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2007 20: 246Journal of Pharmacy PracticeJodi L. Grabinski

Pharmacogenomics of Anticancer Agents: Implications for Clinical Pharmacy Practice  

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Pharmacogenomics of Anticancer Agents:Implications for Clinical Pharmacy Practice

Jodi L. Grabinski, PharmD, MS, BCOP

THE USE OF PHARMACOGENOMIC INFORMA-TION is being investigated increasingly for

incorporation into decisions regarding medical treat-ment as a method to provide personalized medica-tion therapy. Within the field of oncology, the use ofpharmacogenomics is actually fairly mature, as it hasbeen used for the selection of anticancer therapy fora number of years. One of the first examples relatedto this is the molecularly driven therapy trastuzumab(Herceptin), which targets the HER2/neu (epidermalgrowth factor receptor 2, erbB2) receptor in patientswhose tumors overexpress the HER2/neu protein.

Based on increasing pharmacogenomic informa-tion, the package inserts of 2 frequently used anti-cancer agents, 6-mercaptopurine and irinotecan, nowhave specific wording recommending that genotypingbe performed for their respective drug-metabolizingenzymes before initiating therapy with these agents.Additionally, there have been a number of genotypingsystems recently approved by the US Food and DrugAdministration (FDA) for use in clinical practice. The first of these assays to be approved was theAmplichip CYP450 Test by Roche Diagnostics (RocheMolecular Systems, Inc., Pleasanton, California). It pro-vides individual genotype information for theCYP2D6 and CYP2C19 genes, which metabolize a number of agents used today in clinical practice.The assay evaluates 3 allelic variations within theCYP2C19 gene and 27 allelic variations within theCYP2D6 gene. Third Wave Technologies (Madison,Wisconsin) developed a genotyping test for the

UGT1A1 gene, which is involved in the conjugationof irinotecan. As a result of clinical studies validatinghow various polymorphisms influence response totherapy, FDA label changes supported by ClinicalLaboratory Improvement Amendments (CLIA)–approved tests, and current procedural terminology(CPT) codes, pharmacogenomics will become a pro-fessional expectation. The goal of this review is toprovide an update on the pharmacogenomics of vari-ous treatments used in hematology and oncology andhow they are influencing practice today.

TAMOXIFEN

In recent years, the pharmacogenomics of tamox-ifen has become an intense area of research. Themajority of the data focused on the evaluation of both

Hematology and oncology have been two of the leading areasin pharmacogenomics. The use of genetic information toguide therapy has been practiced for a number of years. Theidentification of polymorphisms within drug-metabolizingenzymes of anticancer agents such as 6-mercaptopurine andirinotecan has led to subsequent changes in package-insertlabeling and tests approved by the US Food and DrugAdministration to identify polymorphisms. Many studieswithin oncology are now conducting pharmacogenomic

analyses in drug development to identify predictors ofresponse and/or toxicity. For clinical pharmacists, knowl-edge in the area of pharmacogenomics and drug metabolismis important to understand and integrate pharmacoge-nomics into clinical practice. This article will review anumber of different agents used in the realm of oncology andwill identify how pharmacogenomics has or will potentiallyaffect treatment decisions in the future with the goal ofimproving patient care and outcomes.

To whom correspondence should be addressed: Jodi L. Grabinski,Director, Center for Pharmacogenomic Research, University ofTexas College of Pharmacy, Pharmacotherapy Education andResearch Center, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC–6220, San Antonio,TX 78229-3900; E-mail: grabinski@uthscsa.edu.

Jodi L. Grabinski, assistant professor, director, Center for Pharma-cogenomic Research, University of Texas College of Pharmacy,Pharmacotherapy Education and Research Center, University ofTexas Health Science Center at San Antonio, San Antonio, Texas.

JOURNAL OF PHARMACY PRACTICE 2007. 20;3:246–251© 2007 Sage PublicationsDOI: 10.1177/0897190007304822

KEY WORDS: Pharmacogenomics, oncology, drug metabolism, polymorphism.

ANTICANCER AGENTS

Phase I and Phase II drug-metabolizing enzyme poly-morphisms as they relate to formation of metabolitesand therapeutic outcomes. One of the first studies to evaluate the correlation of genotype to outcome was conducted by Nowell and colleagues.1 Theycollected retrospective data to evaluate the influenceof the (human sulfotransferase 1A1) SULT1A1 geneon outcome in early-stage breast cancer patients whoreceived adjuvant tamoxifen therapy. SULT1A1 is aPhase II metabolizing enzyme involved in the conju-gation of tamoxifen. In this case-control study, 160patients who had received tamoxifen and 177 whohad not were genotyped for the SULT1A1 gene. Theinvestigators observed that patients receiving tamox-ifen, homozygosity for the SULT1A1*2 allele wasassociated with 3 times the risk of death (HR = 2.9, CI1.1-7.6). There was no association between theSULT1A1 genotype and survival in patients who didnot receive tamoxifen.

