Table of Contents
1. Overview 6
1.1 About This Report 6
1.2 Scope of the Report 6
1.3 Objectives 6
1.4 Methodology 7
1.5 Drugs Covered in This Report 8
1.6 Summary of Major Findings 10
2. About Breast Cancer 14
2.1 Tumorigenesis 14
2.2 Classification of Breast Cancer 15
2.3 Breast Cancer Epidemiology 15
2.4 Risk Factors 20
2.4.1 Gender, Age and Reproductive Status 20
2.4.2 Genetic Mutations and Family History 21
2.4.3 Environmental Factors 21
2.4.4 Breast Density 22
3. Currently Available Treatment Options 23
3.1 Common Approaches to Treating Breast Cancer 23
3.1.1 Hormone Therapy 23
3.1.2 Surgery 24
3.1.3 Radiation 24
3.1.4 Molecular Targeted Therapy 25
3.1.5 Chemotherapy 25
3.1.5.1 Selected Classes of Chemotherapies 25
3.1.5.2 Chemotherapies Available as Generics 27
3.1.5.3 Branded Chemotherapies 29
3.1.6 Hormone Treatments 30
3.1.7 Targeted Drug Therapy 33
4. Game Changers for Her2 Positive BC for the Current Decade 38
4.1 Targeted Her2 Therapies are Coming into their Prime 38
4.2 About Her2+ Breast Carcinoma 38
4.3 Molecular Targeted Agents 39
4.4 Herceptin 40
4.4.1 Herceptin Mechanism of Action 40
4.4.2 Herceptin Drug Profile 42
4.4.3 Herceptin Resistance 46
4.4.4 Herceptin Product Positioning 48
4.4.5 Herceptin in the Adjuvant Setting 48
4.4.6 Herceptin Biosimilars in Development 49
4.4.7 Herceptin SC Reformulation 50
4.5 Predictive Testing for Her2+ Breast Cancer 50
4.6 New and Emerging Her2 Targeted Options 52
4.6.1 Pertuzumab 53
4.6.2 T-DM1: Chemotherapy with Fewer Side Effects Set to be a Winner for Patients 57
4.6.3 Roches Her2 Portfolio and Oncology Pipeline 61
4.6.4 Tykerb: Data Emerging Predict Drug Utility after Failure of Herceptin Monotherapy 63
4.6.4.1 ALTTO and NEOALTTO: Moving Care for Her2+ Tumors into the Adjuvant Setting 69
4.6.4.2 The TEACH Trial 73
4.6.4.3 Tykerb Product Positioning 73
4.6.4.4 GSKs Oncology Pipeline 74
4.7 Emerging Diagnostics will Aid Her2 Targeted Drug Selection 74
4.8 The More Distant Future for Her2 Targeted Therapy 75
4.8.1 Afinitor 75
4.8.2 Afatinib 75
4.8.3 Neratinib 76
5. Game Changers for Estrogen Receptor Positive BC for the Current Decade 77
5.1 About ER+ Breast Cancer 77
5.1.1 Standard of Care for the Treatment of ER+ Breast Cancer 78
5.2 Adjuvant Chemotherapy in ER+ Breast Cancer 79
5.3 Adjuvant Hormone Therapy in ER+ Breast Cancer 80
5.4 Afinitor Expected to be a Game Changer in ER+ Breast Cancer 80
5.4.1 mTOR/pI3k Resistance 86
5.4.2 Novartis Oncology Pipeline 86
5.4.3 Bisphosphonates Shown to Reduce Bone Metastases 88
6. Triple Negative Breast Cancer (TNBC) 91
6.1 Avastin 91
6.2 Antiangiogenesis Drugs in Development 95
6.3 PARP Inhibitors 96
7. Advances in Chemotherapy 99
7.1 Standard of Care for Chemotherapy 99
7.2 Physician Preference 102
7.3 New and Emerging Chemotherapies 102
7.4 Using Existing Chemotherapies in Novel Ways 104
7.5 Chemotherapies Reformulations 105
7.6 Chemotherapies and the Drug Shortage Crisis 106
7.7 Future Trends: Tailoring Care 106
7.8 Elderly Patients 106
7.9 Adjuvant Chemotherapy in ER+ Breast Cancer 107
7.10 Adjuvant Chemotherapy in Her2+ Breast Cancer 107
8. Biomarkers, Molecular Diagnostics and Personalized Medicine in the Treatment of Breast Cancer 109
8.1 Overview of Markers and Diagnostics as Game Changers in the Treatment of Breast Cancer 109
8.2 Personalized Medicine: Applied Biomarkers and Companion Diagnostics 109
8.3 Multigene Diagnostic Tests: Game Changers in Breast Cancer 113
8.4 Biomarkers: Drug Tolerability and Toxicity 116
8.5 Personalized Medicine and Companion Diagnostic Tests in Breast Cancer 117
8.5.1 Her2 and Herceptin 120
8.5.2 Bayers Advia Centaur Her2 Assay 122
8.5.3 Epidermal Growth Factor Receptor Companions 122
8.5.4 Companies Marketing Her2 Assays 123
8.5.5 Myriads BRCA Companion Diagnostics Testing for BioMarins PARP Inhibitor BMN 673 123
8.6 Biomarkers as Endpoints in Drug Discovery 123
