Until superior therapeutic treatments are developed to prevent, treat and cure cancer, the best means of reducing mortality and morbidity in a disease this complex is early detection and diagnosis. In the major solid cancer types such as lung, breast, colon and prostate, long-term survival rates drop precipitously once metastatis has occurred. The case is clear for development of biomarkers for early detection and screening tests for diseases such as breast, colon, ovarian and lung cancer. In addition, diagnostic measurement of cancer disease progression is essential to successful disease management. For these reasons, development of new and effective biomarkers for cancer detection and diagnosis is central to the cancer problem. The use of nucleic acid biomarker diagnostics have begun to answer these questions. Protein biomarkers are also useful. The purpose of this TriMark Publications report is to describe the specific segment of the cancer diagnostics market which develops new biomarker technology platforms for diagnosing and treating cancer. Biomarkers are useful in following the course of cancer and evaluating which therapeutic regimes are most effective for a particular type of cancer, as well as determining long-term susceptibility to cancer or recurrence. This study particularly examines those clinical measurement devices, and their reagents and supplies, which are meant to be used in hospitals, clinics, commercial laboratories and doctor's offices to diagnose and monitor cancer. The examination also provides an in-depth discussion of the application of biomarkers in developing novel targeted cancer therapeutics, their predication response and efficacy, as well as their use in diagnosis of cancer.

TABLE OF CONTENTS

1.    Overview    13
1.1    Statement of Report    13
1.2    About This Report    13
1.3    Scope of the Report    13
1.4    Objectives    14
1.5     Methodology    14
1.6     Executive Summary    15

2.    Introduction to Cancer Biology and the Diagnostic Industry        20
2.1    Biomarkers    20
2.1.1    The Biomarker Market for Cancer and Key Sectors        20
2.1.1.1     The Sector    20
2.1.1.2     The Critical Path Opportunities    20
2.1.1.3     Capital Markets        20
2.1.1.4     Molecular Diagnostics Technology Platforms    21
2.2    Cancer Detection and Treatment Using Biomarkers as a Guide        21
2.2.1    The Problem    23
2.3    Next Generation Sequencing and Biomarker Discovery    25
2.3.1    Second-Generation Sequencing    26
2.3.2    Whole Genome Sequencing (WGS)        26
2.3.3    Epigenomics    26
2.3.4    Bioinformatics and Next Generation Sequencing    27
2.3.5    Third Next Generation Sequencing        27

3.    Market Analysis of the Cancer Biomarkers Space    28
3.1    Scope of This Chapter    28
3.2    The Overall Market Opportunity and Segmentation of the Total Cancer Biomarkers Marketplace    28
3.3    Potential Cancer Biomarker Commercial Applications    32
3.3.1    Market for Routine Tumor Markers        32
3.3.2    PSA Testing Market Size        39
3.3.3    Market Size and Forecasts for Companion Diagnostic Tests for Cancer Therapeutics    41
3.3.4    SWOT Analysis of the Major Cancer Biomarker Market Segments    44
3.3.4.1    Traditional Serum Cancer Biomarkers    44
3.3.4.2    Proteomic Cancer Biomarkers    44
3.3.4.3    Companion Diagnostic Cancer Biomarkers        45
3.4    Cancer Biomarker Market Estimates by Tissue of Origin    46
3.4.1    Colorectal    47
3.4.2    Prostate        47
3.4.3    Lung        48
3.4.4    Breast        48
3.4.5    Ovarian        49
3.5    Challenges Facing Cancer Biomarker Developers    49
3.6    Unmet Product Needs in the Cancer Biomarkers Space    51
3.7    Epigenic Markers for Cancer    56
3.8    Molecular Diagnostics Testing for Cancer    56
3.9    Market Opportunities    57
3.9.1    Industry Overview    57
3.9.2    Medical Indications and Medically Useful Information    59
3.9.3    Research Market        61
3.9.4    Competition    61
3.9.5    Diagnostic Services    61
3.9.6    Clinical Image Analysis    61
3.9.7    Research Imaging Market        61
3.9.8    Genomic Disease Management and In Vitro Diagnostic Multivariate Index Assays (IVDMIA)    62
3.9.9    Predictive Expression Profiles    63

4.    Major Clinical Applications of Cancer Biomarkers    64
4.1    Launched Products and Pipeline    64
4.2    Launched Products and Pipeline    66
4.3    CYP2C9 Pharmacogenetics and Role in Personalized Medicine    71
4.4    Personalized Breast Cancer Therapy    72
4.5    Personalized NSCLC Therapy    72
4.6    AmpliChip-Based Personalized Medicine    72