Overall, the metabolism of tamoxifen is very com-plex (Figure 1). Not only is the SULT1A1 gene involvedin the conjugation of the drug, but tamoxifen first goesthrough Phase I metabolism to form the active metabo-lites 4-hydroxytamoxifen and endoxifen. Thesemetabolites have a greater affinity for the estrogenreceptor than does the parent drug, tamoxifen. Jin et al2

examined the influence of CYP2D6, CYP2C9, CYP3A5,and SULT1A1 genes and CYP2D6 inhibitors on tamox-ifen metabolism. This study enrolled patients whowere beginning tamoxifen therapy and collectedplasma samples at 1 and 4 months to evaluate plasmaconcentrations of tamoxifen and its metabolites.Patients with a CYP2D6 homozygous variant (ie,CYP2D6*4/*4, poor metabolizer) or a heterozygousgenotype had significantly lower concentrations of themetabolite endoxifen. Patients who were homozygouswild-type but receiving CYP2D6 inhibitors had endox-ifen concentrations that were 58% lower than those ofpatients who were not on inhibitors. In this study, theother genes that were tested did not influence tamox-ifen or its metabolite concentrations.

Our group conducted a similar study to evalu-ate the CYP2C9, CYP2D6, SULT1A1, and estrogen-receptor alpha genes on tamoxifen metabolism.3 Weenrolled more than 300 breast cancer patients whohad been receiving adjuvant tamoxifen therapy for atleast 8 weeks. We assessed the correlations betweengenotype and levels of tamoxifen and metabolite. Weidentified a correlation between the CYP2D6 geno-type and levels of 4-hydroxytamoxifen (P = .0002).There was also an association between the estrogenreceptor alpha Pvu II genotype and levels of tamox-ifen (P = .02). These studies helped to establish acorrelation between genotype and metabolite levels.However, further prospective data is needed todemonstrate an effect on outcomes. Goetz and col-leagues4 conducted a retrospective study of CYP2D6genotypes from nearly 200 women who had receivedtamoxifen. They identified that women with theCYP2D6*4/*4 genotype had shorter relapse-freetime (P = .023) and disease-free survival (P = .012);however, overall survival (P = .169) was not statisti-cally significant.

These recent studies comparing tamoxifen metab-olism to response and drug concentration demon-strate the potentially strong association between theCYP2D6 genotype and tamoxifen metabolism. If fur-ther prospective data confirm these findings, genotyp-ing before tamoxifen therapy may become a standardof care. For patients who are considered poor metabo-lizers of CYP2D6, treatment with an alternative ther-apy such as an aromatase inhibitor may be a betteroption. Further studies will answer this question.These studies also demonstrate that the use of potentCYP2D6 inhibitors (eg, paroxetine) in combinationwith tamoxifen therapy should be used with cautionand/or avoided if possible.

IRINOTECAN

Pharmacogenomic investigations of irinotecanhave centered on polymorphisms in the UGT1A1gene. Evaluations have centered primarily on a poly-morphism within the promoter region of the gene,where a dinucleotide repeat is thought to play a sig-nificant role in the development of toxicity in patientsreceiving irinotecan therapy. Irinotecan is a prodrugthat is converted to its active metabolite SN-38 viacarboxylesterases. SN-38 has a stronger inhibitoryeffect on topoisomerase I than does irinotecan.5 SN-38is inactivated via glucuronidation, primarily byUGT1A1, to form SN-38G. UGT1A1 also catalyzesbilirubin glucuronidation and has been studied inrelation to hyperbilirubinemia syndromes such as

JOURNAL OF PHARMACY PRACTICE 2007(20.3) •• 247

SULT1A1

CYP3A4/5

4-hydroxy-N-desmethyltamoxifen(Endoxifen)CYP2D6 SULT1A1

CYP3A4/5

CYP2D64-hydroxytamoxifenTamoxifen

N-desmethyltamoxifen

Figure 1. Major genes involved in the metabolism of tamoxifen.2

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248 •• JOURNAL OF PHARMACY PRACTICE 2007(20.3)

Crigler-Najjar and Gilbert syndrome.6 The wild-typegene contains 6 dinucleotide repeats (TA6), whereasthe variant has 7 repeats (TA7) and is referred to asUGT1A1*28. In vitro data have demonstrated that thehomozygous variant (TA7/7) genotype results indecreased glucuronidation of SN-38.7 This causes theaccumulation of SN-38, which may lead to increasedtoxicity such as neutropenia and prolonged diarrhea.

