CIRCULATING TUMOR CELL (CTC) DIAGNOSTICS: TECHNOLOGIES AND GLOBAL MARKETS

CIRCULATING TUMOR CELL (CTC) DIAGNOSTICS: TECHNOLOGIES AND GLOBAL MARKETS PHM153A January 2014 Usha Nagavarapu Project Analyst ISBN: 1-56965-671-1 BCC Research 49 Walnut Park, Building 2 Wellesley, MA 02481 USA 866-285-7215 (toll-free within the USA), or (+1) 781-489-7301 www.bccresearch.com information@bccresearch.com

TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 2 STUDY GOALS AND OBJECTIVES 2 REASONS FOR DOING THIS STUDY 2 INTENDED AUDIENCE 2 SCOPE OF THE STUDY 3 METHODOLOGY 3 INFORMATION SOURCES 4 ABOUT THE AUTHOR 4 RELATED BCC RESEARCH REPORTS 4 BCC RESEARCH ONLINE SERVICES 4 DISCLAIMER 5 CHAPTER 2 SUMMARY 7 SUMMARY TABLE GLOBAL MARKET SALES AND FORECAST FOR CIRCULATING TUMOR CELL TECHNOLOGY, THROUGH 2018 ($ MILLIONS) SUMMARY FIGURE GLOBAL MARKET SALES AND FORECAST FOR CIRCULATING TUMOR CELL TECHNOLOGY, 2012-2018 ($ MILLIONS) 8 8 CHAPTER 3 CIRCULATING TUMOR CELLS 10 CANCER 10 RECENT ADVANCES IN TECHNOLOGY 10 INVASIVE POWER 11 CIRCULATING TUMOR CELL 11 PHENOTYPIC CHARACTERISTICS 11 CTC CLUSTERS 12 CTC DETECTION 12 CANCER STEM CELLS (CSC) 13 TABLE 1 CATEGORIES OF STEM CELLS 14 TABLE 2 PRODUCT CATEGORIES 15 CIRCULATING TUMOR CELLS - POTENTIAL USES 15 TABLE 3 KEY FACTORS OF CTC S 16 What Are Circulating Tumor Cells? 16 Biology and Characteristics of CTCs 17 TABLE 4 CIRCULATING TUMOR CELLS - FEATURES 18 PROLIFERATIVE ACTIVITY 18 EPITHELIAL MARKER GENES ON CIRCULATING TUMOR CELLS 19 CTCs as Biomarkers 20 Biomarker Qualification Program 21 Epithelial to Mesenchymal Transition 21 CIRCULATING TUMOR CELLS AND STEM CELL-LIKE PHENOTYPE 22 CTCS AND PRIMARY TUMOR CELLS: COMPARISON 22 METASTASIS 23 The Metastatic Process 23 FUTURE DIRECTIONS 24 TABLE 5 METASTATIC CASCADE 24 METASTATIC DEVELOPMENT IN CANCER PATIENTS 25

CIRCULATING TUMOR CELL MIGRATION 25 IMPORTANT MARKERS OF DISTANT METASTASIS 25 CIRCULATING TUMOR CELL DETECTION 25 TABLE 6 EPCAM-BASED ASSAYS 26 CHALLENGES FOR DETECTION 26 THE CLINICAL APPLICATION OF CIRCULATING TUMOR DNA 27 CIRCULATING TUMOR CELLS AS PREDICTOR OF RESPONSE TO THERAPY 27 MEASUREMENT OF CTCS - APPLICATIONS 28 CONCLUSION 28 TABLE 7 CTC DETECTION - ADVANTAGES 29 CHAPTER 4 INCIDENCE OF CANCER 31 WORLDWIDE GROWTH IN THE INCIDENCE OF CANCER 31 TABLE 8 CANCER - KEY FACTS 32 CAUSES OF CANCER 32 TABLE 9 CANCER CAUSES 33 RISK FACTORS FOR CANCERS 33 BURDEN OF CANCER 33 AVOIDING RISK FACTORS 33 TABLE 10 CANCER CAUSING FACTORS 34 Prevention Strategies 34 EARLY DETECTION 34 Early Diagnosis 34 Screening 34 TABLE 11 CANCER SCREENING METHODS 35 TREATMENT 35 