Biomarker Technology Platforms for Cancer Diagnoses & Therapies

TABLE OF CONTENTS

1. Overview 14
1.1 Statement of Report 14
1.2 About This Report 14
1.3 Scope of the Report 15
Objectives 15
1.5 Methodology 15
1.6 Executive Summary 17

2. Introduction to Cancer Biology and the Diagnostic Industry 19
2.1 Biomarkers 19
2.1.1 The Biomarker Market Drivers 19
2.1.1.1 The Sector 19
2.1.1.2 The Critical Path Opportunities 19
2.1.1.3 Capital Markets 19
2.2 Cancer Detection and Treatment with Biomarkers 19
2.2.1 The Problem 21
2.3 Cancer: The Disease 23
2.3.1 Metastasis 23
2.3.2 Demographics and Statistics of Cancer 24
2.4 Drivers of the Biotech and Diagnostics Industry 31
2.4.1 Technological Innovation 32
2.4.2 Government Funding 32
2.4.3 Pharmaceutical Development and Bioanalytical Services 33
2.4.4 The War on Cancer 34
2.4.5 Current Oncology Drug Development 35
2.5 Outlook for Tumor Markers 35
2.6 Focus on Proteomics 38
2.6.1 Scientific Background 38
2.6.2 The Relationship between Proteins and Diseases 39
2.6.3 Limitations of Existing Diagnostic Approaches 39
2.6.4 Addressing the Heterogeneity of Cancer 40
2.6.5 Validation of Biomarkers Through Proper Study Design 40
2.6.6 Exploiting the Power of MS to Improve Assay Specificity 41
2.6.7 Creating and Maintaining a Multi-Disease Product Pipeline 42
2.6.8 Partnerships for Developing Proteomic Biomarkers 43
2.7 Epigenic Markers for Cancer 44
2.8 Molecular Diagnostics Testing for Cancer 44
2.9 Market Opportunities 45
2.9.1 Industry Overview 46
2.9.2 Medical Indications and Medically Useful Information 47
2.9.3 Research Market 49
2.9.4 Competition 49
2.9.5 Diagnostic Services 49
2.9.6 Clinical Image Analysis 50
2.9.7 Research Imaging Market 50
2.9.8 Genomic Disease Management and In Vitro Diagnostic Multivariate Index Assays (IVDMIA) 50
2.9.9 Predictive Expression Profiles 51

3. Market Analysis of the Cancer Biomarkers Space 52
3.1 Scope of this Chapter 52
3.2 The Overall Market Opportunity and Segmentation of the Total Cancer Biomarkers Marketplace 52
3.3 Potential Cancer Biomarker Commercial Applications 55
3.3.1 Market for Routine Tumor Markers 56
3.3.2 Market for Genomic Cancer Biomarkers 62
3.3.3 Market Size and Forecasts for Companion Diagnostic Tests for Cancer Therapeutics 64
3.3.4 SWOT Analysis of the Major Cancer Biomarker Market Segments 66
3.3.4.1 Traditional Serum Cancer Biomarkers 66
3.3.4.2 Proteomic Cancer Biomarkers 67
3.3.4.3 Companion Diagnostic Cancer Biomarkers 68
3.4 Cancer Biomarker Market Estimates by Tissue of Origin 69
3.4.1 Colorectal 71
3.4.2 Prostate 71
3.4.3 Lung 71
3.4.4 Breast 72
3.4.5 Ovarian 72
3.5 Challenges Facing Cancer Biomarker Developers 73
3.6 Unmet Product Needs in the Cancer Biomarkers Space 75
3.7 Competitive Landscape of the Cancer Biomarkers Marketplace 77

4. Major Clinical Applications of Cancer Biomarkers 80
4.1 Launched Products and Pipeline 80
4.2 CYP2C9 Pharmacogenetics and Role in Personalized Medicine 82
4.3 Personalized Breast Cancer Therapy 82
4.4 Personalized NSCLC Therapy 83
4.5 AmpliChip-based Personalized Medicine 83