8.7 Risks and Uncertainties of Companion Diagnostics 125
8.8 Biomarkers, Companion Diagnostics and the Regulatory Environment 127
9. Drug Development for the Treatment of Breast Cancer 130
9.1 Targeted Drugs of the PI3K/mTOR Pathway 131
9.2 Her2 Targeted Agents 133
9.2.1 Neratinib 133
9.2.2 Afatinib 133
9.3 VEGF Modulators 135
9.4 Biologics 136
9.5 Vaccines 136
9.6 Overview of Safety Profiles of Pipeline Agents 138
10. Regulatory Trends: How Authorities May Change the Game 141
10.1 Introduction to Regulatory Trends 141
10.2 Case Study Avastin: Regulators Look to Overall Survivor Data 142
10.3 Case Study: T-DM1 and Unmet Need 144
10.4 Case Study: Halaven and Trial Design 145
10.5 Postmarketing Surveillance 145
10.6 Regulators Look Towards Longer Term Outcomes 146
10.7 Regulatory Trends for Combination Therapies 146
10.8 Austerity Measures 147
10.9 Reimbursement 148
10.10 U.S. Healthcare Reform and its Potential Impact on Regulation 148
10.11 New PDUFA V Recommendations 150
10.12 Generics and Drug Shortages 150
10.13 Biomarker, Companion Diagnostics and the Regulatory Pathway 151
10.13.1 Regulatory Perspectives on Pharmacogenomics and Biomarker Validation 151
10.13.2 Role of Governmental Agencies in Driving the Adoption of Companion Diagnostics 152
10.13.3 Role of the Insurance Industry in Driving Adoption of Pharmacogenomics 152
10.13.4 Role of the Pharma Industry in Driving the Adoption of Pharmacogenomics 152
10.13.5 FDA Guidance Document on Co-development 153
10.13.6 Role of the Diagnostic Industry in Driving the Adoption of Pharmacogenomics 153
10.14 2012 Regulatory Guidance for Biosimilars 153
10.15 Off-Label Use and Good Publication Practices 154
10.16 The Future Regulatory Environment for Oncology 155
Appendix 1: Breast Cancer Drug Therapies: Marketed and in Development 156
Appendix 2: References 162
List of Tables
Table 2.1: Estimated New Cancer Cases and Deaths for Ten Leading Cancer Sites in the U.S. by Sex,
2010 16
Table 2.2: Worldwide Number of New Cancer Cases and Deaths by Leading Cancer Sites and by Level of Economic Development, 2008 17
Table 2.3: Number of New Cancer Cases and Deaths by World Area, 2008 18
Table 2:4: Outcomes Among 1,000 Women Undergoing Annual Mammography for Ten Years 20
Table 3.1: Selected, Partial List of Chemotherapies Used in the Treatment of Breast Cancer, Illustrating the Range and Complexity of Prescribing 26
Table 3.2: Currently Available Drugs for the Treatment of Breast Cancer 35
Table 4.1: Trastuzumab (Herceptin): Key Points 44
Table 4.2: Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies 46
Table 4.3: Incidence of Cardiac Disfunctiona in Metastatic Breast Cancer Studies 46
Table 4.4: Selected Ongoing Pertuzumab Studies 56
Table 4.5: Pertuzumab (Omnitarg): Key Points 56
Table 4.6: Key efficacy results from Tykerbs EGF100151 Study 66
Table 4.7: Tykerb: Recommendations for Diarrhea Management 68
Table 4.8: Tykerb (Lapatinib): Key Points 69
Table 4.9: GSKs Oncology Pipeline Includes Expanded and New Indications for Tykerb 74
Table 6.1: Drugs Targeting Angiogenesis 95
Table 7.1: Selected, Partial List of Chemotherapies Used in the Treatment of Breast Cancer, Illustrating the Range and Complexity of Prescribing 99
Table 7.2: Currently Available Chemotherapies 100
Table 7.3: Chemotherapies Reformulations 105
Table 8.1: Timeline for Development of Companion Diagnostics 112
Table 8.2: Personalized Medicine at the Nexus Point 113
Table 8.3: Percentage of Non-Responders in Various Drug Classes 116
Table 8.4: High-Profile Drug Withdrawals from the Marketplace 117
Table 8.5: Selected List of Personalized Medicine Tests 119
Table 8.6: ASCO-CAP Guidelines for Her2 Testing in Breast Cancer: How to Interpret Test Results 120
Table 8.7: Potential Benefits of Biomarkers as Companion Diagnostics 124
Table 8.8: Utility of Biomarker as Companion Diagnostics to Drug Development 125