Treatment of Early-Detectable Cancers 35 Treatment of Other Cancers with Potential for Cure 35 PALLIATIVE CARE 35 Palliative Care Strategies 36 WORLD HEALTH ORGANIZATION RESPONSE 36 TABLE 12 NONCOMMUNICABLE DISEASES ACTION PLAN 36 WORLD CANCER STATISTICS 36 TABLE 13 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 (MILLIONS) 37 FIGURE 1 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 (MILLIONS) 37 TABLE 14 ESTIMATED GLOBAL CANCER INCIDENCE, 2008 (THOUSANDS) 38 CANCER AND THE GLOBAL IMPACT 38 Prevalence 39 Global Patterns 39 THE FUTURE OF CANCER 40 TABLE 15 INCREASE IN CANCER BURDEN - FACTORS 41 Common Types of Cancer 42 TABLE 16 THE MAIN TYPES OF CANCER AND ASSOCIATED MORTALITY 43 TABLE 17 GENERAL GLOBAL CANCER INCIDENCE BY TYPE 43 TABLE 18 GLOBAL INCIDENCE OF CANCER BY TYPE, 2008 (THOUSANDS/%) 44 Global Incidence in Men 45 TABLE 19 CANCER INCIDENCE IN MEN, 2008 (THOUSANDS/%) 45

Global Incidence in Women 46 TABLE 20 CANCER INCIDENCE IN WOMEN, 2008 (THOUSANDS/%) 46 Developed Countries 47 TABLE 21 GLOBAL INCIDENCE OF CANCER IN DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000, 2008 Men 48 TABLE 22 GLOBAL INCIDENCE OF CANCER IN MEN - DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000 (WORLD), 2008 Incidence in Women 49 TABLE 23 GLOBAL INCIDENCE OF CANCER IN WOMEN - DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000 (WORLD), 2008 UNITED STATES CANCER INCIDENCE 50 TABLE 24 UNITED STATES - COMMON TYPE OF CANCER ESTIMATES, 2013 50 FIGURE 2 UNITED STATES - COMMON TYPE OF CANCER ESTIMATES, 2013 50 BREAST CANCER 51 TABLE 25 GLOBAL BREAST CANCER FACTS 51 TABLE 26 BREAST CANCER IN THE UNITED STATES 52 COLORECTAL CANCER 53 TABLE 27 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF COLORECTAL CANCER IN MEN, 2008 TABLE 28 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF COLORECTAL CANCER IN WOMEN, 2008 U.S. Incidence 55 TABLE 29 UNITED STATES - COLORECTAL CANCER INCIDENCE ESTIMATES, 2013 55 FIGURE 3 UNITED STATES - COLORECTAL CANCER INCIDENCE ESTIMATES, 2013 56 PROSTATE CANCER 56 TABLE 30 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF PROSTATE CANCER, 2008 Westernization Trends 57 TABLE 31 PROSTATE CANCER INCIDENCE AND MORTALITY WORLDWIDE, 2008 (THOUSANDS) FIGURE 4 PROSTATE CANCER INCIDENCE AND MORTALITY WORLDWIDE, 2008 (THOUSANDS) Prostate Cancer Mortality 60 TABLE 32 GLOBAL ESTIMATED PROSTATE CANCER DEATHS AND AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 FIGURE 5 GLOBAL ESTIMATED PROSTATE CANCER DEATHS AND AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 Prostate Cancer a Burden Globally 