5. Breast Cancer 84
5.1 Overview of Breast Cancer Disease 84
5.2 BRCA1 and BRCA2 Genes 85
5.2.1 Types of Genetic Testing Available for Breast Cancer 87
5.2.1.1 DNA Sequencing 87
5.2.1.2 Multi-Site Analysis 88
5.2.1.3 Single-Site Analysis 88
5.2.2 BRCA Test Results 88
5.2.2.1 What Does a Positive BRCA1 or BRCA2 Test Result Mean? 88
5.2.2.2 What Does a Negative BRCA1 or BRCA2 Test Result Mean? 88
5.2.2.3 What Does an Ambiguous BRCA1 or BRCA2 Test Result Mean? 89
5.2.2.4 What are the Options for a Person Who Tests Positive? 89
5.2.3 What are Some of the Benefits of Genetic Testing for Breast Cancer Risk? 90
5.2.4 What Are Some of the Risks of Genetic Testing for Breast and Ovarian Cancer Risk? 90
5.3 Estrogen Receptors and Breast Cancer 90
5.3.1 Expression and Prognostic Value of ER 90
5.3.2 Progesterone Receptors and Breast Cancer 91
5.3.3 ER and PR Predict Response to Endocrine Therapy 91
5.4 HER2 Gene and Protein 92
5.4.1 HER2 Tests 92
5.4.1.1 IHC Test 92
5.4.1.2 FISH Test 93
5.4.1.3 Questions About Testing 95
5.4.1.4 HER2 Tumor Status 96
5.5 Herceptin Treatment 96
5.6 Tumor Assays for Adjuvant Chemotherapy 98
5.7 Use of Genomics to Understand Breast Cancer 99
5.8 Genetic Analysis Solution 100
5.8.1 The Use of Proteomics in Breast Cancer 101
5.8.2 Tissue Microarrays 102
5.8.3 Protein Microarrays 104
5.9 Gene Expression Microarrays and Recurrence Prediction 105
5.9.1 Oncotype DX 106
5.9.2 Oncotype DX for Breast Cancer 107
5.9.3 Risk Assessment 107
5.9.4 Use of Chemotherapy 107
5.9.5 Utility of the Oncotype Test 107
5.9.6 Clinical Development and Validation of Oncotype DX 108
5.9.6.1 Clinical Development of the Oncotype DX Recurrence Score 108
5.9.6.2 Clinical Validation of Prediction of Recurrence and Survival in N-, ER+ Patients Treated with Tamoxifen 108
5.9.6.3 Oncotype DX Predicts the Likelihood of Recurrence 108
5.9.6.4 Oncotype DX Predicts the Likelihood of Breast Cancer Survival in a Community Hospital Setting 109
5.9.6.5 Oncotype DX Predicts both Prognosis and Tamoxifen Benefit 110
5.10 Economic Benefits of Oncotype DX 110
5.11 Increased Clinical Utility of Oncotype DX 111
5.12 Second Generation Oncotype DX 111
5.12.1 Recurrence and Benefit Test for N-, ER- Breast Cancer 112
5.12.2 Taxane Benefit Test 112
5.13 MammaPrint 112
5.14 Rotterdam Signature 76-Panel 113
5.15 Summary of Microarray Technologies 113
5.16 MS-based Approaches 114
5.16.1 Gel-based Approaches 114
5.16.2 Non-Gel-based Approaches 115
5.16.2.1 SELDI-TOF MS 115
5.16.2.2 SELDI and Prognosis 116
5.16.2.3 SELDI and Treatment Monitoring 117
5.16.3 Limitations of MS 117
5.17 Outlook 118
5.18 Future Perspectives 120
5.19 Breast Cancer Program (NMP66) 121
5.20 Myriad Genetics 121
5.21 Veridex GeneSearch Breast Lymph Node 121
5.22 OncoVue® Cancer Risk Test 122
5.23 Research Biomarkers for Breast Cancer 122
5.24 Protein Biomarkers for Breast Cancer Prevention 123
5.25 Biomarker Prognosis of Breast Cancer Treated with Doxorubicin 123

6. Ovarian Cancer 124
6.1 Serum Markers 126
6.2 Biomarkers 127
6.2.1 Strategies for Discovering New Cancer Biomarkers 128
6.3 Serum Protein Biomarkers for Ovarian Cancer 128
6.3.1 Clinical Proteomics 129
6.4 Ovarian Cancer Triage Testing 131
6.4.1 Vermillion’s Ovarian Cancer Triage Diagnostic Program 131

7. Prostate Cancer 133
7.1 Overview 133
7.1.1 Prevalence 133
7.1.2 Prostate Cancer Progression and Recurrence Test 133
7.1.3 Current Market Size 133
7.2 Genes Involved in Prostate Cancer 134
7.3 Androgen Independence 135
7.4 Gene Markers in Prostate Cancer 136
7.5 Microarray Gene Identification of Prostate Biomarkers 136
7.6 GEArray DNA Microarrays 138
7.7 Vermillion’s Cancer Diagnostic Program 139
7.8 Hepsin 139
7.9 Matritech’s Prostate Cancer Program (NMP48) 140
7.10 Gen-Probe’s PCA3 Assay 140
7.11 Early Prostate Cancer Antigen-2 (EPCA-2) 140
7.12 MS 141
7.13 Summary 143

