Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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156 Applying Pharmacogenomics in TherapeuticsTABLE 6.4 (Continued)PGx Biomarkers for the Selection of Cancer TherapyPGxBiomarkerPML-RAR-αtranslocationin APLBRAFMEKTherapeuticAgentsArsenictrioxide(Trisenox ® )Vemurafenib(Zelboraf ® ),dabrafenib(Tafinlar ® ),trametinib(Mekinist ® )Mutations to BeDetected Potential Clinical Impact ASCO or NCCN Guidelinest(15:17)translocationdetermined byFISH orPML-RAR-αgene expressionSubstitution ofglutamic acid forvaline at aminoacid 600(V600E)Substitution oflysine for valineat the amino acid600 (V600K)Presence of PML-RAR-αfusion gene predictsclinical outcomefollowing arsenic trioxidetreatment.Presence of the substitutionmutations in the BRAFgene predicts andindicates clinical outcomefollowing the BRAFinhibitortherapies such asvemurafenib, dabrafenib,and trametinib.Arsenic trioxide induces PML-RAR-α degradation.Diagnostic testing of PML-RAR-α is required fortreatment with arsenic trioxide.Used for remission induction and consolidation inpatients with relapsed or refractory APL characterizedby PML-RAR-α expression. 45Recommends genetic testing for metastatic melanomato detect the presence of BRAF mutation to considerwhether or not BRAF inhibitors are valid therapyoptions.Sources: FDA Drug Package Inserts, Lexi-Comp Drug Monographs, ASCO Clinical Guidelines, NCCN Clinical Guidelines. (Adapted from Feng X,et al., US Pharmacist, 36(11), 5–12, 2011. With permission.)Note: APL, acute promyelocytic leukemia; CML, chronic myelogenous leukemia; EGFR, epidermal growth factor receptor; FISH, fluorescencein situ hybridization; GIST, gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry;K-RAS, Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NSCLC, non–small cell lung cancer; PML-RAR-α, promyelocytic leukemiaprotein-retinoic acid receptor alpha; SCCHN, squamous cell carcinoma of head and neck.
Clinical Applications of Pharmacogenomics in Cancer Therapy157glucuronidation, prolonged SN-38 half-life, increased exposure to SN-38 (AUC), andlate-onset diarrhea. UGT1A1 expression is highly variable. Clinical evidence indicatesthat the steady-state concentrations of SN-38 may vary by up to 50-fold betweenUGT1A1*28 homozygous and heterozygous groups. Patients have a five- to ninefoldgreater risk of grade 4 leukopenia with the standard dosage of irinotecan. 46–48The US FDA recommends dose reduction in patients homozygous for theUGT1A1*28 allele, and some studies recommend 20% dose reduction for patientshomozygous for UGT1A1*28. Caution and possible dose reduction are advised forpatients with heterozygous UGT1A1*28 allele (Table 6.2). 25,26,46,47Nilotinib is indicated for the treatment of chronic myeloid leukemia (CML)(Ph +). Nilotinib is an inhibitor of the Bcr-Abl kinase that binds to and stabilizes theinactive conformation of the kinase domain of the Abl protein. It is also an inhibitorof UGT1A1 in vitro, and individuals with the UGT1A1*28 (TA) 7 /(TA) 7 are at anincreased risk of hyperbilirubinemia when taking nilotinib compared to those withthe (TA) 6 /(TA) 6 or (TA) 6 /(TA) 7 genotypes. The largest increases in bilirubin wereobserved in the UGT1A1*28 (TA) 7 /(TA) 7 patients. (TA) 7 /(TA) 7 polymorphism occursat up to 42% in individuals with African or South Asian ancestry. 27,49The mechanism by which hyperbilirubinemia occurs with both nilotinib andUGT1A1(TA) 7 /(TA) 7 is still unclear. Hypothetically, nilotinib inhibits UGT1A1activity, which includes the glucuronidation of bilirubin. The already sensitized(TA) 7 /(TA) 7 genotype will further push patients into a hyperbilirubinemia state. TheUS FDA recommends, but does not require, genetic testing for UGT1A1 variantsprior to initiating or reinitiating treatment with nilotinib. 27,48,49PATIENT CASE 2KC is a 13-year-old boy who was diagnosed with ALL. He has finished his inductionand consolidation therapies and will need to move on to his maintenance therapy.Question: Knowing that the maintenance portion of his therapy requires mercaptopurine(6-MP), what should be considered for KC?Answer: TPMT genetic testing should be considered. If KC is a PM of TPMT, areduction of 6-MP dose should be warranted in order to reduce side effects. 6-MPtoxicity may include drug fever, hyperpigmentation, myelosuppression (anemia,thrombocytopenia, and neutropenia).TPMT Polymorphisms and 6-MP6-MP is extensively used in the maintenance chemotherapy for ALL in children.TPMT is responsible for the S-methylation of 6-MP to 6-methylmercaptopurine,which diverts the prodrug 6-MP from converting to 6-thioguanine for its incorporationinto DNA and suppresses tumor DNA synthesis. 6-Thioguanine is the activemetabolite of 6-MP that affects drug efficacy and toxicity.Most large-scale PGx studies indicate that TPMT activity is highly variable andpolymorphic. Approximately 90% of individuals have high activity (EMs), 10% haveintermediate activity (IMs), and 0.3% have low activity or complete deficiency of
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DedicationWe dedicate this book to
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viiiContentsChapter 10 Pharmacogeno
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EditorsXiaodong Feng, PhD, PharmD,
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ContributorsWeiguo Chen, PhDDepartm
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BIOMEDICAL SCIENCEApplying Pharmaco
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Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

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