Table of Contents

TABLE OF CONTENTS

1. Overview 8
1.1 Statement of Report 8
1.2 About This Report 8
1.3 Scope of the Report 9
1.4 Objectives 10
1.5 Methodology 10
1.6 Executive Summary 11

2. Introduction to Cancer Biology and the Diagnostic Industry 14
2.1 Cancer 14
2.1.1 The Disease 14
2.1.2 Metastasis 14
2.1.3 Demographics and Statistics of Cancer 14
2.2 The Drivers of the Biotech and Diagnostics Industry 19
2.2.1 Technological Innovation 20
2.2.2 Government Funding 21
2.3 Outlook for Tumor Markers 21

3. Tumor Markers Market Segment Analysis: Size, Growth and Share 23
3.1 Market Description 24
3.2 Clinical Diagnostic Serum Based Cancer Markers 31
3.3 PSA Testing Market Size 32
3.4 DNA Markers 33
3.5 Serum Proteins 33
3.6 Enzymes 34
3.7 Occult Blood 34
3.8 Histology and In Situ Hybridization (ISH) 35
3.9 Cervical Cytology 36
3.10 Immunohistochemistry 38
3.11 In Vivo Detection Cancer Products 39
3.12 Radionuclides and X-Ray Detection Products 39
3.13 Human Papillomavirus (HPV) Testing 39
3.14 Bladder Cancer Testing 43
3.15 Tumor Assays for Adjuvant Chemotherapy 46

4. Diagnostic Methods for Cancer Detection 59
4.1 Organ Specific Tumor Markers 59
4.1.1 Colon Cancer 59
4.1.2 Prostate Cancer 66
4.1.3 Pancreatic Cancer 83
4.1.4 Breast Cancer 85
4.1.5 Ovarian Cancer 94
4.1.6 Cervical Cancer 99
4.1.7 Lung Cancer 101
4.1.8 Testicular Cancer 106
4.1.9 Bladder Cancer 106
4.1.10 Hepatic Cancer 112
4.1.11 Stomach Cancer 114
4.1.12 Malignant Melanoma 115
4.1.13 Acute Myeloid Leukemia (AML) and Acute Lymphoblastoid Leukemia (ALL) 115
4.1.14 Lymphoma 116
4.2 Clinical Laboratory Methods for Measuring Tumor Markers 117
4.2.1 Abbott Diagnostics AxSYM 117
4.2.2 Roche Diagnostics Elecsys 117
4.2.3 Beckman Coulter Diagnostics Access 117
4.2.4 Bayer Diagnostics ADVIA Centaur 118
4.2.5 Dade Diagnostics Stratus 118
4.2.6 Diagnostic Products Corporation Immulite 118
4.2.7 Tosoh Medics A1A 119
4.2.8 CIS bio International Kryptor 120
4.2.9 Ortho-Clinical Diagnostics Vitros ECiQ 120
4.2.10 Fujirebio Diagnostics, Inc. 120
4.2.11 bioMérieux Vidas 121
4.2.12 Eisai Picolumi 121
4.2.13 Tosoh Medics, Inc. 121
4.3 New Technologies for Cancer Diagnostics 122
4.3.1 New and Improved Immunoassays 122
4.3.2 Immunohistochemical Tests 123
4.3.3 Molecular (DNA and Genomic) Diagnostic Assays 124
4.3.4 Genomics and Genetic Markers 125
4.3.5 Proteomics and New Protein Markers 126
4.3.5.1 Inside the ProteinChip System 126
4.3.5.2 Rapid Biological Assays on a Chip 126
4.3.5.3 Proteome Pattern Recognition 127
4.3.6 New Platform Technologies Including Flow Cytometry 127
4.3.7 Stem Cell Markers 130
4.3.8 Monoclonal Antibodies 130
4.3.9 Proteomics and Cancer Antibodies 134
4.3.10 Pharmacogenomics and Oncology Diagnostics 134
4.3.11 DNA Microarrays 137
4.3.12 In Vitro Diagnostic Multivariate Index Assays (IVDMIA) 139
4.3.13 Prostate PX Score 139
4.3.14 Prostate-63 139
4.3.15 Future Directions 139
4.4 Clinical Methods for Diagnosis of Cancer 140
4.4.1 Screening 140
4.4.2 Sigmoidoscopy 142
4.4.3 Imaging 142
4.4.4 Theranostics 144