A prospective study in humans evaluated the effectof this particular polymorphism on toxicity associatedwith irinotecan therapy.8 Twenty patients with solidtumors receiving irinotecan every 3 weeks wereenrolled. Patients were genotyped for the UGT1A1*28polymorphism, and plasma levels for irinotecan, SN-38, and SN-38G were analyzed. Patients with variantUGT1A1 alleles had lower glucuronidation rates.They also experienced more diarrhea and neutropeniathan did those without the polymorphism. Inno-centi et al9 conducted a similar study, evaluating theassociation between UGT1A1 variants and toxicity in66 patients receiving irinotecan. The prevalence ofgrade 4 neutropenia was 50% among those homozy-gous for the UGT1A1*28 allele, 12.5% among heterozygous individuals, and 0% among wild-typehomozygous individuals. This translated into a rela-tive risk of neutropenia of 9.3 (95%, CI 2.4-36.4) inthe UGT1A1*28 homozygous patients compared tothose with other genotypes. The overall incidence ofgrade 3 diarrhea was extremely low in this study,and differences among genotype groups could not bedetected. Bilirubin levels before treatment corre-lated with genotype (P < .01), and higher bilirubinlevels were seen in the patients who developedgrade 4 neutropenia. Bilirubin levels should be assessedbefore therapy, regardless of the patient’s geneticinformation.

In July 2005, the irinotecan package insert under-went labeling changes regarding the dosing ofpatients with a UGT1A1 polymorphism. The recom-mendation in patients who are known to be homozy-gous for the UGT1A1*28 is to reduce the startingdose by at least 1 dose level.10 This recommendationapplies both to irinotecan as a single agent and toirinotecan in combination with other agents. There iscurrently no recommendation for a dose reductionfor patients who are heterozygous (TA6/7). However,these patients may be at higher risk for developingneutropenia with typical starting doses of irinotecan.Shortly after the FDA labeling changes, Third WaveTechnologies Invader UGT1A1 Molecular Assay wasapproved by the FDA. This genotyping assay tests forthe UGT1A1*28 allele. Multiple sites across theUnited States are now genotyping for this polymor-phism, and results are available within days.

6-MERCAPTOPURINE

Acute lymphocytic leukemia (ALL) is the mostcommon type of cancer in children, and 6-MP is acommon agent used in the treatment. The pharma-cogenomic evaluation of 6-mercaptopurine (6-MP)has primarily focused on 3 variant alleles of TPMT:TPMT*2, TPMT*3A, and TPMT*3C. These accountfor 95% of the variant alleles detected. 6-MP andazathioprine are prodrugs that are converted to theiractive metabolites, thioguanine nucleotides (TGNs).The TGNs inhibit nucleic-acid synthesis throughincorporation into DNA.11 TPMT deficiency is anautosomal recessive trait affecting approximately 1in 300 individuals, and it can lead to severe tox-icity in patients receiving 6-MP or azathioprinetherapy.

Evans and colleagues examined the TPMT geno-type-to-phenotype relationship in 23 patients who hadbeen referred as a result of 6-MP or azathioprine (AZA)toxicity.12 Six patients carried the homozygous variant(TPMT deficient, TPMT*3A/TPMT*3A), 9 were het-erozygous, and the remainder were homozygous wildtype (TPMT*1/*1). Concordance between phenotypeand genotype was demonstrated in all homozygous-variant and wild-type individuals. Toxicity presentedprimarily as hematopoietic toxicity. In patients whowere homozygous variant, a median 90.8% dosagereduction was necessary to avoid the toxicity associ-ated with 6-MP.

Through statistical modeling, Relling and col-leagues compared the pharmacology of 6-MP and tol-erance in patients who achieved a total remission on weekly methotrexate (40 mg/m2) and daily 6-MP(75 mg/m2).13 Phenotypic data was assessed eitherthrough TPMT activity (n = 154) or by erythrocytethioguanine nucleotides (n = 26). Of the 180 patients,2 were homozygous deficient, 17 were heterozygous,and 161 were homozygous wild type. The TPMTgenotype was evaluated in 28 patients representingeach of the various phenotypes. Dose reductionsbecause of toxicity occurred in 100% of the patientswho were homozygous deficient, 35% of the het-erozygous patients, and 7% of the homozygous wild-type patients. The average (SD) final weekly 6-MPdoses were 72 mg/m2 (± 60), 449 mg/m2 (± 160), and528 mg/m2 (± 90), respectively.