5.    Breast Cancer    74
5.1    Overview of Breast Cancer Disease        74
5.2    Incidence and Mortality Rates    74
5.2.1    Incidence Rates        74
5.2.2    Mortality Rates        75
5.3    BRCA1 and BRCA2 Genes    76
5.3.1    Types of Genetic Testing Available for Breast Cancer        79
5.3.1.1     DNA Sequencing    79
5.3.1.2     Multi-Site Analysis    79
5.3.1.3     Single-Site Analysis    79
5.3.2    BRCA Test Results    79
5.3.2.1     What Does a Positive BRCA1 or BRCA2 Test Result Mean?        79
5.3.2.2     What does a Negative BRCA1 or BRCA2 Test Result Mean?        80
5.3.2.3     What does an Ambiguous BRCA1 or BRCA2 Test Result Mean?    80
5.3.2.4     What are the Options for a Person who Tests Positive?    80
5.3.3    What are Some of the Benefits of Genetic Testing for Breast Cancer Risk?    81
5.3.4    What are Some of the Risks of Genetic Testing for Breast and Ovarian Cancer Risk?    81
5.4    Estrogen Receptors and Breast Cancer    81
5.4.1    Expression and Prognostic Value of ER    82
5.4.2    Progesterone Receptors and Breast Cancer        82
5.4.3    ER and PR Predict Response to Endocrine Therapy        83
5.5    HER2 Gene and Protein        83
5.5.1    HER2 Tests    83
5.5.1.1    IHC Test    84
5.5.1.2    FISH Test    84
5.5.1.3    Questions About Testing        86
5.5.1.4    HER2 Tumor Status    87
5.6    Herceptin Treatment    87
5.7    Tumor Assays for Adjuvant Chemotherapy        89
5.8    Use of Genomics to Understand Breast Cancer    90
5.9    Genetic Analysis Solution        91
5.9.1    The Use of Proteomics in Breast Cancer    93
5.9.2    Tissue Microarrays    95
5.9.3    Protein Microarrays    97
5.10    Gene Expression Microarrays and Recurrence Prediction    98
5.10.1    Oncotype DX        98
5.10.2    Oncotype DX for Breast Cancer    99
5.10.3    Risk Assessment        99
5.10.4    Use of Chemotherapy    100
5.10.5    Utility of the Oncotype DX Test    100
5.10.6    Clinical Development and Validation of Oncotype DX    100
5.10.6.1    Clinical Development of the Oncotype DX Recurrence Score        100
5.10.6.2    Clinical Validation of Prediction of Recurrence and Survival in N−, ER+ Patients Treated with
Tamoxifen    101
5.10.6.3    Oncotype DX Predicts the Likelihood of Recurrence        101
5.10.6.4    Oncotype DX Predicts the Likelihood of Breast Cancer Survival in a Community Hospital Setting    102
5.10.6.5    Oncotype DX Predicts both Prognosis and Tamoxifen Benefit        102
5.11    Economic Benefits of Oncotype DX    103
5.12    Increased Clinical Utility of Oncotype DX        104
5.13    Second Generation Oncotype DX        104
5.13.1    Recurrence and Benefit Test for N−, ER− Breast Cancer    104
5.13.2    Taxane Benefit Test    104
5.14    MammaPrint    104
5.15    Rotterdam Signature 76-Panel    105
5.16    Summary of Microarray Technologies    106
5.17    Mass Spectrometry-Based Approaches    106
5.17.1    Gel-Based Approaches    106
5.17.2    Non-Gel-Based Approaches    107
5.17.2.1    SELDI-TOF MS        108
5.17.2.2    SELDI and Prognosis    109
5.17.2.3    SELDI and Treatment Monitoring        109
5.18    Outlook        111
5.19    Future Perspectives    113
5.20    Breast Cancer Program (NMP66)        114
5.21    Myriad Genetics        114
5.22    Janssen Diagnostics, LLC GeneSearch Breast Lymph Node    115
5.23    OncoVue® Cancer Risk Test (InterGenetics, Inc.)    115
5.24    Research Biomarkers for Breast Cancer    116
5.25    Protein Biomarkers for Breast Cancer Prevention    117
5.26    Biomarker Prognosis of Breast Cancer Treated with Doxorubicin    117

6.    Ovarian Cancer        118
6.1    Incidence Rates        118
6.1.1    Incidence Rates        118
6.1.2    Mortality Rates        119
6.2    Serum Markers        121
6.3    Biomarkers    122
6.3.1    Strategies for Discovering New Cancer Biomarkers        123
6.4    Serum Protein Biomarkers for Ovarian Cancer    123
6.4.1    Clinical Proteomics    124
6.5    Ovarian Cancer Triage Testing    125
6.5.1    Vermillion’s Ovarian Cancer Triage Diagnostic Program    126

7.    Prostate Cancer        128
7.1    Overview    128
7.1.1    Incidence Rates        128
7.1.2    Mortality Rates        128
7.1.3    Prostate Cancer Progression and Recurrence Test    128
7.1.4    Current Market Size    129
7.2    Genes Involved in Prostate Cancer        130
7.3    Androgen Independence        131
7.4    Gene Markers in Prostate Cancer        131
7.5    Microarray Gene Identification of Prostate Biomarkers    132
7.6    GEArray DNA Microarrays    134
7.7    Vermillion’s Cancer Diagnostic Program    135
7.8    Hepsin        135
7.9    Hologic Gen-Probe’s PCA3 Assay        135
7.10    Early Prostate Cancer Antigen-2 (EPCA-2)        136
7.11    New and Novel Methods for Detection of Prostate Cancer    137
7.12    Mass Spectrometry    137
7.13    Summary    139