5. Implications of Molecular Biology for New Diagnostic Cancer Tests 145

6. Companies Entering the Cancer Diagnostics Market with Novel Technology Platforms 146
6.1 Abbott Diagnostics 146
6.2 Affymetrix, Inc. 147
6.3 Agendia BV 148
6.4 Agensys, Inc. 148
6.5 Ambrilla Biopharma, Inc. 149
6.6 AMDL, Inc. 149
6.7 Asuragen, Inc. 151
6.8 Aureon Biosciences Corporation 151
6.9 Bard Diagnostics, Inc. 151
6.10 Bayer Diagnostics 152
6.11 Beckman Coulter, Inc. 152
6.12 Biocode S.A. 154
6.13 BioCurex 154
6.14 Biomedical Diagnostics 154
6.15 Biomerica 155
6.16 bioMérieux 155
6.17 Biomira 155
6.18 BioModa, Inc. 156
6.19 Bruker Daltonics 156
6.20 Byk Gulden 156
6.21 Cepheid 156
6.22 Clarient, Inc. 157
6.23 CytoCore (Formerly known as Molecular Diagnostics, Inc.) 159
6.24 Correlogic Systems, Inc. 159
6.25 Cytogen Corporation 159
6.26 diaDexus, LLC 162
6.27 DiagnoCure, Inc. 163
6.28 Diagnostic Products Corporation 164
6.29 Diagnostic Systems Laboratories, Inc. 164
6.30 DRG International, Inc. 164
6.31 Eisai Co., Ltd. 165
6.32 Enigma Diagnostics Ltd. 166
6.33 Epigenomics 166
6.34 Exact Sciences Corporation 166
6.35 Exagen Diagnostics, Inc. 167
6.37 Gene Logic, Inc. 167
6.38 Gen-Probe, Inc. 168
6.39 Genomic Health 168
6.40 Geron Corporation 169
6.42 Immunicon Corporation 170
6.43 Immunomedics, Inc. 174
6.44 Incyte Pharmaceuticals, Inc. 175
6.45 Ipsogen 175
6.46 LabCorp 175
6.47 Matritech 176
6.48 Mitsubishi Kagaku Medical 180
6.49 Molecular Devices (Formerly known as Arcturus Bioscience, Inc.) 180
6.50 Myriad Genetics, Inc. 180
6.51 Poniard Corporation 185
6.52 Nexell Therapeutics, Inc. 186
6.53 Northwest Biotherapeutics, Inc. 186
6.54 Nuvelo, Inc. 187
6.55 Panacea Pharmaceuticals, Inc. 187
6.56 Oncotech, Inc. 188
6.57 Polymedco, Inc. 189
6.58 Princeton BioMeditech Corporation 189
6.59 Qiagen 191
6.60 Sanko Junyaku Co., Ltd. 192
6.61 Tosoh Medics, Inc. 192
6.62 TriPath Imaging, Inc. 192
6.63 UroCor, Inc. 194
6.64 Ventana Medical Systems, Inc. 198
6.65 Veridex 199
6.66 Vermillion, Inc. (Formerly known as Ciphergen) 199
6.67 Worldwide Medical Corporation 200
6.68 Xenomics, Inc. 200

7. Business Trends in the Industry 201
7.1 Industry Consolidation 201
7.2 Breadth of Product Offering and Pricing 201
7.3 Government Regulation of Medical Devices 202
7.4 Strategic Business and Marketing Considerations 203
7.5 Commercial Opportunities in Cancer Markers 204
7.6 Moderators of Growth 205
7.7 Biotechnology Industry Trends 205
7.8 Pharmaceutical Industry Trends 206
7.9 Acquisition, License Agreement, Partnerships 208
7.10 Legal Developments 210
7.11 Sales and Marketing Strategies for Tumor Marker Tests 211
7.11.1 North American Market 212
7.11.2 International Markets 213
7.11.2.1 Europe 213
7.11.2.2 Central and South America 214
7.11.2.3 Asia/Pacific 214

8. Tumor Marker Testing: Important Issues 215
8.1 Trends in Patient Care and Reimbursement 215
8.2 Trends in Reimbursement Practice 216
8.3 Clinical Laboratory Improvement Act (CLIA) 218
8.4 Unmet Needs in Tumor Markers 219

9. Important New Technology Areas 220
9.1 Proteins 220
9.2 DNA Sequencing 221
9.3 The Human Genome Project (HGP) 222
9.4 Liquid Phase Chromatography 223
9.5 Polymerase Chain Reaction (PCR) 223
9.6 Capillary Electrophoresis 224
9.7 Proteomics 225
9.8 Use of Mass Spectroscopy in Sequencing 226
9.9 High-Throughput Organic Synthesis 230