8. Bladder Cancer 144
8.1 Overview 144
8.1.1 Prevalence 144
8.1.2 Progression and Recurrence 144
8.1.3 Bladder Cancer Risk Factors 144
8.1.4 Bladder Cancer Symptoms 144
8.2 Bladder Cancer Tests 144
8.3 UroVysion Bladder Cancer Kit 145
8.4 Ikoniscope® Robotic Digital Microscopy Platform 146
8.4.1 The CellOptics Platform 146
8.4.2 Cell Staining and Genetic Characterization 146
8.4.3 Ikoniscope/IkoniLAN Automated Microscopy 146
8.5 Nuclear Matrix Protein Markers 147
8.6 ImmunoCyt™/uCyt+™ 149
8.7 Cangen Microsatellite DNA 151
8.8 Bladder Cancer Market 151
8.8.1 Urologist Market 151
8.8.2 Clinical Lab Market 151
8.8.3 Primary Care Market 151
8.8.4 Private and Public Sector Markets 152
8.8.5 POC Market 152
8.8.6 Market Distribution 152
8.8.7 Reimbursement 152

9. Colorectal Cancer 153
9.1 Overview 153
9.1.1 Prevalence 153
9.1.2 Progression and Recurrence 153
9.2 Screening for CRC 155
9.2.1 Stool-based DNA (sDNA) Screening 156
9.3 Almac Diagnostics DSA™ 157
9.4 Colon Cancer Program (NMP35) 158
9.5 Myriad Genetics COLARIS AP Risk Assessment 159
9.6 Summary 159

10. Genetic Diagnostics Set to Revolutionize Cancer Diagnostic Testing 160
10.1 Overview 160
10.1.1 Clinicians’ Need for More Information with Regard to Therapeutic Treatment Drives Demand for Pharmacogenomic Testing 160
10.1.2 Predictive Medicine Shows Potential for Genetic Diagnostics 160
10.1.3 Different Rates of Growth 161
10.1.4 Effective Competitive Strategies 161
10.1.5 Improvements in Marketing Effectiveness 161
10.1.6 Emerging Technologies Imply Start of a New Era and Offer Tremendous Growth Opportunities 161
10.1.7 Increased Market Share 162
10.1.8 Technologies Used in Genetic Testing 162
10.2 AMAS Test 162
10.3 Corixa (now GSK) Antibodies as Tumor Markers 162
10.4 CytoVision 163
10.5 Ariol System 163
10.6 Mammaglobin Protein Expression 163
10.7 L523S or KOC RNA Binding Protein 164
10.8 CA1-18 from EDP Biotech Corporation 164

11. Leukemia Biomarkers 165
11.1 Overview 165
11.1.1 Prevalence 165
11.1.1.1 Progression and Recurrence 165

12. Lung Cancer 166

13. Enabling Technologies for Oncology Biomarker Discovery 167
13.1 Automated Cellular Imaging System (ACIS) 167
13.1.1 ACIS for HER2 Protein Expression Testing 168
13.1.2 ACIS for ER Protein Expression Testing 168
13.1.3 ACIS for PR Protein Expression Testing 168
13.1.4 ACIS for Cell Proliferation Expression 169
13.1.5 ACIS for Protein Expression 169
13.1.6 ACIS for Protein Micrometastases in Bone Marrow 169
13.1.7 ACIS for Protein Micrometastases in Tissue 169
13.1.8 ACIS for TMA 169
13.1.9 ACIS for DNA Ploidy 169
13.1.10 ACIS for HPV 169
13.2 DNA Methylation 170
13.2.1 DMH 170
13.2.2 MIRA-Assisted Microarrays for DNA Methylation Analysis and Cancer Diagnosis 170
13.3 Proteomics 171
13.3.1 Proteomics Technologies for Cancer Marker Discovery 171
13.3.2 Validation of Candidate Biomarkers 172
13.3.3 Requirements Bringing a New Marker into the Market 172
13.3.4 Value Chain in the Development of New Cancer Biomarkers 173
13.4 Secreted Proteins as Cancer Biomarkers 173
13.4.1 Markers of Known Tissue Origin 173
13.4.2 Secreted Proteins as Low Abundance Markers 173
13.4.3 Secreted Proteins in Tissue and Blood 173
13.5 Non-coding RNAs as Potential Tumor Markers 173
13.5.1 miRNA Meets Microarray 174
13.5.2 Mimetics and Inhibitors 174
13.5.3 Clinical Patterns in Cancer 174
13.6 Architect TIMP-1 (Tissue Inhibitor of Metalloproteinases-1) Immunoassay for CRC Detection 174
13.7 Companies Developing Automated Microscope-based Analysis Systems 174
13.8 Companies Developing Research Products for Tumor Cell Isolation 175
13.9 Companies Supplying Fluorescently Labeled Antibodies to Characterize Tumor Cells 175
13.10 PerkinElmer High-Throughput Platforms: AlphaScreen®, AequoScreen®, DELFIA® and LANCE® Technologies 175