8.    Bladder Cancer        140
8.1    Overview    140
8.2    Incidence and Mortality Rates    140
8.2.1    Incidence Rates        140
8.2.2    Mortality Rates        140
8.3    Progression and Recurrence    140
8.3.1    Bladder Cancer Risk Factors    141
8.3.2    Bladder Cancer Symptoms        141
8.4    Bladder Cancer Tests    141
8.5    UroVysion Bladder Cancer Kit (Abbott Molecular)    142
8.6    The oncoFISH Bladder (Ikonisys)        142
8.6.1    The CellOptics Platform (Ikonisys)        142
8.6.2    Cell Staining and Genetic Characterization        143
8.6.3    Ikoniscope/IkoniLAN Automated Microscopy    143
8.7    Nuclear Matrix Protein Markers    143
8.8    ImmunoCyt/uCyt+    146
8.9    Bladder Cancer Market    147
8.9.1    Urologist Market        147
8.9.2    Clinical Lab Market    147
8.9.3    Primary Care Market    147
8.9.4    Private and Public Sector Markets        148
8.9.5    POC Market    148
8.9.6    Market Distribution    150
8.9.7    Reimbursement        151

9.    Colorectal Cancer    152
9.1    Overview    152
9.2    Incidence and Mortality Rates    152
9.2.1    Incidence Rates        152
9.2.2    Mortality Rates        152
9.2.3    Progression and Recurrence    152
9.3    Screening for CRC    154
9.3.1    Stool-Based DNA Screening    155
9.4    Almac Diagnostics DSA        156
9.5    Colon Cancer Program (NMP35)        157
9.6    Myriad Genetics COLARIS AP Risk Assessment    158
9.7    Summary    158

10.    Genetic Diagnostics Set to Revolutionize Cancer Diagnostic Testing    159
10.1    Overview    159
10.1.1    Clinicians’ Need for More Information with Regard to Therapeutic Treatment Drives Demand for Pharmacogenomic Testing        159
10.1.2    Predictive Medicine Shows Potential for Genetic Diagnostics        159
10.1.3    Different Rates of Growth        160
10.1.4    Effective Competitive Strategies    160
10.1.5    Improvements in Marketing Effectiveness        160
10.1.6    Emerging Technologies Imply Start of a New Era and Offer Tremendous Growth Opportunities    161
10.1.7    Increased Market Share        161
10.1.8    Technologies Used in Genetic Testing    161
10.2    AMAS Test    161
10.3    Corixa (now GSK) Antibodies as Tumor Markers    161
10.4    CytoVision    162
10.5    Ariol System    162
10.6    Mammaglobin Protein Expression        162
10.7    L523S or KOC RNA Binding Protein    163
10.8    CA1-18 from EDP Biotech Corporation    163

11.    Leukemia Biomarkers    164
11.1    Overview    164
11.2    Incidence and Mortality Rates    164
11.2.1    Incidence Rates        164
11.2.2    Mortality Rates        164
11.3    Progression and Recurrence    164

12.    Lung Cancer    166
12.1    Introduction    166
12.2    Incidence and Mortality Rates    166
12.2.1    Incidence Rates        166
12.2.2    Mortality Rates        166
12.3    Lung Cancer Diagnostic Tests    167

13.    Enabling Technologies for Oncology Biomarker Discovery    168
13.1    Automated Cellular Imaging System (ACIS III)    168
13.1.1    ACIS for HER2 Protein Expression Testing        169
13.1.2    ACIS for ER Protein Expression Testing    169
13.1.3    ACIS for PR Protein Expression Testing    170
13.1.4    ACIS for Cell Proliferation Expression    170
13.1.5    ACIS for Protein Expression    170
13.1.6    ACIS for Protein Micrometastases in Bone Marrow        170
13.1.7    ACIS for Protein Micrometastases in Tissue        170
13.1.8    ACIS for TMA        170
13.1.9    ACIS for DNA Ploidy    170
13.1.10    ACIS for HPV        171
13.2    DNA Methylation    171
13.2.1    Differential Methylation Hybridization (DMH)    171
13.2.2    MIRA-Assisted Microarrays for DNA Methylation Analysis and Cancer Diagnosis    172
13.3    Proteomics    172
13.3.1    Proteomics Technologies for Cancer Marker Discovery    172
13.3.2    Validation of Candidate Biomarkers    173
13.3.3    Requirements Bringing a New Marker into the Market    173
13.3.4    Value Chain in the Development of New Cancer Biomarkers        174
13.4    Secreted Proteins as Cancer Biomarkers    174
13.4.1    Markers of Known Tissue Origin        174
13.4.2    Secreted Proteins as Low Abundance Markers    174
13.4.3    Secreted Proteins in Tissue and Blood    175
13.5    Non-coding RNAs as Potential Tumor Markers    175
13.5.1    miRNA Meets Microarray        175
13.5.2    Mimetics and Inhibitors        176
13.5.3    Clinical Patterns in Cancer        176
13.6    Architect TIMP-1 (Tissue Inhibitor of Metalloproteinases-1) Immunoassay for CRC Detection    176
13.7    Companies Developing Automated Microscope-Based Analysis Systems    176
13.8    Companies Developing Research Products for Tumor Cell Isolation    176
13.9    Companies Supplying Fluorescently Labeled Antibodies to Characterize Tumor Cells    176
13.10    PerkinElmer High-Throughput Platforms: AlphaScreen, AequoScreen, DELFIA and LANCE
Technologies    177

