Drugs for HER-2-positive Breast Cancer (eBook)

Drugs for HER-2-positive Breast Cancer 3
Preface 5
Drugs for HER-2-positive Breast Cancer: A Major Approval for Translational Cancer Research 5
Reference 7
Contents 9
The EGFR/ErbB Family in Breast Cancer: From Signalling to Therapy 11
1 Introduction: Breast Cancer: A Molecularly Heterogeneous Disease 11
2 Anatomy of the ErbB Network (see Fig.1) 12
2.1 The Receptors and Cognate Growth Factors 12
2.2 Intracellular Signalling Pathways Activated by ErbB Receptors 15
2.2.1 The Adaptors 15
2.2.2 Signalling Pathways and Transcription Factors 15
2.2.3 Nuclear Signalling of ErbB Receptors and Ligands 16
3 ErbB Signalling as a Robust Information Relay System 16
3.1 From Linear Pathways to Scale-Free Feedback-Controlled Networks 16
3.2 Clinical Implications of Tumours as Robust Systems 17
3.3 Feedback Control of the ErbB Network 18
3.3.1 Early Feedback Regulation 18
3.3.2 Late Feedback Regulation of Transcription 18
3.3.3 Late Feedback Regulation of ErbB Signalling 19
4 Aberrant Functions of the ErbB Network in Breast Cancer (see Fig.2) 19
4.1 The Her-2/neu Amplicon 21
4.2 Transcriptional Control of ErbB Receptor Expression 22
4.3 Variant Receptors 22
4.4 Ligands 23
4.5 Adaptor Proteins and Substrates 24
5 Beyond Receptors and Adaptors: Global Aberrations in ErbB- Regulated Pathways in Breast Cancer 26
5.1 Aberrations in the PI3K-AKT Pathway 26
5.2 Perturbations of the Endocytic Machinery in ErbB-Driven Mammary Tumours 27
5.2.1 Evading the CBL Hub 27
5.2.2 Aberrations in Endocytic Components 28
5.3 Perturbations of Protein and Lipid Phosphatases Acting at and Downstream to ErbB Receptors 29
5.4 Implications to Targeting ErbB Receptors and Their Downstream Pathways 30
6 Outlook 31
References 32
Trastuzumab as Adjuvant Treatment for Early Stage HER-2-positive Breast Cancer 43
1 Introduction 44
1.1 Role of Her-2 in Healthy Tissue 44
1.2 Assessment of Her-2 Status 44
2 Trastuzumab 45
2.1 Mechanism of Action 45
2.2 Mechanisms of Resistance 45
2.3 Combination of Chemotherapy with Trastuzumab in Advanced Breast Cancer 46
3 Trastuzumab in the Adjuvant Setting 46
3.1 HERA 48
3.2 NSABP B-31 and NCCTG N9831 48
3.3 BCIRG 006 49
3.4 FinHER 49
3.5 PACS 04 50
3.6 Discussion of Adjuvant Trials 50
4 Trastuzumab in the Neo-adjuvant Setting 52
5 Side Effects of Adjuvant Trastuzumab Therapy 53
6 Ongoing Studies 54
7 Conclusion 55
References 55
Trastuzumab Resistance in Breast Cancer 60
1 Introduction 60
2 Trastuzumab: Clinical Efficacy and Resistance 61
3 Trastuzumab: Mechanisms of Resistance 63
3.1 Steric Hindrance of Receptor-Antibody Interaction: Over-expression of MUC4 63
3.2 PTEN and PI3K Signalling 63
3.3 Serum HER-2 Extracellular Domain 64
3.4 Amplification of Ligand-Induced Activation of ErbB Receptors 65
4 IGF-IR Signalling Pathway in Breast Cancer 65
5 Conclusions 67
References 67
Treatment with Trastuzumab Beyond Progression 70
1 Introduction 70
2 Mechanisms of Action of Trastuzumab 71
3 Preclinical Evidence for Treatment Beyond Progression with Trastuzumab 72
4 Evidence from Retrospective Cohort and Phase II Studies Supporting Treatment Beyond Progression with Trastuzumab 72
5 Phase III Evidence Supporting the Concept of Treatment Beyond Progression with Trastuzumab 74
6 The GBG 26 Treatment Beyond Progression Study 75
7 Further Randomised Trials Exploring Treatment Beyond Progression 77
8 Trastuzumab Beyond Progression in Combination with Other Targeted Agents 77
9 Conclusion and Future Perspectives 77
References 78
Pertuzumab - a HER-2 Dimerisation Inhibitor - for the Treatment of Breast and Other Cancers 81
1 Introduction 81
2 The HER Family and Its Role in Cancer 82
3 Pertuzumab 83
3.1 Preclinical Data 83
3.1.1 Pertuzumab Alone 83
3.1.2 Pertuzumab in Combination with Other Targeted Agents 84
3.1.3 Pertuzumab in Combination with Chemotherapy 86
3.2 Phase I Data 86
3.2.1 Pertuzumab Monotherapy 86
3.2.2 Pertuzumab Combination Therapy 88
3.2.3 Pertuzumab Dosing and Scheduling 89
3.3 Clinical Trials in Breast Cancer 89
3.4 Clinical Trials in Ovarian Cancer 92
3.5 Clinical Trials in Other Malignancies 93
4 Conclusions and Future Directions 94
References 95
Beyond Trastuzumab: Second-Generation Targeted Therapies for HER-2-positive Breast Cancer 99
1 Introduction 100
1.1 HER-2 and EGFR/HER1 are ErbB Receptor Family Members 100
1.2 The Role of HER-2 and EGFR/HER1 in Tumourigenesis 101
2 Small-Molecule Inhibitors Targeting Both HER-2 and EGFR/HER1 104
2.1 Lapatinib 104
2.2 XL647 105
2.3 AEE788 106
2.4 Neratinib 106
2.5 Pelitinib 107
2.6 BIBW 2992 107
3 Conclusion 109
References 110
Index 116