14. Biomarker Tests Co-developed with Cancer Therapeutics as Companion Diagnostics 176
14.1 Sector Overview 176
14.2 Companion Diagnostics 178
14.3 EGFR for CRC and Camptostar (Irinotecan) 178
14.4 EGFR Express and Erbitux (Cetuximab) 179
14.5 HER2 and Heceptin 179
14.6 Myriad’s TheraGuide 5-Fluorouracil (5-FU)™ 179
14.7 TheraScreen: EGFR29 180
14.8 Drivers and Barriers to Companion Diagnostics 180
14.9 Partnerships with Pharma Companies to Identify Therapeutic Targets 181
14.10 Future Developments for Companion Diagnostics 181

15. Companion Diagnostics and Personalized Medicine: Biology, Approaches, Pipeline and Regulatory Trends 183
15.1 Scope of this Chapter 183
15.2 Introduction to Companion Diagnostics and Personalized Medicine 183
15.3 The Compelling Case for Personalized Medicine 184
15.4 Drug Metabolism and Implications for Companion Diagnostics and Personalized Medicine 186
15.5 Examples of Personalized Medicine 190
15.6 Personalized Medicine and Companion Diagnostics Testing Product Pipeline 192
15.7 The Personalized Medicine Coalition 194
15.8 Regulatory Trends and Guidelines in the Personalized Medicine Space 201
15.8.1 The Changing Regulatory Landscape for Personalized Medicine 203
15.9 Patenting Personalized Medicine 204
15.10 The Leading Edge of Personalized Medicine: Specific Examples of Clinical Situations Where Personalized Medicine and Companion Diagnostics are Appropriate and Being Deployed 206
15.10.1 EGFR Assay 206
15.10.2 Individualized Warfarin Therapy 207
15.10.3 UGT1A1 Molecular Assay for Camptosar 208
15.10.4 Response to Gleevec in Gastrointestinal Stromal Tumors 208
15.10.5 LabCorp/ARCA Personalized Medicine Deal for Cardiovascular Diseases 208
15.10.6 Osmetech Licenses Epidauros Biotechnologie AG CYP2D6 Biomarker to Push into Companion Diagnostics 208
15.11 Companion Diagnostics and Personalized Medicine: Qualitative and Quantitative Market Analysis 209
15.11.1 Market Analysis of Molecular Diagnostics and Companion Diagnostics and Personalized Medicine 209
15.11.2 Diagnostics vs. Pharmaceuticals 210
15.11.3 Molecular Diagnostic Market 211
15.11.4 Molecular Diagnostics Technology Platforms and their Impact on Personalized Medicine 213
15.12 Snapshot of Companion Diagnostics Industry Structure 215
15.13 The Case for Theranostics (Therapeutic/Companion Diagnostic) 216
15.14 Personalized Medicine Market Analysis—Market Survey Data Characterizing the Qualitative and Quantitative Industry Parameters 217
15.15 How the Market Segregates Today 218
15.16 Timeline for Impact of Various Segments in Personalized Medicine 219
15.17 Challenges for Personalized Therapeutics and Companion Diagnostics Development 221
15.18 Macro Trends in Personalized Medicine 222
15.19 Personalized Medicine and Companion Diagnostics: Industry SWOT Analysis 225

16. Cancer Biomarker Testing Sector and Company Analysis 227
16.1 Abbott Molecular, Inc. 227
16.2 Agendia 227
16.3 Agilent Technologies 228
16.4 AMDL, Inc. 228
16.5 Applied Biosystems 228
16.6 Aureon Laboratories, Inc. 229
16.7 BioCurex 230
16.8 Biomarker Technologies 230
16.9 Biomedical Diagnostics LLC 230
16.10 Biomerica 231
16.11 Biomira, Inc. 231
16.12 Biomoda 231
16.13 Byk Gulden 231
16.14 Clarient (now a GE Healthcare Company) 231
16.15 Correlogic Systems, Inc. 232
16.16 Cytogen Corporation 232
16.17 Dako (Formerly Dako Cytomation) 233
16.18 diaDexus 234
16.19 Diagnocure, Inc. (ImmunoCyt/uCyt+) 234
16.20 DxS Ltd. (Acquired by QIAGEN) 235
16.21 Epigenomics 235
16.22 Exagen Diagnostics, Inc. 237
16.23 Genesis Genomics 238
16.24 Gen-Probe 238
16.25 Health Discovery Corporation 238
16.26 Illumina 239
16.27 Immunicon 239
16.28 Ipsogen 239
16.29 InterGenetics 239
16.30 Life Technologies 240
16.31 Miraculins, Inc. 240
16.32 Myriad Genetics, Inc. 240
16.33 Orion Genomics 241
16.34 Pacific Biosciences 241
16.35 Power3 Medical Products 241
16.36 Qiagen N.V. 242
16.37 Roche Molecular Diagnostics 242
16.38 SuperArray Bioscience Corporation (now SABiosciences) 243
16.39 Upstream Biosciences, Inc. 243
16.40 Ventana Medical Systems, Inc. 243
16.41 Veridex 245
16.42 Vermillion, Inc. 245