14.    Biomarker Tests Co-Developed with Cancer Therapeutics as Companion Diagnostics    178
14.1    Sector Overview        178
14.2    Companion Diagnostics    180
14.3    EGFR for CRC and Camptostar (Irinotecan)        180
14.3.1    Companion Diagnostic Test Developed for UGT1A1 for Irinotecan        180
14.3.2    Companion Diagnostic Test Developed for Bristol-Myers’ SPRYCEL        181
14.3.3    EGFR Express and Erbitux (Cetuximab)    181
14.4    Companions Based on Myriad’s IVDMIA Technology    181
14.4.1    Myriad’s TheraGuide 5-Fluorouracil (5-FU)        181
14.4.2    BRACAnalysis Test    182
14.5    Companions for Tyrosine Kinase Inhibitors: Erlotinib and Gefitinib    183
14.5.1    TheraScreen: EGFR29    183
14.5.2    The K-RAS Mutation Detection Kit        183
14.8    Drivers and Barriers to Companion Diagnostics    183
14.9    Partnerships with Pharma Companies to Identify Therapeutic Targets        184
14.10    Future Developments for Companion Diagnostics    185

15.    Companion Diagnostics and Personalized Medicine: Biology, Approaches, Pipeline and
Regulatory Trends    187
15.1    Scope of This Chapter    187
15.2    Introduction to Companion Diagnostics and Personalized Medicine    187
15.2.1    Stakeholders in Companion Diagnostics    187
15.2.2     Development of Stakeholders’ Business Models for Companion Diagnostics for Personalized
Medicine    189
15.2.2.1    Pharmaceutical Company Business Models for Developing Companion Diagnostics Products    189
15.2.2.2    Diagnostic Company Business Models for Developing Companion Diagnostics Products        190
15.2.2.3    Life Science Company Business Models for Developing Companion Diagnostics Products    190
15.2.2.4    Pharmacy Benefit Management Company Business Models for Developing Companion Diagnostics Products        191
15.2.3    Trends in Companion Diagnostic Deals    192
15.2.3.1    Market Size of Companion Diagnostics    193
15.2.4    Companion Diagnostics: Industry SWOT Analysis        200
15.2.5    Challenges for Companion Diagnostics Development        200
15.2.6    Timeline for Impact of Various Segments in Companion Diagnostics    202
15.2.7    Use of Proteomics to Develop Individualized Tests    204
15.3    The Compelling Case for Personalized Medicine    206
15.4    Drug Metabolism and Implications for Companion Diagnostics and Personalized Medicine    207
15.5    Examples of Personalized Medicine    211
15.6    Personalized Medicine and Companion Diagnostics Testing Product Pipeline    215
15.7    The Personalized Medicine Coalition    216
15.8    Regulatory Trends and Guidelines in the Personalized Medicine Space        221
15.8.1    The Changing Regulatory Landscape for Personalized Medicine    222
15.9    Patenting Personalized Medicine    223
15.10    The Leading Edge of Personalized Medicine: Specific Examples of Clinical Situations Where Personalized Medicine and Companion Diagnostics are Appropriate and Being Deployed    226
15.10.1    EGFR Assay    226
15.10.2    UGT1A1 Molecular Assay for Camptosar    227
15.10.3    Response to Gleevec in Gastrointestinal Stromal Tumors    227
15.10.4    LabCorp and Qiagen and Personalized Medicine for the treatment of Colorectal Cancer        227
15.10.5    Labcorp and ARCA Discovery, Inc. and Personalized Medicine for Cardiovascular Disease    228
15.11    Companion Diagnostics and Personalized Medicine: Qualitative and Quantitative Market
Analysis        228
15.11.1    Market Analysis of Molecular Diagnostics and Companion Diagnostics and Personalized
Medicine    229
15.11.2    Diagnostics vs. Pharmaceuticals    230
15.11.3    Molecular Diagnostic Market    230
15.11.4    Molecular Diagnostics Technology Platforms and their Impact on Personalized Medicine        233
15.12    Snapshot of Companion Diagnostics Industry Structure    235
15.13    The Case for Theranostics (Therapeutic/Companion Diagnostic)    236
15.14    Personalized Medicine Market Analysis—Market Survey Data Characterizing the Qualitative and Quantitative Industry Parameters        237
15.15    How the Market Segregates Today        238
15.16    Timeline for Impact of Various Segments in Personalized Medicine    239
15.17    Challenges for Personalized Therapeutics and Companion Diagnostics Development    241
15.18    Macro Trends in Personalized Medicine    242
15.19    Personalized Medicine and Companion Diagnostics: Industry SWOT Analysis        245

