing copies of the tandem repeats [52, 53].

Clinical studies have demonstrated that individuals who were homozygous for the TS promoter alleles TSER*3 (three tandem repeats) had significantly higher TS mRNA expression levels in tumor tissue than those with TSER*2 (two tandem repeats) and that these findings correlated with a lower response rate to 5-FU [54]. Another study in rectal cancer patients reported a very significant correlation between TSER genotypes and tumor downstaging after preoperative chemoradiation [55]. In addition, a recent study [56] reported that a G>C variation within the tandem repeats of the TSER*3 genotype affected the transcriptional activation of the TS gene. Together, these studies suggest that TSER genotyping may be useful in selecting patients who are likely to respond to treatment with 5-FU or its analogues.


   PHARMACOGENOMICS TECHNOLOGY
Top
 Learning Objectives
 Abstract
 Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
Application of Pharmacogenomics...
 Conclusions
 References
 
During the past decade, technologies to identify genetic variations have evolved from labor-intensive, time-consuming, and expensive processes to being highly automated, efficient, and relatively inexpensive. Indeed, genotyping can be performed on readily available whole blood samples. Genomic DNA can be extracted from the buffy coat fraction of whole blood samples, and high-throughput genotyping analyses can be efficiently performed to evaluate whether particular genetic variations (germline polymorphisms) are associated with drug response or toxicity. These advances in genotyping technology provide the ability to assess the prognostic and predictive values of candidate genetic markers when evaluating drug pharmacokinetics or effects.

Current high-throughput genotyping techniques are mostly based on polymerase chain reaction (PCR) technology, in which DNA containing the polymorphic area of interest is amplified. The polymorphisms can then be detected through band pattern analysis on an agarose gel, by annealing temperature, or by direct DNA sequencing. Similar techniques can be applied to detecting somatic mutations (tumor mutations) or variations in tumor gene expression for further evaluation of genotype-phenotype correlations. This technology has recently been applied to the detection of activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) that are associated with clinical response to gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE, http://www.astrazeneca-us.com) [57, 58].


   APPLICATION OF PHARMACOGENOMICS TO DRUG DEVELOPMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
Conclusions
 References
 
One of the most promising areas in which pharmacogenomic analysis can be applied is cancer drug development and early-stage clinical trials [59, 60]. For example, selective genotyping can be performed in stratifying the trial population (genostratification) to achieve better treatment success in clinical trials. By creating a genetically preselected (or predefined) population, the application of pharmacogenomics to clinical trials may assist in reaching "proof of concept" in a shorter time and also allow for a reduction in sample size and/or trial duration. Figure 2Go illustrates the processes of pharmacogenomic studies for identification of genetic markers predictive of patient responses to or toxicity from cancer chemotherapy. Identification of genetic/molecular markers with diagnostic and prognostic power may help not only to accelerate drug approval, but also to manage postapproval risks. With the advances of pharmacogenomic technologies (e.g., genotyping, expression profiling, proteomics), the functional significance of candidate genetic markers can be examined in terms of mRNA/protein expression (e.g., gene microarrays, proteomics, immunohistochemistry) and in vitro functional assays. The clinical significance of inherited variations can be further defined through rationally designed prospective clinical trials.



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  		Figure 2. Processes of cancer pharmacogenomic studies for identification of genetic/molecular markers predictive of patient response to chemotherapy.

 

   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
References
 
Given the narrow therapeutic indices and marked heterogeneity in patient responses, a better understanding of the genetic bases for interindividual differences in drug effect has the potential to significantly enhance the efficacy of chemotherapeutic agents. Moreover, such information may allow for rational selection of chemotherapy agents and optimization of dosing regimens for individual cancer patients. Indeed, inclusion of pharmacogenomic information and DNA collection may become essential during early phases of clinical drug development. Large, prospectively designed clinical trials will be necessary to assess the impact and cost-effectiveness of pretreatment genotyping approaches. Accordingly, the application of cancer pharmacogenomics has the potential for "individualized cancer therapy" in terms of the optimal drug combinations and doses that maximally benefit individual patients.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Genetic Variations Affecting...
 Pharmacogenomics Technology
 Application of Pharmacogenomics...
 Conclusions
 References
 

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