Pharmacogenetics : making cancer treatment safer and more effective

Chemotherapy has made a dramatic difference to improved survival in patients with cancer. However, not all patients respond and some experience serious side effects. "Pharmacogenetics: Making cancer treatment safer and more effective" is an up to date summary of the exciting new field of how genetic testing can tailor more effective prescription in oncology. It is targeted at oncologists and professionals involved in the treatment of patients with cancer. It provides a core background in genetics and pharmacological principles before providing chapters from acknowledged experts in the field on genetic tests in specific cancer types, including breast, bowel and lung cancer. Clinical cases are used to illustrate the practical application of this knowledge. Chapters on ethics, health economics and the industry aspects of pharmacogenetics set out the challenges and opportunities afforded by this new science. Contents Contributors Abbreviations Introduction 1 Principles of Cancer Treatment 1.1 Introduction 1.2 Context of Chemotherapy 1.3 Classes of Chemotherapy Drugs 1.4 Clinical Trials of Chemotherapeutic Agents 1.5 Defining Outcomes to Treatment 1.5.1 Trial Endpoints 1.6 What is an Adverse Drug Reaction to Chemotherapy? 1.7 Concluding Remarks References 2 Clinical Pharmacology and Anticancer Drugs 2.1 Introduction 2.2 Pharmacokinetics 2.2.1 Drug Absorption 2.2.2 Drug Distribution 2.2.2.1 Protein Binding 2.2.2.2 Blood--Brain Barrier 2.2.2.3 Enterohepatic Circulation 2.2.3 Drug Metabolism 2.2.3.1 First-Pass Metabolism 2.2.4 Drug Excretion 2.2.4.1 Renal Excretion 2.2.4.2 Biliary Elimination 2.3 Drug Metabolizing Enzymes 2.3.1 Phase I Drug Metabolism 2.3.2 Phase II Drug Metabolism 2.4 Drug Transporters 2.4.1 Multidrug Resistance (MDR1) P-glycoprotein 2.4.2 Multidrug Resistance-Associated Proteins (MRPs) 2.5 Pharmacokinetic-Pharmacodynamic Relations 2.6 Variability in Drug Response 2.7 Clinical Pharmacology of Anticancer Drugs 2.7.1 Non-Targeted Chemotherapy 2.7.2 Targeted Therapies 2.8 Concluding Remarks References 3 Principles of Genetics and Pharmacogenetics 3.1 Genetic Principles 3.2 DNA, RNA and Proteins 3.2.1 DNA Replication 3.2.2 Transcription to Form RNA 3.2.3 Translation to Form Proteins 3.3 Types of Genetic Variation 3.3.1 Mutations 3.3.2 Polymorphisms 3.3.3 Variable Nucleotide Tandem Repeats (VNTR) 3.3.4 Copy Number Variants (CNVs) 3.3.5 Inversions 3.4 Human Genome and HapMap Projects 3.5 Detection of Genetic Variants 3.5.1 Polymerase Chain Reaction (PCR) 3.5.2 Techniques to Use When the Genetic Variant is Unknown 3.5.2.1 DNA Sequencing 3.5.2.2 Alternative Techniques for Mutation Screening 3.5.3 Techniques When the Genetic Variant is Known 3.5.3.1 Restriction Endonuclease (Enzyme) Digestion 3.5.3.2 Hybridisation Techniques 3.5.3.3 Single Base-Pair Extension 3.6 Pharmacogenetics 3.6.1 Principles of Pharmacogenetics 3.6.2 Genetic Studies of Drug Response 3.6.2.1 Linkage Analysis 3.6.2.2 Candidate Gene Association Studies 3.6.2.2 3.6.2.3 Genome Wide Association Studies (GWAS) 3.6.3 Challenges in Cancer Pharmacogenetics 3.6.3.1 Prospective vs Retrospective Studies 3.6.3.2 Somatic Mutation Testing 3.7 Conclusion References 4 Pharmacogenetics in the Management of Breast Cancer 4.1 Introduction 4.2 Pharmacogenomics and Risk Prediction 4.3 Pharmacogenomics, Drug Targets and Trastuzumab 4.4 Pharmacogenetics, Drug Metabolism and Tamoxifen 4.5 Concluding Remarks 4.5.1 Case Scenario 4.5.1.1 Scenario 1: The ER Positive Endocrine