17. Business Trends in the Industry 246
17.1 Industry Consolidation 246
17.2 Breadth of Product Offering and Pricing 247
17.3 Government Regulation of Medical Devices 247
17.3.1 FDA Guidance on Drug Test Co-development 249
17.4 Strategic Business and Marketing Considerations 249
17.5 Commercial Opportunities in Cancer Markers 249
17.5.1 Licensing and Intellectual Property (IP) Constraints and how they will Impact New Product Development 250
17.6 Moderators of Growth 250
17.6.1 Roadblocks to Integrating Cancer Biomarkers into Clinical Practice 251
17.7 Biotechnology Industry Trends 251
17.8 Pharmaceutical Industry Trends 252
17.9 Sales and Marketing Strategies for Tumor Marker Tests 253
17.9.1 North American Market 253
17.9.2 International Markets 254
17.9.2.1 Europe 255
17.9.2.2 Central and South America 255
17.9.2.3 Asia/Pacific 256
17.10 Product Commercialization 256
17.11 Reimbursement 257
17.12 Self Referral Rules 257
17.13 Health Insurance Portability and Accountability Act 258
17.14 Clinical Laboratory Improvement Amendments (CLIA) 259
17.15 In-Vitro Diagnostic Directive (IVDD) and Medical Device Regulations 259
17.16 FDA’s Quality System Regulation (QSR) 260
17.17 FDA’s OIVD on IVDMIAs 261
17.18 FDA’s Qualification of Cancer Biomarkers 261
17.18.1 Regulatory Perspectives of Biomarker Validation 261
17.19 Genetic Tests and Medical Records 262
17.19.1 Laws against Genetic Discrimination 263
17.20 Medicare Reimbursement 263
17.20.1 Medicare Spending Trends 263
17.21 Global Drivers of Clinical Laboratory Testing 265
17.22 Global Outlook for Cancer Biomarkers 266
17.22.1 Which Companies are Utilizing Cutting-Edge Technologies to Develop, Validate and Implement Cancer Biomarkers for Clinical Use? 267
17.22.2 What Impediments Still Exist to Incorporating Promising Research into Clinical Practice? 267
17.22.3 Which Biomarkers Show the Most Promise for Approval? 267
17.22.4 How can Regulatory Oversight Drive Approval and Adoption of New Technologies? 268
17.22.5 Which Alliances Show the Greatest Synergy in Bringing Valid Biomarkers to Market? 268
17.22.6 Which Shared Technologies are Driving the Most Encouraging Development? 268
17.22.7 How Strategic Alliances and Interdisciplinary Involvement Drive Development and Implementation of Emerging Biomarker Technologies 268
17.23 Oncology Biomarker Qualification Initiative 268
17.24 FDA Critical Path 269
17.25 FDA Criteria for a Valid Biomarker 269