61 TABLE 33 GLOBAL ESTIMATED NEW CASES OF PROSTATE CANCER, 2008 2030 FIGURE 6 GLOBAL ESTIMATED NEW CASES OF PROSTATE CANCER 2008-2030 Prostate Cancer and the U.S. 63 TABLE 34 PROSTATE CANCER CASES AND DEATHS IN THE U.S. 2008-2011 FIGURE 7 PROSTATE CANCER CASES AND DEATHS IN THE U.S., 2008-2011 TABLE 35 ESTIMATED NEW CASES OF PROSTATE CANCER IN THE U.S., 2012-2030 47 48 49 54 55 56 58 58 60 61 62 62 63 63 64

FIGURE 8 ESTIMATED NEW CASES OF PROSTATE CANCER IN THE U.S., 2012-2030 TABLE 36 PROSTATE CANCER INCIDENCE RATES IN THE U.S. BY RACE, 2005-2009 (PER 100,000 MEN) TABLE 37 ESTIMATED PROSTATE CANCER CASES IN THE U S., 2020 AND 2030 FIGURE 9 ESTIMATED PROSTATE CANCER CASES IN THE U.S., 2020 AND 2030 Prostate Cancer Mortality Rates in the U.S. 66 TABLE 38 MORTALITY RATES BY RACE IN U.S., 2005-2009 66 Prostate Cancer in Canada 67 TABLE 39 ESTIMATED PROSTATE CANCER IN CANADA, 2012 67 Prostate Cancer in Europe 67 TABLE 40 EUROPEAN (EU27 COUNTRIES) ESTIMATED PROSTATE CANCER MORTALITY - AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATION, 2008 FIGURE 10 EUROPEAN (EU27 COUNTRIES) ESTIMATED PROSTATE CANCER MORTALITY - AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 Prostate Cancer in the United Kingdom 69 TABLE 41 PROSTATE CANCER DEATHS IN THE U.K., 2010 (RATE PER 100,000 POPULATION) FIGURE 11 PROSTATE CANCER DEATHS IN THE U.K., 2010 (RATE PER 100,000 POPULATION) Prostate Cancer in Asia 71 CONCLUSIONS 72 64 65 65 66 68 68 70 71 CHAPTER 5 TECHNOLOGIES 74 FINDING CIRCULATING TUMOR CELLS 74 TABLE 42 POTENTIAL APPLICATIONS OF CTC-BASED DIAGNOSTICS 74 CURRENT CTC DETECTION AND ISOLATION METHODS 75 NEW TECHNOLOGIES FOR THE DETECTION 75 CANCER PROGNOSIS 76 Carcinoma - CTC and the Metastatic Cascade 77 How many CTCs? 77 The Biological Characteristics of CTC 77 TABLE 43 CLINICAL RELEVANCE OF CTC 78 Cancer Dissemination 78 CTC DETECTION TECHNIQUES - REQUIREMENTS 78 TABLE 44 CTC ENRICHMENT METHODS 78 ENRICHMENT METHODS 79 TABLE 45 TECHNIQUES USED FOR CIRCULATING TUMOR CELL (CTC) ENRICHMENT 80 Morphology-Based Enrichment Methods 80 Cell Separation Based on Density Gradient Centrifugation 80 Size-Based Cell Enrichment by Filtration 81 Immunomagnetic Separation Techniques 81 The RosetteSep-Applied Imaging Rare Event (RARE) Method 82 MagSweeper 83 DETECTION METHODS 83