Resistant Tumour 4.5.1.2 Scenario 2: The ER Positive Endocrine Sensitive Tumour References 5 Pharmacogenetics in Colorectal Cancer 5.1 Introduction 5.2 Systemic Treatment of Colorectal Cancer 5.3 Pharmacogenetics in Colorectal Cancer 5.3.1 Fluoropyrimidines 5.3.2 Irinotecan 5.3.3 Oxaliplatin 5.3.4 Targeted Therapies 5.4 Conclusions 5.5 Case Scenario References 6 Pharmacogenetics in Lung Cancer 6.1 Epidemiology of Lung Cancer 6.2 Early Detection, Diagnosis, Classification and Staging 6.2.1 Early Detection 6.2.2 Diagnosis 6.2.3 Classification and Staging 6.3 Lung Cancer Treatment 6.3.1 Principles of Lung Cancer Treatment 6.3.2 Standard Chemotherapy in Lung Cancer 6.4 EGFRIs: A New Treatment Paradigm for Non-small Cell Lung Cancer 6.4.1 Discovery and Characteristics of EGFR Mutations in NSCLC 6.4.2 Incidence and Clinical Significance of EGFR-TK Mutations in Patients with NSCLC 6.5 K-RAS in NSCLC 6.6 Summary and Perspectives 6.7 Case Example 6.7.1 Comment References 7 Pharmacogenetics and Cancer Treatment in Children 7.1 Introduction 7.1.1 Cancer Treatment in Paediatrics 7.2 Current Dosing Practice in Paediatric Oncology 7.3 Pharmacokinetic Approaches to Therapy Individualization 7.4 Pharmacogenetic Approaches to Therapy Individualization 7.4.1 Pharmacogenetics of Cancer Chemotherapy in Children 7.4.1.1 TPMT and 6-Mercaptopurine in ALL 7.4.1.2 UGT1A1 and Irinotecan in Paediatric Solid Tumours 7.4.1.3 DHFR/MTHFR and Methotrexate in AML/ALL 7.5 Summary 7.6 Case Example References 8 Pharmacogenetics in Palliative Care 8.1 Overview 8.2 Pharmacogenetics of Analgesics 8.2.1 Opioids 8.2.2 Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 8.2.3 Paracetamol (Acetaminophen) 8.3 Pharmacogenetics of Antiemetics 8.3.1 5-HT 3 Receptor Antagonists 8.3.2 Corticosteroids 8.3.3 Dopamine Antagonists 8.4 Pharmacogenetics of Antidepressants 8.4.1 Case Scenario References 9 Genetic Predictors of Normal Tissue Response to Radiotherapy 9.1 Introduction 9.2 Radiotherapy Toxicity 9.3 The Genetic Basis of Individual Sensitivity to Radiation 9.4 Predicting Radiotherapy Toxicity 9.5 Genetic Markers for Predicting Radiotherapy Toxicity 9.6 Radiogenomics and Its Challenges 9.7 Summary References 10 Cancer Pharmacogenetics in Industry 10.1 Introduction 10.2 Pre-clinical Screening 10.3 Pharmacogenetic Selection in Clinical Trials 10.4 Post-registration Use of Pharmacogenetics 10.5 Targeted Therapies 10.6 Regulatory Control 10.7 Future Directions 10.8 Concluding Remarks References 11 Ethical Issues in Pharmacogenetics 11.1 Introduction 11.2 Privacy and Confidentiality 11.3 Informed Consent 11.4 The Therapeutic Misconception 11.5 Pharmacogenetics and Databases 11.6 Returning Results to Research Participants 11.7 Public and Professional Attitudes, Education and Resistance 11.8 Clinical Usefulness 11.9 Clinicians Obligations 11.10 Pharmacogenetics and Race/Ethnicity 11.11 Concluding Remarks References 12 Economics of Cancer Pharmacogenetics 12.1 Introductory Concepts 12.2 Making Choices 12.3 Measuring Efficiency 12.4 Methods of Economic Evaluation 12.5 Collecting and Analysing Cost-Effectiveness Data 12.6 Key Stages of Conducting a Cost-effectiveness Analysis 12.6 Using Economic Evaluation Information 12.7 A Final Note References 13 Future Advances in Cancer Pharmacogenomics 13.1 Advances in Phenotyping Tests 13.2 Point-of-Care Testing 13.3 Clinical Trials 13.4 Advances in Genetic Technology 13.5 Use of Different Biological Samples 13.6 Concluding Remarks References Glossary: A Number of the Common TermsUsed in Pharmacogenetics Index