18. Companies Entering the Cancer Diagnostics Market with Novel Technology Platforms 271
18.1 Abbott Diagnostics 271
18.2 Affymetrix, Inc. 273
18.3 Agendia BV 274
18.4 Agensys, Inc. 275
18.5 Agilent Technologies 275
18.6 Almac Group 276
18.7 AMDL, Inc. 276
18.8 Aureon Laboratories, Inc. 277
18.9 Bayer Diagnostics Corporation 278
18.10 Beckman Coulter, Inc. 278
18.11 Biocode Hycel S.A. 279
18.12 BioCurex, Inc. 280
18.13 Biomarker Technologies LLC 280
18.14 Biomedical Diagnostics LLC 280
18.15 Biomerica 280
18.16 bioMérieux 281
18.17 Biomira, Inc. 281
18.18 Biomoda, Inc. 282
18.19 Bruker Daltonics, Inc. 283
18.20 Byk Gulden 283
18.21 Cangen Biotechnologies, Inc. 283
18.22 Caprion Proteomics 284
18.23 Celera Diagnostics 285
18.24 Cepheid 285
18.25 Clarient, Inc. 286
18.26 Claros Diagnostics, Inc. 287
18.27 Clinical Data, Inc.: PGxHealth and Cogenics 287
18.28 Correlogic Systems, Inc. 287
18.29 CytoCore (Formerly Molecular Diagnostics, Inc.) 287
18.30 Cytogen Corporation 288
18.31 Dako (Formerly Dako Cytomation) 290
18.32 diaDexus LLC 290
18.33 DiagnoCure, Inc. 291
18.34 Diagnostic Products Corporation (now Siemens) 293
18.35 Diagnostic Systems Laboratories, Inc. 293
18.36 DRG International, Inc. 293
18.37 DxS Ltd. (Acquired by Qiagen) 294
18.38 EDP Biotech Corporation 295
18.39 Eisai Co., Ltd. 295
18.40 Epigenomics 295
18.41 Exact Sciences Corporation 296
18.42 Exagen Diagnostics, Inc. 297
18.43 Gene Logic, Inc. 297
18.44 Genesis Genomics, Inc. (Mitomics) 298
18.45 Genomic Health, Inc. 298
18.46 Gen-Probe, Inc. 299
18.47 Health Discovery Corporation 300
18.48 Hologic, Inc. (Formerly Cytyc Corporation) 300
18.49 Ikonisys, Inc. 301
18.50 Illumina 302
18.51 Immunicon Corporation 302
18.52 Immunomedics, Inc. 304
18.53 Incyte Pharmaceuticals, Inc. 305
18.54 InterGenetics 305
18.55 Ipsogen 306
18.56 LabCorp 307
18.57 Life Technologies Corporation 307
18.58 Matritech, Inc. 308
18.59 Miraculins, Inc. 310
18.60 Mitsubishi Kagaku Medical 311
18.61 Myriad Genetics, Inc. 311
18.62 NimbleGen Systems, Inc. 316
18.63 Northwest Biotherapeutics, Inc. 317
18.64 Oncotech, Inc. 318
18.65 Orion Genomics 318
18.66 Oxford BioTherapeutics 319
18.67 Pacific Biosciences 320
18.68 Panacea Pharmaceuticals, Inc. 320
18.69 Polymedco, Inc. 321
18.70 Power3 Medical Products 321
18.71 Proteome Systems Ltd. 322
18.72 Qiagen N.V. 322
18.73 Roche Diagnostics 323
18.74 Upstream Biosciences, Inc. 324
18.75 Ventana Medical Systems, Inc. 324
18.76 Veridex LLC 325
18.77 Vermillion, Inc. (Formerly Ciphergen) 326

Appendix 1: Cancer Biomarker Centers of Research 328
Appendix 2: Myriad Patents on Genes BRCA-1 and BRCA-2 329
Appendix 3: Cancer Markers Currently in Common Clinical Use 330
Appendix 4: International Federation of Gynecology and Obstetrics (FIGO) Staging System for Primary Carcinoma of the Ovary 331
Appendix 5: FDA Guidance for Industry: Pharmacogenomic Data Submission 332
A5.1 Introduction 332
A5.2 Background 332
A5.3 Submission Policy 333
A5.3.1 General Principles 333
A5.3.2 Specific Uses of Pharmacogenomic Data in Drug Development and Labeling 335
A5.3.3 Benefits of Voluntary Submissions to Sponsors and FDA 336
A5.4 Submission of Pharmacogenomic Data 337
A5.4.1 Submission of Pharmacogenomic Data During the IND Phase 337
A5.4.2 Submission of Pharmacogenomic Data to a New NDA, BLA or Supplement 338
A5.4.3 Submission to a Previously Approved NDA or BLA 339
A5.4.4 Compliance with 21 CFR Part 58 339
A5.4.5 Submission of Voluntary Genomic Data from Application-Independent Research 340
A5.5 Format and Content of a VGDS 340
A5.6 Process for Submitting Pharmacogenomic Data 341
A5.7 Agency Review of VGDSs 341