16.    Business Trends in the Industry    247
16.1    Industry Consolidation        247
16.2    Breadth of Product Offering and Pricing    248
16.3    Government Regulation of Medical Devices        248
16.3.1    FDA Guidance on Drug Test Co-Development    250
16.4    Strategic Business and Marketing Considerations    250
16.5    Commercial Opportunities in Cancer Markers    251
16.5.1    Licensing and Intellectual Property Constraints and how they will Impact New Product
Development    252
16.6    Moderators of Growth    252
16.6.1    Roadblocks to Integrating Cancer Biomarkers into Clinical Practice    253
16.7    Biotechnology Industry Trends    253
16.8    Pharmaceutical Industry Trends    254
16.9    Sales and Marketing Strategies for Tumor Marker Tests    254
16.9.1    North American Market        255
16.9.2    International Markets    256
16.9.2.1    Europe        256
16.9.2.2    Central and South America    257
16.9.2.3    Asia-Pacific    257
16.10    Product Commercialization    258
16.11    Reimbursement        259
16.12    Self Referral Rules    260
16.13    Health Insurance Portability and Accountability Act        261
16.14    Clinical Laboratory Improvement Amendments    261
16.15    In Vitro Diagnostic Directive and Medical Device Regulations        262
16.16    FDA’s Quality System Regulation        262
16.17    FDA’s OIVD on IVDMIAs    263
16.18    FDA Approval Process for Protein-Based Biomarkers        264
16.18.1    Classification of Protein-Based Biomarker Assays as Medical Devices        264
16.18.2    Clinical and Analytical Requirements for Biomarker Performance    265
16.18.3    Approval Process Workflow    267
16.19    Genetic Tests and Medical Records        267
16.19.1    Laws Against Genetic Discrimination    268
16.20    Medicare Reimbursement    269
16.20.1    Medicare Spending Trends    269
16.21    Global Drivers of Clinical Laboratory Testing    271
16.22    Global Outlook for Cancer Biomarkers    271
16.22.1    Which Companies are Utilizing Cutting-Edge Technologies to Develop, Validate and Implement Cancer Biomarkers for Clinical Use?    272
16.22.2    What Impediments Still Exist to Incorporating Promising Research into Clinical Practice?        272
16.22.3    Which Biomarkers Show the Most Promise for Approval?    273
16.22.4    How can Regulatory Oversight Drive Approval and Adoption of New Technologies?    273
16.22.5    Which Alliances Show the Greatest Synergy in Bringing Valid Biomarkers to Market?    273
16.22.6    Which Shared Technologies are Driving the Most Encouraging Development?        273
16.22.7    How Strategic Alliances and Interdisciplinary Involvement Drive Development and Implementation of Emerging Biomarker Technologies        274
16.23    Oncology Biomarker Qualification Initiative        274
16.24    FDA Critical Path    275
16.25    FDA Criteria for a Valid Biomarker    275

17.    Companies Entering the Cancer Diagnostics Market with Novel Technology Platforms        276
17.1    Abbott Diagnostics    276
17.2    Affymetrix, Inc.        279
17.3    Agendia BV    286
17.4    Agensys, Inc. (Astellas Pharma US)    288
17.5    Agilent Technologies    289
17.6    Almac Group    290
17.7    AMDL, Inc.    292
17.8    Asuragen, Inc.    293
17.9    Aureon Laboratories, Inc.        294
17.10    Beckman Coulter, Inc.    295
17.11    Biocode Hycel S.A.    299
17.12    BioCurex, Inc.    299
17.13    Biomarker Technologies, LLC    300
17.14    Biomedical Diagnostics, LLC    300
17.15    Biomerica, Inc.        301
17.16    bioMérieux    302
17.17    Biomira, Inc. (Oncothyreon, Inc.)        303
17.18    Biomoda, Inc.    303
17.19    Bruker Daltonics, Inc.    304
17.20    Byk Gulden    305
17.21    Cangen Biotechnologies, Inc.    305
17.22    Caprion Proteomics    306
17.23    Celera Diagnostics    309
17.24    Cepheid        309
17.25    Clarient, Inc. (GE Healthcare)    311
17.26    Claros Diagnostics, Inc.        312
17.27    Clinical Data, Inc.: PGxHealth and Cogenics        312
17.28    Correlogic Systems, Inc.        314
17.29    CytoCore, Inc. (Formerly Molecular Diagnostics, Inc.)    315
17.30    Cytogen Corporation (now EUSA Pharma)        316
17.31    Dako (Agilent Technologies)    318
17.32    diaDexus, LLC        319
17.33    DiagnoCure, Inc.        320
17.34    DRG International, Inc.    322
17.35    EDP Biotech Corporation        323
17.36    Eisai Co., Ltd.    324
17.37    Eli Lilly & Co.    324
17.38    Epigenomics    325
17.39    Exact Sciences Corporation    326
17.40    Exagen Diagnostics, Inc.        326
17.41    Exigon        327
17.42    Gene Logic, Inc.        327
17.43    Genesis Genomics, Inc. (Mitomics)        328
17.44    GenMark Diagnostics    329
17.45    Genomic Health, Inc.    330
17.46    Gen-Probe, Inc. (now known as Hologic Gen-Probe)        331
17.47    Health Discovery Corporation    336
17.48    Ikonisys, Inc.    337
17.49    Illumina        337
17.50    Immunomedics, Inc.    339
17.51    Incyte Pharmaceuticals, Inc.    341
17.52    InterGenetics, Inc.    341
17.53    Ipsogen (Qiagen Marseille)    341
17.54    Janssen Diagnostics    342
17.55    LabCorp        343
17.56    Life Technologies Corporation (Thermo Fisher Scientific)    344
17.57    Matritech, Inc. (Alere)    347
17.58    Miraculins, Inc.        348
17.59    Mitsubishi Kagaku Medical    349
17.60    MolecularMD        349
17.61    Myriad Genetics, Inc.    350
17.62    NimbleGen Systems, Inc.        355
17.63    Northwest Biotherapeutics, Inc.    355
17.64    Oncotech, Inc. (Exiqon A/S)    356
17.65    Oncothyreon, Inc. (Formerly known as Biomira)    357
17.66    OPKO Health, Inc.    359
17.67    Orion Genomics        361
17.68    Oxford BioTherapeutics (Formerly Oxford Genome Sciences)        362
17.69    Panacea Pharmaceuticals, Inc.    363
17.70    Polymedco, Inc.        363
17.71    Power3 Medical Products        364
17.72    Qiagen N.V.    364
17.73    Roche Molecular Diagnostics    368
17.74    SensiGen, LLC (Sequenom Center for Molecular Medicine)        370
17.75    Siemens Healthcare Diagnostics, Inc.    371
17.76    Upstream Biosciences, Inc.    372
17.77    Ventana Medical Systems, Inc. (Part of the Roche Group)    373
17.78    Veridex, LLC (Janssen Diagnostics, LLC)        374
17.79    Vermillion, Inc. (Formerly Ciphergen)    375