TABLE 46 TECHNIQUES USED FOR CIRCULATING TUMOR CELL (CTC) ANALYSIS 84 Immunocytochemical Approaches 84 Fiber-Optic Array Scanning Technology 85 Laser Scanning Cytometer 85 Multiphoton Intravital Flow Cytometry 85 COMBINED ENRICHMENT AND DETECTION METHODS 85 TABLE 47 ENUMERATION TECHNIQUES 86 CellSearch System 86 Microfluidic Devices 87 Microfluidic Chips 87 EPISPOT 88 AdnaTest 88 TelomeScan 89 CTC Chip 89 TABLE 48 FUNCTIONAL ASSAYS 90 NUCLEIC ACID-BASED METHODS 91 Limitations 92 Flow Cytometry 92 Image-Based Approaches 93 Reverse-Transcriptase PCR 93 CLINICAL TESTING 94 CTC Analysis in Cancer Patients 94 CTC Analysis in Patients with Metastatic Disease 95 SUMMARY 96 TABLE 49 KEY FACTS ABOUT CIRCULATING TUMOR CELLS 97 NEW EMERGING TECHNOLOGIES 97 TABLE 50 MICRO-COUNT FEATURES A NEW TECHNOLOGY 98 Herringbone-Chip (HB-Chip) 98 Future Directions 99 CHAPTER 6 CIRCULATING TUMOR CELLS AND CANCER DIAGNOSTICS 101 TABLE 51 CTC ASSAY PRE-ANALYTICAL VALIDATION CONSIDERATIONS 102 TABLE 52 CTC ASSAY ANALYTICAL VALIDATION CONSIDERATIONS 102 TABLE 53 CTC ASSAY POST-ANALYTICAL VALIDATION CONSIDERATIONS 103 USE OF CTC'S FOR DIAGNOSIS 103 TABLE 54 CURRENT ENRICHMENT ASSAYS FOR CTCS 105 TABLE 55 CTC ENUMERATION ASSAYS 108 CURRENT METHODS AND APPLICATIONS 110 CTC Chip 110 TABLE 56 CHARACTERIZATION ASSAYS FOR CTCS 111 IVD Diagnostics 112 TABLE 57 KEY FEATURES-IVD CTC TESTS 112 TABLE 58 TUMOR TYPES: PROJECTED NEW CASES AND ESTIMATED DEATHS, 2010 112 FIGURE 12 TUMOR TYPES - PROJECTED NEW CASES AND ESTIMATED DEATHS, 2010 IVDiagnostics Customized Aptamer Selection Service 114 IVDiagnostics CTC Capture 114 IVDiagnostics CTC Human Genetics 114 113

Biocept 114 CIRCULATING TUMOR CELLS IN PROSTATE CANCER: CASE STUDIES 114 TABLE 59 PROSTATE CANCER DIAGNOSIS AND ROLE OF CTC'S 115 CTC IN COMPANION DIAGNOSTICS 115 TABLE 60 CURRENT DIAGNOSTIC METHODS 115 ApoCell 116 TABLE 61 APOSTREAM KEY FEATURES 116 ApoStream CTC Imaging 116 Clarient Launches Biocept's OncoCEE-BR Test 117 Canopus Bioscience 117 TABLE 62 CANOPUS BIOSCIENCE TECHNOLOGY - BENEFITS 118 Ikonisys 118 TABLE 63 CELLOPTICS' CANCER APPLICATION 118 Technique 119 TABLE 64 CELLOPTICS' KEY FEATURES - ENRICHMENT 119 TABLE 65 CELLOPTICS' KEY FEATURES - LABELING 119 TABLE 66 CELLOPTICS' KEY FEATURES - DETECTION 120 RAREcells Diagnostics 120 TABLE 67 ISET TEST - SPECIFICATIONS 120 NEWER TECHNOLOGIES IN DEVELOPMENT 121 OriGene Technologies 121 Protein Microarray and Its Application 121 Viator Technologies 121 Photoacoustic Detection and Capture of CTCs 121 Micro Technologies 121 Interrogate Signaling in Single Cells 121 NanoVelcro 122 Embedded Microchips 122 MOLECULAR ANALYSES OF CTC 122 The Ephesia Magnetic Arrays Technology 122 New "Biopsy in a Blood Test" 122 CONCLUSIONS 124 CHAPTER 7 CTCS IN CLINICAL TRIALS 126 CTC DIAGNOSTICS 126 CIRCULATING TUMOR CELL TECHNOLOGY 126 POTENTIAL THERAPEUTIC USES OF CIRCULATING TUMOR CELLS 127 CHALLENGES IN THE DETECTION OF CIRCULATING TUMOR CELLS 128 CTC'S AS CLINICAL BIOMARKERS 129 PCR-BASED MARKERS 130 Carcinoma Cells 130 CIRCULATING TUMOR CELLS IN CANCER - CURRENT STATUS 130 Breast Cancer 130 STIC CTC METABREAST (France) 131 SWOG 0500 (USA) 132 CirCe01 (France) 132 Treat CTC (Europe) 133