Glossary 343


INDEX OF FIGURES

Figure 3.1: Potential Market for Cancer Biomarkers 52
Figure 3.2: Segmentation of the Cancer Biomarkers Marketplace Based on Commercial Offerings—Products and Services 55
Figure 3.3: Geographical Distribution of Cancer Tumor Diagnostic Testing 59
Figure 3.4: Cancer Biomarkers Research Market, 2006-2016 65
Figure 3.5: Breast Cancer Biomarker Market Potential, 2010 72
Figure 3.6: Challenges in the Study or Utilization of Proteomic Cancer Biomarkers 74
Figure 3.7: Challenges in the Study or Utilization of Companion Diagnostic Cancer Biomarkers 74
Figure 3.8: Challenges in the Study or Utilization of Serum Cancer Markers 75
Figure 3.9: Top Unmet Needs in Commercial Products in the Cancer Biomarkers Space 76
Figure 5.1: Hybridization Process 93
Figure 5.2: FISH Test Procedure 94
Figure 5.3: Gene Expression Profiling 104
Figure 15.1: Phase I and II Processes of Drug Metabolism 186
Figure 15.2: Human Phase I Enzymes 187
Figure 15.3: Human Phase II Enzymes 187
Figure 15.4: Hepatic Distribution of Human CYP450 188
Figure 15.5: Relative Contribution of CYP450 Enzymes to Drug Metabolism 188
Figure 15.6: Genetic Components Determine Drug Metabolism 189
Figure 15.7: From Genetic Content to Personalized Medicine 210
Figure 15.8: Remuneration for Diagnostics 210
Figure 15.9: Breakout of the Molecular Diagnostics Marketplace 211
Figure 15.10: Molecular Diagnostics Market Segmentation 212
Figure 15.11: Molecular Diagnostics Market Segmentation by Technology 213
Figure 15.12: Market Survey Respondent Demographics 217
Figure 15.13: Breakout of the Respondent Pool by Affiliation 218
Figure 15.14: Segmentation of the Personalized Medicine Market 218
Figure 15.15: Personalized Medicine Market Drivers 222
Figure 15.16: Challenges in the Personalized Medicine Space 223
Figure 16.1: Epigenomics Product Development Pipeline 236
Figure 17.1: Medicare Spending on Clinical Laboratory Services per Enrollee, 2000-2010 264