10. New Cancer Markers in Basic Research 232
10.1 Genetics of Cancer 232
10.2 Telomerase 235
10.3 Stomach Cancer 237
10.4 Head and Neck Cancer 238
10.5 Breast Cancer 239
10.6 Prostate Cancer: p27 (Kip1) A New Molecular Marker for Prostate Cancer 240
10.7 PSMA 241
10.8 Cervical Cancer: NMPI79 242
10.9 Pancreatic Cancer: Peritoneal Cytology 242
10.10 Colorectal Cancer: CEA Doubling Time 242
10.11 Uterine and Kidney Cancer: MN/CA9 242
10.12 MMSC1 Scaffold Gene 242
10.13 p16 Tumor Suppressor Gene 243
10.14 MTS2 and p19 Cell Cycle Genes 243
10.15 Complement Factor H Related Proteins 243
10.16 MUC 2, 3, 4 243
10.17 Cytokeratins 244
10.18 Colon Cancer: Serum VEGF 244
10.19 Ras Oncogenes 244
10.20 Lung Cancer: Ribonucleoprotein A2/B1 245
10.21 BCLA-4 Matrix Protein 245
10.22 RAK Antigens 245
10.23 Serum Urokinase Receptors 245
10.24 Chips 246
10.25 Survivin 246
10.26 Human Endometrial Specific Steroid Binding Factor (hESF1) 246
10.27 Reg-4 Protein 247
10.28 Nox-1 247
10.29 PSP94 Binding Protein 247
10.30 Ettan DIGE Technology 247
10.31 YKL-40 248
10.32 AFP-L3 248
10.33 DNA Methylation Technology 248
10.34 Transthyretin and Apolipoprotein A1 248
10.35 ADAM 12 249
10.36 Ovarian Cancer: Vermillion’s SELDI-based ProteinChip 249
10.37 Lung Cancer: Labeled Porphyrin Binding 249
10.38 C-MAP, A Cervical Cancer Screening System 249
10.39 Lung Cancer: Pro-Gastrin-Releasing Peptide (ProGRP) 249
10.40 Prostate Cancer: PCA3 249
10.41 Bladder Cancer: ImmunoCyt™/uCyt+™ 252
10.42 Shc Proteins 252
10.43 Oncology Biomarker Qualification Initiative 252
10.44 Anti-Glycan Antibodies 253

11. Market Trends and Forecasts 254
11.1 Ultrasensitive Cancer Tests 254
11.2 Mergers and Acquisitions of Diagnostic Companies 255
11.3 RT-PCR 255
11.4 Genetic Tests of Hereditary Cancer Risk 256
11.5 DNA Measurements 256
11.6 Technical and Practical Issues for Potential New Markers 256
11.7 Genetic Profiling 257
11.8 Ploidy 258
11.9 Advances in Sputum Analysis for Screening and Early Detection of Lung Cancer 258
11.10 Pharmacogenetic Tests for Cancer 259
11.11 Worldwide Healthcare Spending 260
11.12 R&D Expenditures 260

Appendix 1: Web Links 261
Appendix 2: Cancer Information Resources 263
Appendix 3: Colon Cancer Staging 264
Appendix 4: Reimbursement for Tumor Marker Testing 265
Appendix 5: The Pathology of Prostate Cancer 267
Appendix 6: Government Regulation of Tumor Marker Tests 269
Appendix 7: The Clinical Laboratory Improvement Act (CLIA) 271
Appendix 8: Marketers of Occult Blood Diagnostic Test Kits 273


INDEX OF FIGURES

Figure 4.1: Model of Colorectal Cancer Development 61
Figure 4.2: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: Equivocal Results with IHC 90
Figure 4.3: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: Results by FISH 91
Figure 4.4: The BTA stat Test vs. Cytology 111
Figure 6.1: Qiagen Global Sales 192
Figure 10.1: Estimates for PCA3 Test Volume in U.S., 2005-2008 251