DETECT III (Germany) 134 PROGNOSTIC AND PREDICTIVE VALUE OF CIRCULATING TUMOR CELLS (CTC'S) Breast Cancer 135 Pancreatic Cancer 136 Lung Cancer 137 CTC'S IN CLINICAL CANCER MANAGEMENT 137 TABLE 68 CTC TECHNOLOGIES FOR CLINICAL MANAGEMENT 137 Clinical Impact of CTCs 138 EXISTING TECHNOLOGIES IN CLINICAL TRIALS 138 Cell Search and AdnaTest - Comparision 138 Size- and Biomechanical Properties-Based Isolation 140 CLINICAL STUDIES USING CELLSEARCH TECHNOLOGY 141 TABLE 69 CTC TECHNOLOGIES FOR CLINICAL MANAGEMENT 142 APPROVALS 142 RECENT STUDIES 143 Tumor Cell (CTC) Enumeration Using Cellsearch 143 CELLSEARCH IN CHINA 144 VERIDEX AND MASSACHUSETTS GENERAL HOSPITAL COLLABORATION 145 POSSIBLE USE OF CTC'S AND DTC'S AS NEW BIOMARKERS 146 EPISPOT 147 CLINCIAL APPLICATIONS 147 TABLE 70 EPISPOT: CLINICAL TRIALS FOR DETECTION OF CTC S 148 Descriptions of Clinical Trials 148 NCT01402154 Trial 148 NCT01558349 Trial 148 NCT01596790 Trial 148 TABLE 71 OUTCOME MEASUREMENTS NCT01596790 TRIAL 149 ApoCell 149 ApoCell and Transgenomic Present Results of Lung Cancer Research Study ApoCell's CTC Capture Technology Detects and Recovers Deadly Liver Cancer Cells Nektar's Ongoing Phase 3 BEACON Study 150 APPLICATIONS 151 Application of ictc Detection and Culture in Personalized Cancer Management Stony Brook University Medical Center 151 Microfluidic Sorting of Blood Cells for Cellular and Molecular Analysis 152 Cancer Sample Preparation with Micromachined Magnetic Sifter and Nanoparticles Stanford Center for Magnetic Nanotechnology 152 The Scripps Research Institute: The Fluid Phase of Solid Tumors 152 ApoCell - Utilization of Dielectrophoresis for Antigen-Independent CTC Capture Allows for Detection of Heterogeneous Tumor Cell Populations APPLICATION OF CTC TECHNOLOGIES TO CLINICAL TESTING 153 CTC TECHNOLOGIES FOR CLINICAL DEVELOPMENT 154 Practical Application 154 135 149 150 151 152 152