INDEX OF TABLES

Table 2.1: Cancer Biomarkers at the Nexus Point 21
Table 2.2: Drug Development by Type of Cancer 24
Table 2.3: Organ-Specific Medicines in Development for Cancer 25
Table 2.4: Estimates for the Leading Types of New Cancer Cases and Deaths in the U.S. by Sex 26
Table 2.5: Estimated New Cancer Cases and Deaths by Sex for All Types of Cancer 27
Table 2.6: New Cancer Cases and Associated Deaths by World Region 28
Table 2.7: Cancer Death Rates per 100,000 Population (and Rank) for All Cancer Sites by Country 29
Table 2.8: Cancer Associated Genes 29
Table 2.9: Carcinogens in the Workplace 30
Table 2.10: Cancer Biomarker Markets 31
Table 2.11: Private Funding for Biotechnology and Medical Devices and Equipment, 1999-2010, U.S. 32
Table 2.12: Global Pharmaceutical Industry R&D Spending, 1995-2010 33
Table 2.13: U.S. Government NIH Research Budget, 1995 to 2011 34
Table 2.14: Tumor Markers Currently in Common Use 36
Table 2.15: Herceptin Worldwide Sales, 2000 to 2016 37
Table 2.16: Classes of Drugs Used to Treat Breast Cancer 38
Table 2.17: Solutions to Biomarker Developments 40
Table 2.18: Vermillion Collaborations 43
Table 2.19: Uses of Molecular Diagnostics in Detection and Management of Cancer 45
Table 2.20: U.S. Cancer Diagnostic Testing Market Size, 2005-2016 46
Table 2.21: Market Opportunities for Cancer Biomarker Technology Platforms 48
Table 3.1: Characteristics of Different Cancer Biomarker Types and Associated Market Opportunities 54
Table 3.2: Segmentation of the Cancer Biomarker Market by Type/Lineage of Cancer Biomarkers and Market Size 54
Table 3.3: In Vitro Cancer Marker Market Segments Worldwide, 2012 56
Table 3.4: Worldwide Market Size in Dollar Volume for Tumor Marker Assays Product Market, 2001-2016 57
Table 3.5: U.S. Market Size in Dollar Volume for Tumor Marker Assays Product Market, 2001-2016 57
Table 3.6: Worldwide In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2016 57
Table 3.7: U.S. In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2016 58
Table 3.8: Japanese In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2016 58
Table 3.9: European In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2016 59
Table 3.10: Global Distribution of IVD Cancer Tumor Marker Diagnostic Testing, 2010 59
Table 3.11: Estimated Market Share of Major Competitors in U.S. Cancer Tumor Marker Diagnostics Market 60
Table 3.12: Major Presence in Cancer Tumor Marker Diagnostics Markets 60
Table 3.13: Worldwide CEA Sales, 2001-2016 61
Table 3.14: U.S. CEA Sales, 2001-2016 62
Table 3.15: Cancer Genomic Biomarker Markets, 2002-2016 62
Table 3.16: Cancer Biomarkers Research Market Forecast, 2006-2016 65
Table 3.17: Cancer Biomarker Market Estimates by Tissue of Origin 70
Table 3.18: Companies Developing New Proteomic Cancer Biomarker Technology Platforms 79
Table 4.1: Cancer Biomarkers Used to Maximize Likelihood of Response 81
Table 4.2: Biomarkers for Monitoring Therapeutic Effectiveness and Resistance 81
Table 4.3: Biomarkers for Dose Response of Therapy 81
Table 4.4: Decision on Optimal Duration of Therapy 81
Table 5.1: Number of New Breast Cancer Patients in the U.S., 2005-2010 84
Table 5.2: BRCA Development Model 86
Table 5.3: BRCA Test Development and Commercialization 87
Table 5.4: BRAC Analysis 87
Table 5.5: Revenue for BRACAnalysis Risk Assessment Test, 2002-2011 87
Table 5.6: GEArray DNA Microarrays and RT2 Profiler PCR Arrays 104
Table 5.7: Product Development Opportunities in Breast Cancer 111
Table 5.8: Concentration of Some Abundant Proteins, New Cancer Biomarkers Identified by SELDI-TOF, and Classical Cancer Biomarkers in Serum 118
Table 5.9: Questions Related to Diagnostic SELDI-TOF Technology 120
Table 6.1: Worldwide CA-125 Sales, 2001-2016 125
Table 6.2: U.S. CA-125 Sales, 2001-2016 125
Table 6.3: Some Clinically Established Cancer Serum Markers Currently in Use for Cancer 126
Table 6.4: Pathophysiology of Ovarian Cancer and Characterization of Ovarian Epithelial Tumors 132
Table 7.1: Worldwide PSA Sales, 2000-2016 134
Table 7.2: U.S. PSA Sales, 2000-2016 134
Table 7.3: Molecular Gene Markers for Prostate Cancer 137
Table 8.1: Worldwide Bladder Cancer Marker Sales, 2001-2016 148
Table 8.2: U.S. Bladder Cancer Marker Sales, 2001-2016 148
Table 8.3: Worldwide NMP22 Sales, 2001-2016 149
Table 8.4: Summary of Matritech’s Product Development Programs 150
Table 8.5: Opportunities for Bladder Cancer Biomarkers 151
Table 9.1: TNM Staging for CRC 154
Table 10.1: Genetic Diagnostics Market, 2004-2016 161
Table 13.1: Genomic and Proteomic Technologies 172
Table 14.1: Potential Benefits of Biomarkers as Companion Diagnostics 178
Table 14.2: Utility of Biomarker as Companion Diagnostics to Drug Development 178
Table 14.3: Device Submission Elements for the FDA 181
Table 14.4: Summary of Biomarker Use in the Commercialization of Novel Oncology Pharmacotherapeutics 182
Table 14.5: Pharmacoeconomic Challenges to the Implementation of Biomarkers as Companion Diagnostic Tests 182
Table 15.1: Percentage of Non-Responders in Various Drug Classes 185
Table 15.2: High Profile Drug Withdrawals from the Marketplace 185
Table 15.3: Drug Metabolism Drives Drug Efficacy/Toxicity 190
Table 15.4: Population Frequency of the Various Cytochromes 190
Table 15.5: Selected List of Personalized Medicine Tests 192
Table 15.6: Personalized Medicine and Companion Diagnostics Product Pipeline 193
Table 15.7: Marketed Personalized Therapies 194
Table 15.8 Members of the Personalized Medicine Coalition 195
Table 15.9: Various Molecular Diagnostics Technologies: Timeline for Impact 213
Table 15.10: Various Molecular Diagnostics Technologies: Impact on Different Therapeutic Areas in Personalized Medicine 214
Table 15.11: Technical Challenges in the Deployment for Personalized Medicine 214
Table 15.12: Classification of Diagnostics by Risk 216
Table 15.13: Areas in Personalized Medicine—Timeline of Impact 219
Table 15.14: Impact of Personalized Medicine on Various Therapeutic Areas 220
Table 15.15: Hurdles in Personalized Medicine and Companion Diagnostics Development in Various Therapeutic Areas 221
Table 15.16: Market Opportunities in Personalized Medicine 224
Table 15.17: Challenges for Market Adoption of the Various Personalized Medicine Tests 225
Table 15.18: Personalized Medicine Industry SWOT 226
Table 16.1: Opportunities for Biomarkers in Cancer Diagnosis and Treatment 232
Table 17.1: List and Discounted Prices for Abbott Tumor Marker Tests 247
Table 17.2: Increases in Total Allowed Charges for Laboratory Services per Enrollee, 2000-2010 264
Table 17.3: Incurred Reimbursement Amounts for Laboratory Services, 2000-2010 265
Table 17.4: Medicare Part B Benefit Payments, 2003-2010 265
Table 18.1: Tumor Diagnosis Immunoassay 294
Table 18.2: Tumor Diagnosis Radioimmunoassay 294
Table 18.3: Summary of Matritech’s Product Development Programs 310
Table A1: Team Descriptions 328
Table A3: Cancer Markers in Use 330