The results of these and other studies led to label-ing changes in July 2004 for the package insert of 6-MP. These changes addressed the issue of patientswho are TPMT deficient and acknowledged that thissubset has a higher incidence of toxicity while receiv-ing 6-MP. The insert also acknowledges that startingdoses in patients who are homozygous deficient have

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not been established and that tests to assess TPMTstatus are available.14 CLIA-certified laboratories forgenotyping and CPT codes for billing are available.

FLUOROURACIL

Fluorouracil (5-FU) has a complex metabolic pro-file. A number of genes have been evaluated in associ-ation with 5-FU. The most common enzyme evaluatedis dihydropyrimidine dehydrogenase (DPD), whichhas been associated with increased toxicity on 5-FUtherapy. DPD is an important enzyme involved in theinactivation of 5-FU. Patients with low DPD activityexperience the accumulation of metabolites, whichcan result in excessive toxicity. Approximately 3% ofthe population is considered heterozygous for muta-tions involved in the inactivation of DPD, and 0.1% ishomozygous for these mutations.15

A splice-site mutation (G → A) in the DPD gene(DPYD*2A) leads to truncated mRNA, and subse-quently to a defective protein. This mutated proteinis quickly degraded and leads to decreased DPDenzyme activity.16,17 The DPYD*2A mutation and theinability to degrade 5-FU have been associated withlethal outcomes in patients receiving 5-flurorouraciltherapy.18 DPD deficiency and toxicity associatedwith 5-FU therapy are well documented. However,there are currently no recommendations for screeningpatients before therapy, principally because of theavailability of a genotyping assay. Investigators fromthe University of Alabama have developed an oral [2-13C] uracil breath test (UraBT), which discriminatesbetween normal and DPD-deficient individuals.19,20

Although the test is not currently commercially avail-able, in the future, it may offer a method of assessingDPD status in patients receiving 5-FU. Additionally,other enzymes also known to be polymorphic, such asthymidylate synthase (TS), play a role in the metabo-lism and activity of 5-FU.21-24

GEFITINIB, ERLOTINIB

Gefitinib and erlotinib, epidermal growth factorreceptor (EGFR) inhibitors, were approved in 2003and 2004, respectively, for the treatment of patientswith advanced non–small-cell lung cancer (NSCLC)who did not respond to conventional chemotherapy.The Iressa Dose Evaluation in Advanced Lung Cancer(IDEAL) 1 trial assessed the efficacy and tolerability of2 different doses (250 mg, 500 mg) of gefitinib. Efficacywas similar in both groups, with objective tumor-response rates of about 19% as second- and third-linetreatment.25 The IDEAL 2 trial assessed symptomaticand radiographic differences in response between the

2 doses of gefitinib. Partial radiographic responseswere seen in 12% of the group that received 250 mgdaily and in 9% of the group that received 500 mgdaily.26 In these studies, certain subgroups seemed tohave higher response rates. Responders includedpatients who were female, Japanese, and whose tumorhistology was adenocarcinoma. Miller and colleaguesretrospectively reviewed the use of gefitinib therapy to identify predictors of sensitivity to gefitinib.27

They determined that adenocarcinomas of the bron-chioloalveolar subtype and patients who had neversmoked were significant predictors of response.

Investigators have also evaluated the use of molec-ular predictors of response to EGFR inhibitors.28,29

Although the overall response rates to EGFR inhibitorshave been low, the response rates among those who dorespond are profound. Lynch and colleagues extractedDNA from surgical tumor specimens and sequencedthe coding region of EGFR. Somatic mutations withinthe tyrosine kinase domain of the EGFR gene wereidentified in 8 of 9 patients who were responsive togefitinib. In contrast, none of the 7 patients who didnot respond to therapy had mutations in their tumors(P < .001).29 These mutations led to increased growth-factor signaling and increased sensitivity to EGFRinhibition. Paez and colleagues identified patientswho contained somatic substitution mutations withintumor tissue at G719S and L858R and a site that con-tained a deletion.28 These mutations were more fre-quently identified in adenocarcinomas, women, andJapanese patients and were associated with responseto therapy. Certain mutations may be better predictorsof response to gefitinib or erlotinib therapy. Riely andcolleagues evaluated the exon 19 deletion and theL858R mutation.30 In patients who had received eithererlotinib or gefitinib, those with EGFR mutations hada median survival of 20 months. Those with exon 19deletions had a significantly longer median survivalthan patients with the L858R mutation (34 vs 8months, P = .01). Another study published similarresults in that patients with exon 19 deletions had asignificantly longer overall survival compared withthose who had the L858R mutation (38 vs 17 months,P = .04).31

