Pharmacogenetics: Making cancer treatment safer and more effective (eBook)

Contents 6
Contributors 8
Abbreviations 10
Introduction 11
1 Principles of Cancer Treatment 14
1.1 Introduction 15
1.2 Context of Chemotherapy 15
1.3 Classes of Chemotherapy Drugs 16
1.4 Clinical Trials of Chemotherapeutic Agents 16
1.5 Defining Outcomes to Treatment 18
1.5.1 Trial Endpoints 19
1.6 What is an Adverse Drug Reaction to Chemotherapy? 19
1.7 Concluding Remarks 21
References 21
2 Clinical Pharmacology and Anticancer Drugs 23
2.1 Introduction 24
2.2 Pharmacokinetics 24
2.2.1 Drug Absorption 25
2.2.2 Drug Distribution 26
2.2.2.1 Protein Binding 26
2.2.2.2 Blood--Brain Barrier 26
2.2.2.3 Enterohepatic Circulation 26
2.2.3 Drug Metabolism 27
2.2.3.1 First-Pass Metabolism 27
2.2.4 Drug Excretion 27
2.2.4.1 Renal Excretion 28
2.2.4.2 Biliary Elimination 28
2.3 Drug Metabolizing Enzymes 28
2.3.1 Phase I Drug Metabolism 28
2.3.2 Phase II Drug Metabolism 30
2.4 Drug Transporters 30
2.4.1 Multidrug Resistance (MDR1) P-glycoprotein 31
2.4.2 Multidrug Resistance-Associated Proteins (MRPs) 31
2.5 Pharmacokinetic-Pharmacodynamic Relations 31
2.6 Variability in Drug Response 32
2.7 Clinical Pharmacology of Anticancer Drugs 33
2.7.1 Non-Targeted Chemotherapy 33
2.7.2 Targeted Therapies 34
2.8 Concluding Remarks 35
References 35
3 Principles of Genetics and Pharmacogenetics 39
3.1 Genetic Principles 40
3.2 DNA, RNA and Proteins 40
3.2.1 DNA Replication 40
3.2.2 Transcription to Form RNA 41
3.2.3 Translation to Form Proteins 42
3.3 Types of Genetic Variation 42
3.3.1 Mutations 43
3.3.2 Polymorphisms 43
3.3.3 Variable Nucleotide Tandem Repeats (VNTR) 45
3.3.4 Copy Number Variants (CNVs) 45
3.3.5 Inversions 46
3.4 Human Genome and HapMap Projects 46
3.5 Detection of Genetic Variants 47
3.5.1 Polymerase Chain Reaction (PCR) 47
3.5.2 Techniques to Use When the Genetic Variant is Unknown 47
3.5.2.1 DNA Sequencing 47
3.5.2.2 Alternative Techniques for Mutation Screening 48
3.5.3 Techniques When the Genetic Variant is Known 48
3.5.3.1 Restriction Endonuclease (Enzyme) Digestion 49
3.5.3.2 Hybridisation Techniques 49
3.5.3.3 Single Base-Pair Extension 50
3.6 Pharmacogenetics 52
3.6.1 Principles of Pharmacogenetics 52
3.6.2 Genetic Studies of Drug Response 53
3.6.2.1 Linkage Analysis 53
3.6.2.2 Candidate Gene Association Studies 53
3.6.2.2 3.6.2.3 Genome Wide Association Studies (GWAS) 54
3.6.3 Challenges in Cancer Pharmacogenetics 55
3.6.3.1 Prospective vs Retrospective Studies 55
3.6.3.2 Somatic Mutation Testing 55
3.7 Conclusion 55
References 56
4 Pharmacogenetics in the Management of Breast Cancer 57
4.1 Introduction 57
4.2 Pharmacogenomics and Risk Prediction 58
4.3 Pharmacogenomics, Drug Targets and Trastuzumab 60
4.4 Pharmacogenetics, Drug Metabolism and Tamoxifen 61
4.5 Concluding Remarks 66
4.5.1 Case Scenario 66
4.5.1.1 Scenario 1: The ER Positive Endocrine Resistant Tumour 67
4.5.1.2 Scenario 2: The ER Positive Endocrine Sensitive Tumour 67
References 67
5 Pharmacogenetics in Colorectal Cancer 72
5.1 Introduction 73
5.2 Systemic Treatment of Colorectal Cancer 73
5.3 Pharmacogenetics in Colorectal Cancer 74
5.3.1 Fluoropyrimidines 75
5.3.2 Irinotecan 77
5.3.3 Oxaliplatin 81
5.3.4 Targeted Therapies 82
5.4 Conclusions 85
5.5 Case Scenario 86
References 87
6 Pharmacogenetics in Lung Cancer 98
6.1 Epidemiology of Lung Cancer 99
6.2 Early Detection, Diagnosis, Classification and Staging 99