Appendix 1: Cancer Biomarker Centers of Research        377
Appendix 2: Myriad Patents on Genes BRCA-1 and BRCA-2        378
Appendix 3: Cancer Markers Currently in Common Clinical Use    379
Appendix 4: International Federation of Gynecology and Obstetrics (FIGO) Staging System for Primary Carcinoma of the Ovary    380
Appendix 5: FDA Guidance for Industry: Pharmacogenomic Data Submission        381
A5.1    Introduction    381
A5.2    Background    381
A5.3    Submission Policy    382
A5.3.1    General Principles    382
A5.3.2    Specific Uses of Pharmacogenomic Data in Drug Development and Labeling    384
A5.3.3    Benefits of Voluntary Submissions to Sponsors and FDA    385
A5.4    Submission of Pharmacogenomic Data    386
A5.4.1    Submission of Pharmacogenomic Data During the IND Phase        386
A5.4.2    Submission of Pharmacogenomic Data to a New NDA, BLA or Supplement    387
A5.4.3    Submission to a Previously Approved NDA or BLA        388
A5.4.4    Compliance with 21 CFR Part 58        388
A5.4.5    Submission of Voluntary Genomic Data from Application-Independent Research    388
A5.5    Format and Content of a VGDS    389
A5.6    Process for Submitting Pharmacogenomic Data    390
A5.7    Agency Review of VGDSs    390
Appendix 6: E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure, and Format of Qualification Submissions    392
A6.1    Introduction    392
A6.2    Background    392
A6.3    Scope        392
A6.4    General Principles    392
A6.5    Structure of Biomarker Qualification Submissions    393

Glossary        400


INDEX OF FIGURES

Figure 3.1: Potential Market for Cancer Biomarkers        28
Figure 3.2: Segmentation of the Cancer Biomarkers Marketplace Based on Commercial Offerings—Products and Services        31
Figure 3.3: Geographical Distribution of Cancer Tumor Diagnostic Testing    35
Figure 3.4: Cancer Biomarkers Research Market, 2006-2016        43
Figure 3.5: Breast Cancer Biomarker Market Potential, 2010        49
Figure 3.6: Challenges in the Study or Utilization of Proteomic Cancer Biomarkers    50
Figure 3.7: Challenges in the Study or Utilization of Companion Diagnostic Cancer Biomarkers    50
Figure 3.8: Challenges in the Study or Utilization of Serum Cancer Markers    51
Figure 3.9: Top Unmet Needs in Commercial Products in the Cancer Biomarkers Space        52
Figure 5.1: Hybridization Process        85
Figure 5.2: FISH Test Procedure        85
Figure 5.3: Gene Expression Profiling    96
Figure 15.1: Strategic and Tactical Considerations for Co-Development of Companion Diagnostics    192
Figure 15.2: Global Market for Companion Diagnostics    193
Figure 15.3: Number of Companion Diagnostic Agreements, 2000-2013    194
Figure 15.4: Surface Binding Produces Phase Shifts that Increases the Diffraction Signal Intensity        205
Figure 15.5: Phase I and II Processes of Drug Metabolism    207
Figure 15.6: Human Phase I Enzymes    208
Figure 15.7: Human Phase II Enzymes    208
Figure 15.8: Hepatic Distribution of Human CYP450        209
Figure 15.9: Relative Contribution of CYP450 Enzymes to Drug Metabolism    209
Figure 15.10: Genetic Components Determine Drug Metabolism    210
Figure 15.11: From Genetic Content to Personalized Medicine        229
Figure 15.12: Remuneration for Diagnostics        230
Figure 15.13: Breakout of the Molecular Diagnostics Marketplace    231
Figure 15.14: Molecular Diagnostics Market Segmentation        232
Figure 15.15: Molecular Diagnostics Market Segmentation by Technology    233
Figure 15.16: Market Survey Respondent Demographics    237
Figure 15.17: Breakout of the Respondent Pool by Affiliation        238
Figure 15.18: Segmentation of the Personalized Medicine Market    238
Figure 15.19: Personalized Medicine Market Drivers        242
Figure 15.20: Challenges in the Personalized Medicine Space        243
Figure 16.1: Medicare Spending on Clinical Laboratory Services per Enrollee, 2003-2016        269