Shepherd and colleagues conducted a similar studyevaluating erlotinib after the failure of first- or second-line chemotherapy.32 The primary endpoint wasoverall survival, and secondary endpoints includedprogression-free survival, overall response rate, dura-tion of response, toxic effects, and quality of life. Theresponse rate in the erlotinib group was 8.9%, and itwas less than 1% in the placebo group (P < .001).Differences favoring erlotinib were also significant in relation to progression-free survival and overall

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survival, and the median duration of response waslonger in the erlotinib group (7.9 vs 3.7 months).Response was higher among women, nonsmokers,Asians, patients with adenocarcinoma, and patientsin whom 10% or more of the tumor cells expressedEGFR. Tumor biopsy samples from this trial wereused to evaluate mutations within the EGFR gene.33

Samples were tested immunohistochemically forEGFR expression, and sequencing of exons 18through 21 was done to identify mutations withinthis area. Fluorescence in situ hybridization (FISH)was conducted to determine the number of copies ofthe EGFR gene to identify molecular predictors ofresponse. In the univariate analysis, survival waslonger in those patients whose tumor expressed EGFRor had a higher number of copies of EGFR. In the mul-tivariate analysis, adenocarcinoma, nonsmokers, andexpression of EGFR were all significantly associatedwith an objective response. In this study, mutationalstatus did not significantly affect survival.

Acquired resistance to these agents can also be aproblem. Progression-free survival in patients whoharbor an EGFR mutation ranges from 5 months inpatients with L858R mutations to 12 months for thosewith exon 19 deletion mutations.30 Balak and col-leagues evaluated tumor cells from patients who haddeveloped acquired resistance to either gefitinib orerlotinib.34 Of the 16 patients who developed resis-tance, 8 had tumor cells that contained second-siteEGFR mutations. Of these 8 patients, 7 had T790Mmutations located in exon 20, and 1 was a novelD761Y mutation. In 4 of the T790M patients in whichtissue was available pretreatment and posttreatment,the mutation was not present in the pretreatment spec-imen. A comparison of predictors of response andresistance to EGFR therapy are listed in Table 1.

At this time, the use of genetic testing in this areato evaluate EGFR therapy is still investigational.EGFR mutation testing identifies somatic mutationswithin the tumor, whereas most pharmacogenomicstudies are evaluating germline polymorphisms. As

pharmacogenomic tests become more advanced andthe significance of various EGFR polymorphisms isdiscovered, the use of genetic testing to guide ther-apy may be standard practice in the future.

These are just a few examples of how pharma-cogenomics is currently being used within the area ofhematology and oncology. As pharmacogenomics isincorporated into more clinical trials and phase IVstudies, the FDA will incorporate changes to packageinserts and approve additional genotype assays.These changes on the part of the FDA will allow fur-ther expansion of pharmacogenomics into clinicalpractice. A firm understanding of the area of phar-macogenomics and genetic-test interpretation willallow pharmacists to lead the way in the incorpora-tion of pharmacogenomics into clinical practice withthe hope of individualized treatment and subsequentimprovement in therapy and outcomes.

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Table 1Predictors of Response and Resistance to

EGFR Tyrosine Kinases

Response Resistance

Women (Asian) SmokersNonsmokers Kras mutationAdenocarcinoma (bronchioloalveolar) Squamous cell histologyRash No rashEGFR mutation (deletion exon EGFR mutation (T790M)

19 > L858R)

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JOURNAL OF PHARMACY PRACTICE 2007(20.3) •• 251

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26. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, aninhibitor of the epidermal growth factor receptor tyrosinekinase, in symptomatic patients with non-small cell lung can-cer. JAMA. 2003;290(16):2149-2158.

27. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar patho-logic subtype and smoking history predict sensitivity to gefi-tinib in advanced non-small-cell lung cancer. J Clin Onc.2004;22(6):1103-1109.

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31. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 mutationsof epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patientstreated with gefitinib or erlotinib. Clin Cancer Res. 2006;12(13):3908-3914.

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33. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N EnglJ Med. 2005;353(2):133-144.

34. Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and commonsecondary T790M mutations in epidermal growth factorreceptor-mutant lung adenocarcinomas with acquired resis-tance to kinase inhibitors. Clin Cancer Res. 2006;12(21):6494-6501.