6.2.1 Early Detection 99
6.2.2 Diagnosis 99
6.2.3 Classification and Staging 100
6.3 Lung Cancer Treatment 100
6.3.1 Principles of Lung Cancer Treatment 100
6.3.2 Standard Chemotherapy in Lung Cancer 101
6.4 EGFRIs: A New Treatment Paradigm for Non-small Cell Lung Cancer 101
6.4.1 Discovery and Characteristics of EGFR Mutations in NSCLC 102
6.4.2 Incidence and Clinical Significance of EGFR-TK Mutations in Patients with NSCLC 103
6.5 K-RAS in NSCLC 104
6.6 Summary and Perspectives 105
6.7 Case Example 107
6.7.1 Comment 108
References 108
7 Pharmacogenetics and Cancer Treatment in Children 111
7.1 Introduction 112
7.1.1 Cancer Treatment in Paediatrics 112
7.2 Current Dosing Practice in Paediatric Oncology 113
7.3 Pharmacokinetic Approaches to Therapy Individualization 113
7.4 Pharmacogenetic Approaches to Therapy Individualization 114
7.4.1 Pharmacogenetics of Cancer Chemotherapy in Children 115
7.4.1.1 TPMT and 6-Mercaptopurine in ALL 115
7.4.1.2 UGT1A1 and Irinotecan in Paediatric Solid Tumours 117
7.4.1.3 DHFR/MTHFR and Methotrexate in AML/ALL 117
7.5 Summary 119
7.6 Case Example 120
References 121
8 Pharmacogenetics in Palliative Care 124
8.1 Overview 125
8.2 Pharmacogenetics of Analgesics 125
8.2.1 Opioids 125
8.2.2 Non Steroidal Anti-Inflammatory Drugs (NSAIDs) 128
8.2.3 Paracetamol (Acetaminophen) 128
8.3 Pharmacogenetics of Antiemetics 129
8.3.1 5-HT 3 Receptor Antagonists 129
8.3.2 Corticosteroids 130
8.3.3 Dopamine Antagonists 130
8.4 Pharmacogenetics of Antidepressants 130
8.4.1 Case Scenario 131
References 132
9 Genetic Predictors of Normal Tissue Response to Radiotherapy 135
9.1 Introduction 135
9.2 Radiotherapy Toxicity 136
9.3 The Genetic Basis of Individual Sensitivity to Radiation 136
9.4 Predicting Radiotherapy Toxicity 138
9.5 Genetic Markers for Predicting Radiotherapy Toxicity 138
9.6 Radiogenomics and Its Challenges 139
9.7 Summary 141
References 141
10 Cancer Pharmacogenetics in Industry 144
10.1 Introduction 144
10.2 Pre-clinical Screening 145
10.3 Pharmacogenetic Selection in Clinical Trials 147
10.4 Post-registration Use of Pharmacogenetics 147
10.5 Targeted Therapies 148
10.6 Regulatory Control 149
10.7 Future Directions 150
10.8 Concluding Remarks 150
References 151
11 Ethical Issues in Pharmacogenetics 153
11.1 Introduction 153
11.2 Privacy and Confidentiality 154
11.3 Informed Consent 155
11.4 The Therapeutic Misconception 156
11.5 Pharmacogenetics and Databases 157
11.6 Returning Results to Research Participants 157
11.7 Public and Professional Attitudes, Education and Resistance 158
11.8 Clinical Usefulness 159
11.9 Clinicians Obligations 160
11.10 Pharmacogenetics and Race/Ethnicity 161
11.11 Concluding Remarks 163
References 163
12 Economics of Cancer Pharmacogenetics 167
12.1 Introductory Concepts 168
12.2 Making Choices 168
12.3 Measuring Efficiency 169
12.4 Methods of Economic Evaluation 169
12.5 Collecting and Analysing Cost-Effectiveness Data 173
12.6 Key Stages of Conducting a Cost-effectiveness Analysis 174
12.6 Using Economic Evaluation Information 177
12.7 A Final Note 178
References 179
13 Future Advances in Cancer Pharmacogenomics 181
13.1 Advances in Phenotyping Tests 182
13.2 Point-of-Care Testing 182
13.3 Clinical Trials 183
13.4 Advances in Genetic Technology 183
13.5 Use of Different Biological Samples 184
13.6 Concluding Remarks 184
References 184
Glossary: A Number of the Common TermsUsed in Pharmacogenetics 186
Index 189