INDEX OF TABLES

Table 2.1: Cancer Biomarker Stakeholders        23
Table 3.1: Characteristics of Different Cancer Biomarker Types and Associated Market Opportunities    30
Table 3.2: Segmentation of the Cancer Biomarker Market by Type/Lineage of Cancer Biomarkers and
Market Size    31
Table 3.3: In Vitro Cancer Marker Market Segments Worldwide, 2007-2012    32
Table 3.4: Worldwide Market Size in Dollar Volume for Tumor Marker Assays Product Market,
2009-2019    33
Table 3.5: U.S. Market Size in Dollar Volume for Tumor Marker Assays Product Market, 2009-2019    33
Table 3.6: Worldwide In Vitro Cancer Tumor Marker Diagnostics Market Size, 2009-2019    34
Table 3.7: U.S. In Vitro Cancer Tumor Marker Diagnostics Market Size, 2009-2019    34
Table 3.8: Japanese In Vitro Cancer Tumor Marker Diagnostics Market Size, 2009-2019        34
Table 3.9: European In Vitro Cancer Tumor Marker Diagnostics Market Size, 2009-2019        35
Table 3.10: Global Distribution of IVD Cancer Tumor Marker Diagnostic Testing, 2013        35
Table 3.11: Estimated Market Share of Major Competitors in U.S. Cancer Tumor Marker Diagnostics
Market        36
Table 3.12: Major Presence in Cancer Tumor Marker Diagnostics Markets    36
Table 3.13: Worldwide CEA Sales, 2009-2019    37
Table 3.14: U.S. CEA Sales, 2009-2019    37
Table 3.15: Japan CEA Sales, 2009-2019    38
Table 3.16: Europe CEA Sales, 2009-2019        38
Table 3.17: Rest of the World CEA Sales, 2009-2019        38
Table 3.18: Worldwide PSA Sales 2009-2019    39
Table 3.19: U.S. PSA Sales 2009-2019    40
Table 3.20: Cancer Biomarkers Research Market Forecast, 2006-2016        42
Table 3.21: Cancer Biomarker Market Estimates by Tissue of Origin        46
Table 3.22: Companies Developing New Proteomic Cancer Biomarker Technology Platforms    55
Table 3.23: Uses of Molecular Diagnostics in Detection and Management of Cancer    57
Table 3.24: U.S. Cancer Diagnostic Testing Market Size, 2005-2016        58
Table 3.25: Market Opportunities for Cancer Biomarker Technology Platforms    59
Table 4.1: Use of Biomarkers in Clinical Use    64
Table 4.2: Use of Biomarkers in Cancer Research    65
Table 4.3: Currently Approved Targeted Therapies for Solid Malignancies and Their Molecular Targets    66
Table 4.4: Tumor Biomarkers Currently in Common Use    68
Table 4.5: Clinically Relevant Biomarkers    69
Table 4.6: Biomarkers for Monitoring Therapeutic Effectiveness and Resistance        70
Table 4.7: Biomarkers for Dose Response of Therapy        71
Table 4.8: Decision on Optimal Duration of Therapy        71
Table 5.1: Estimated New Female Breast Cancer Cases and Deaths by Age in the U.S., 2013    75
Table 5.2: BRCA Development Model    77
Table 5.3: BRCA Test Development and Commercialization    78
Table 5.4: BRACAnalysis        78
Table 5.5: Revenue for BRACAnalysis Risk Assessment Test, 2002-2013    78
Table 5.6: Key Players in the Breast Cancer Molecular Diagnostic Space    92
Table 5.7 Companies Offering IVDMIA Microarray Breast Cancer Biomarker Analysis        92
Table 5.8: GEArray DNA Microarrays and RT2 Profiler PCR Arrays        97
Table 5.9: Product Development Opportunities in Breast Cancer    103
Table 5.10: Concentration of Some Abundant Proteins, New Cancer Biomarkers Identified by SELDI-TOF and Classical Cancer Biomarkers in Serum    110
Table 5.11: Questions Related to Diagnostic SELDI-TOF Technology        113
Table 6.1: Worldwide CA-125 Sales, 2001-2018    119
Table 6.2: U.S. CA-125 Sales, 2001-2018        120
Table 6.3: Some Clinically Established Cancer Serum Markers Currently in Use for Cancer    121
Table 6.4: Pathophysiology of Ovarian Cancer and Characterization of Ovarian Epithelial Tumors        127
Table 7.1: Worldwide PSA Sales, 2000-2018    129
Table 7.2: U.S. PSA Sales, 2000-2018    130
Table 7.3: Molecular Gene Markers for Prostate Cancer    132
Table 8.1: Worldwide Bladder Cancer Marker Sales, 2001-2018    144