Table 9.1: Selected Drugs and Classes in Development, Agents in Phase II or Later 130
Table 9.2: PI3K/mTOR Targeted Drugs in Development 132
Table 9.3: Breast Cancer Vaccines in Development 137
Table 9.4: Emerging Drugs and Selected Side Effect Profiles 138
List of Figures
Figure 2.1: Total Worldwide Burden, New Breast Cancer Cases, 2009 19
Figure 4.1: Schematic Describing Herceptin Mechanism of Action 41
Figure 4.2: Herceptin Blocks Her2 Dimerization 41
Figure 4.3: Design of the Herceptin H0648g Pivotal Trial 42
Figure 4.4: Overall Response Rates were Improved by Addition of Xeloda to Herceptin Therapy 43
Figure 4.5: Overall Survival was Extended by 4.8 Months when Herceptin was Used in Combination with
Xeloda 44
Figure 4.6: Herceptins Black Box Warning 46
Figure 4.7: Four Pivotal Trials Involving more than 10,000 Women Demonstrated that One Year of Herceptin Therapy Provided Significant Clinical Benefit 49
Figure 4.8: Example of Her2 ICH and FISH 51
Figure 4.9: Herceptin, Tykerb and Pertuzumab Intercept the EGF Pathway at Different Points 52
Figure 4.10: CLEOPATRA Trial Design 53
Figure 4.11: CLEOPATRA Study Progression Free Survival 54
Figure 4.12: CLEOPATRA Study Safety 55
Figure 4.13: T-DM1 Study design 59
Figure 4.14: T-DM1 Results, Phase II Evaluations 59
Figure 4.15: Complimentary Mechanisms of Action of Roches 3 HER Agents 61
Figure 4.16: Roches HER Targeted Therapy Clinical Development Program 61
Figure 4.17: Roche Oncology Pipeline, Phase II and Later 62
Figure 4.18: Tykerb/Tyverb is an Oral Her2 Blocking Agent 64
Figure 4.19: Tykerb/Tyverb Works Differently than Herceptin, but on the Same Target 65
Figure 4.20: EGF100151 Study Design 66
Figure 4.21: Efficacy of Tykerb in the EGF100151 Study 67
Figure 4.22: Tykerb Safety and Tolerability: The EGF100151 Study 68
Figure 4.23: ALTTO Study Design 70
Figure 4.24: NEO-ALTTO Study Design 71
Figure 4.25: Strong Efficacy for the Combination of Herceptin and Tykerb in NEO-ALTTO 72
Figure 4.26: Benefit in Hormone Receptor-Negative and -Positive Her2+ Tumors 72
Figure 5.1: Response Rates to Endocrine Manipulation in ER+ Patients, Based on Receptor Type 77
Figure 5.2: Adjuvant Chemotherapy in ER+ Breast Cancer 80
Figure 5.3: Novartis BOLERO Registrational Program for Afinitor in Breast Cancer 82
Figure 5.4: BOLERO-2 Study Design 82
Figure 5.5: BOLERO-2 Progression Free Survival, Local 83
Figure 5.6: BOLERO-2 Progression Free Survival, Central 84
Figure 5.7: BOLERO-2 Progression Free Survival, Subgroups 84
Figure 5.8: BOLERO-2 Overall Survival 85
Figure 5.9: BOLERO-2 Safety 85
Figure 5.10: Intersection of mTOR and Estrogen Receptor Growth Pathways 86
Figure 5.11: Novartis Oncology Pipeline and PI3k Modulators in Development 87
Figure 5.12: Novartis Planned Filings 2012 and Later 87
Figure 5.13: Novartis Candidate PI3k Modulators 88
Figure 7.1: Halavens EMBRACE Trial: Improved Survival in Heavily Pretreated Patients 102
Figure 7.2: Halavens EMBRACE Trial: Improved Overall Survival 103
Figure 7.3: Halaven Effective Largely Irrespective of Prior Chemotherapy Experience 103
Figure 7.4: Halaven Safety 104
Figure 7.5: Access and Rationale for Adjuvant Chemotherapy in ER+ Breast Cancer 107
Figure 8.1: Personalizing Drug Treatment 111
Figure 8.2: Approaches to Personalized Medicine 112
Figure 8.3: The Oncotype DX Assay Provides an Individualized Recurrence Score Result 114
Figure 8.4: MammaPrint Genes, by Biological Function 115
Figure 8.5: MammaPrint Gene Signature Predicts Survival 115
Figure 8.6: ASCO-CAP Guidelines for Her2 Testing in Breast Cancer: Equivocal Results with IHC 121
Figure 8.7: ASCO-CAP Guidelines for Her2 Testing in Breast Cancer: Results by FISH 121
Figure 8.8: Personalized Medicine Drugs in Development 126
Figure 9.1: EGF and Her2 Receptors 134
Figure 9.2: Afatinib PFS Results in NSCCL 135
Figure 10.1: Healthcare Spending in the U.S. and Selected OECD Countries, 1970-2008 149