INDEX OF TABLES

Table 2.1: Organ-Specific Medicines in Development for Cancer, 2007 15
Table 2.2: Estimates for the Leading Sites of New Cancer Cases and Deaths in the U.S. by Sex 16
Table 2.3: Estimated Worldwide Number of New Cancer Cases and Deaths by Type of Cancer 16
Table 2.4: Estimated Number of New Cancer Cases and Deaths by Region 17
Table 2.5: Cancer Death Rates per 100,000 Population (and Rank) for all Cancer Sites by Country 18
Table 2.6: Cancer Associated Genes 18
Table 2.7: Carcinogens in the Workplace 19
Table 2.8: Private Funding Levels for the Biotechnology Segment, 1995-2006 20
Table 2.9: Herceptin Worldwide Sales, 2000-2007 21
Table 2.10: Classes of Drugs Used to Treat Breast Cancer 22
Table 3.1: In Vitro Cancer Marker Market Segments Worldwide, 2001 and 2007 24
Table 3.2: Tumor Markers Currently in Common Use 26
Table 3.3: Global IVD Cancer Tumor Marker Testing Market Segments Projected Growth Rates, 2005-2010 28
Table 3.4: Worldwide Market Size in Dollar Volume for Tumor Marker Assays Product Market, 2001-2010 28
Table 3.5: U.S. Market Size in Dollar Volume for Tumor Marker Assays Product Market, 2001-2010 28
Table 3.6: Worldwide In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2010 29
Table 3.7: U.S. In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2010 29
Table 3.8: Japanese In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2010 30
Table 3.9: European In Vitro Cancer Tumor Marker Diagnostics Market Size, 2001-2010 30
Table 3.10: Global Distribution of IVD Cancer Tumor Marker Diagnostic Testing, 2005 30
Table 3.11: Estimated Market Share of Major Competitors in U.S. Cancer Tumor Marker Diagnostics Market 31
Table 3.12: Major Presence in Cancer Tumor Marker Diagnostics Markets 31
Table 3.13: Worldwide PSA Sales, 2000-2010 32
Table 3.14: U.S. PSA Sales, 2000-2010 33
Table 3.15: Serum Markers Used Clinically 33
Table 3.16: ASCO-CAP Guidelines for HER-2 Testing in Breast Cancer 38
Table 3.17: Drivers of IHC Growth 39
Table 3.18: Bladder Cancer Testing Efforts in the U.S. and Germany 43
Table 3.19: Worldwide Bladder Cancer Marker Sales, 2001-2010 45
Table 3.20: U.S. Bladder Cancer Marker Sales, 2001-2010 45
Table 3.21: Worldwide NMP22 Sales, 2001-2010 46
Table 3.22: Current Breast Cancer Product and Product Opportunities 54
Table 3.23: Products in Various Stages of Development for Cancers Other than Breast Cancer 55
Table 4.1: Colorectal Cancer Stages 60
Table 4.2: Worldwide CEA Sales, 2001-2010 62
Table 4.3: U.S. CEA Sales, 2001-2010 62
Table 4.4: Population Statistics of Serum Levels of PSA in Men Over 50 Years of Age 71
Table 4.5: PSA Doubling Time and Time to Reach PSA of 1,000 72
Table 4.6: PSA Doubling Times 72
Table 4.7: Worldwide CA-19-9 Sales, 2001-2010 84
Table 4.8: U.S. CA-19-9 Sales, 2001-2010 84
Table 4.9: CA-19-9 Levels in Management of Pancreatic Cancer 85
Table 4.10: Worldwide CA-15-3 Sales, 2001-2010 86
Table 4.11: U.S. CA-15-3 Sales, 2001-2010 86
Table 4.12: TPA Marker Sensitivity 88
Table 4.13: ASCO-CAP Guidelines for HER2 Testing in Breast Cancer: How to Interpret Test Results 89
Table 4.14: Siemens Oncogene Science Biomarker Group Reagents 92
Table 4.15: Worldwide CA-125 Sales, 2001-2010 95
Table 4.16: U.S. CA-125 Sales, 2001-2010 96
Table 4.17: Number of Pap Smears Performed by Country 101
Table 4.18: Lung Cancer Survival Rates 102
Table 4.19: Lung Cancer Facts 103
Table 4.20: Patient Category Applications 108
Table 4.21: Worldwide AFP Marker Sales, 2001-2010 113
Table 4.22: U.S. AFP Cancer Marker Sales, 2001-2010 114
Table 4.23: Potential Uses of Molecular Diagnostics in Cancer Management 124
Table 4.24: Colorectal Cancer Monoclonal Antibody Imaging Kits 132
Table 6.1: Product Sales as a Percent of Total Product Sales, 2004-2006 153
Table 6.2: Tumor Diagnosis Immunoassay 165
Table 6.3: Tumor Diagnosis Radioimmunoassay 165
Table 6.4: Summary of Matritech’s Product Development Programs 178
Table 6.5: Statements of Operations Data for Matritech, 2002-2006 178
Table 6.6: Results of Operations of Matritech, 2005 and 2006 179
Table 6.7: PBM Product List 190
Table 7.1: List and Discounted Prices for Abbott Tumor Marker Tests 202
Table 8.1: CPT Codes for Tumor Markers 217
Table 10.1: Familial Cancer Syndromes and Tumor Suppressor Genes 233
Table 10.2: Oncogenes and Anti-oncogenes 233
Table A3: TNM Classification 264
Table A7: Financial Comparison for Moderate and Waived CLIA Labs 271
Table A8: List of Marketers of Occult Blood Diagnostic Test Kits 273