Table 8.2: U.S. Bladder Cancer Marker Sales, 2001-2018    144
Table 8.3: Worldwide NMP22 Sales, 2001-2018    145
Table 8.4: Summary of Matritech’s Product Development Programs    146
Table 8.5: Opportunities for Bladder Cancer Biomarkers    147
Table 9.1: TNM Staging for CRC        153
Table 10.1: Genetic Diagnostics Market, 2004-2018        160
Table 13.1: Genomic and Proteomic Technologies        173
Table 14.1: Potential Benefits of Biomarkers as Companion Diagnostics    180
Table 14.2: Utility of Biomarker as Companion Diagnostics to Drug Development    180
Table 14.3: Device Submission Elements for the FDA    184
Table 14.4: Summary of Biomarker Use in the Commercialization of Novel Oncology
Pharmacotherapeutics    185
Table 14.5: Pharmacoeconomic Challenges to the Implementation of Biomarkers as Companion
Diagnostic Tests        186
Table 15.1: FDA Approved Companion Diagnostic Devices: In Vitro and Imaging Tools        195
Table 15.2: Personalized Medicine Industry SWOT Analysis        200
Table 15.3: Hurdles to Personalized Medicine and Companion Diagnostics Development        201
Table 15.4: Timeline of Impact in Areas of Personalized Medicine    202
Table 15.5: Impact of Personalized Medicine on Various Therapeutic Areas    203
Table 15.6: Percentage of Non-Responders in Various Drug Classes    206
Table 15.7: High Profile Drug Withdrawals from the Marketplace    206
Table 15.8: Drug Metabolism Drives Drug Efficacy/Toxicity        211
Table 15.9: Population Frequency of the Various Cytochromes        211
Table 15.10: Selected List of Personalized Medicine Tests    214
Table 15.11: Personalized Medicine and Companion Diagnostics Product Pipeline    215
Table 15.12: Marketed Personalized Therapies, 2013        216
Table 15.13: Members of the Personalized Medicine Coalition        217
Table 15.14: Various Molecular Diagnostics Technologies: Timeline for Impact        233
Table 15.15: Various Molecular Diagnostics Technologies: Impact on Different Therapeutic Areas in Personalized Medicine    234
Table 15.16: Technical Challenges in the Deployment for Personalized Medicine    234
Table 15.17: Classification of Diagnostics by Risk        236
Table 15.18: Areas in Personalized Medicine—Timeline of Impact    239
Table 15.19: Impact of Personalized Medicine on Various Therapeutic Areas    241
Table 15.20: Hurdles in Personalized Medicine and Companion Diagnostics Development in Various Therapeutic Areas        241
Table 15.21: Market Opportunities in Personalized Medicine        244
Table 15.22: Challenges for Market Adoption of the Various Personalized Medicine Tests    245
Table 15.23: Personalized Medicine Industry SWOT        246
Table 16.1: List and Discounted Prices for Abbott Tumor Marker Tests        248
Table 16.2: Increases in Total Allowed Charges for Laboratory Services per Enrollee, 2000-2016        269
Table 16.3: Incurred Reimbursement Amounts per Fee-for-Service for Laboratory Services per Enrollee,
2003-2016    270
Table 16.4: Medicare Part B Benefit Payments, 2003-2016    270
Table 17.1: Major GeneChip Instrument Products        282
Table 17.2: Major GeneChip Array and Reagent Products    282
Table 17.3: Gene Titan Products    282
Table 17.4: Gene Atlas Products    283
Table 17.5: Gene Atlas Products    283
Table 17.6: Opportunities for Biomarkers in Cancer Diagnosis and Treatment    311
Table 17.7: Tumor Diagnosis Immunoassay        323
Table 17.8: Tumor Diagnosis Radioimmunoassay    323
Table 17.9: Myriad Molecular Diagnostic Revenues, 2012 and 2013    350
Table 17.10: Roche Group Financial Figures—Net Sales by Business Sector, 2008-2013        370
Table 17.11: Roche Group Diagnostics Division—Net Sales by Geographic Region, 2012 and 2013    370
Table 17.12: Roche Group Financial Figures—Net Sales by Diagnostics Sub-Division, 2008-2013        370
Table A1.1: Team Descriptions        377
Table A3.1: List of FDA-Approved Protein Tumor Markers Currently Used in Clinical Practice    379