TABLE 72 CTC ASSAY CLINICAL READINESS EVALUATION 155 TABLE 73 CTC ASSAY ANALYTICAL VALIDATION CONSIDERATIONS 156 STANDARD RECOMMENDATIONS 156 Specificity of a CTC Assay 157 Clinical Trial Design Considerations 158 TABLE 74 CTC QUALIFICATION STUDIES 158 SWOG S0500 Trial 159 Study Strategy and Process 159 CTC NUMBER AS A PROGNOSTIC BIOMARKER 161 Breast Cancer 161 Metastatic Castrate-resistant Prostate Cancer 161 Colorectal Cancer 162 Lung Cancer 162 PROGNOSTIC STUDIES 162 CTC'S AS A SURROGATE RESPONSE BIOMARKER 163 CTC'S AS A REAL-TIME BIOPSY 163 CTC CHIP TECHNOLOGY AND EGFR MUTATION ANALYSIS 164 CTC CHARACTERIZATION AFTER ENRICHMENT USING THE CELLSEARCH PLATFORM FINAL REMARKS 165 164 CHAPTER 8 CIRCULATING TUMOR CELL MARKET 167 THE INVASIVE CANCER! 167 TABLE 75 GLOBAL CANCER INCIDENCE - ESTIMATES, 2008-2030 (MILLIONS) 167 FIGURE 13 GLOBAL CANCER INCIDENCE - ESTIMATES, 2008-2030 (MILLIONS) 167 CANCER SURVIVAL 168 TABLE 76 GLOBAL CANCER SURVIVORS, 2008 (MILLIONS) 169 FIGURE 14 GLOBAL CANCER SURVIVORS 2008 (MILLIONS) 169 TABLE 77 UNITED STATES CANCER SURVIVORS, 2008-2022 (MILLIONS) 169 TABLE 78 MALE CANCER SURVIVORS (%) 170 TABLE 79 FEMALE CANCER SURVIVORS (%) 170 GLOBAL ANNUAL ONCOLOGY MARKET 171 CANCER THERAPY 172 TABLE 80 MAJOR PLAYERS 172 TABLE 81 GLOBAL CANCER DRUG MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 15 GLOBAL CANCER DRUG MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) AGING AND CANCER 174 CANCER DRUG PIPELINE 174 TABLE 82 DRUGS APPROVED IN 2013 175 CANCER COSTS IN THE U.S. 175 TABLE 83 CANCER FORECAST IN U.S., 2020 - KEY FACTS 176 TABLE 84 CANCER CARE COST IN U.S., 2010 AND 2020 ($ BILLIONS) 177 BREAST CANCER 177 Treatment and Survival 177 Common Side Effects of Treatment 178 COLON AND RECTUM 179 173 173

Treatment and Survival 179 Common Side Effects of Treatment 179 PROSTATE 180 Treatment and Survival 180 Common Side Effects of Treatment 180 CHEMOTHERAPY MARKET 180 CANCER TESTING MARKET 181 TABLE 85 GLOBAL IN VITRO DIAGNOSTICS MARKET SALES AND FORECAST THROUGH 2018 ($ MILLIONS) FIGURE 16 GLOBAL IN VITRO DIAGNOSTICS MARKET SALES AND FORECAST 2012-2018 ($ MILLIONS) TABLE 86 CANCER TESTING MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) 183 FIGURE 17 CANCER TESTING MARKET AND FORECAST, 2012-2018 ($ MILLIONS) 183 TABLE 87 KEY PLAYERS 184 IVD Market in China 185 CURRENT CANCER DIAGNOSTIC TESTS 186 Cancer Testing in Developing Nations 186 New Opportunities 186 TABLE 88 SIGNIFICANT DEVELOPMENTS IN CANCER FOLLOW-UP 187 A UNIVERSAL TUMOR TEST- IS IT POSSIBLE? 187 TABLE 89 CANCER TESTS AND LIMITATIONS - THE CASE AGAINST DEVELOPMENT OF A UNIVERSAL TEST CANCER BIOMARKER TESTING MARKET 188 TABLE 90 GLOBAL BIOMARKER MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 18 GLOBAL BIOMARKER MARKET AND FORECAST, 2012-2018 ($ MILLIONS) 188 TABLE 91 THE KEY PLAYERS 189 TABLE 92 U.S. BIOMARKER CANCER TESTING MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 19 U.S. BIOMARKER CANCER TESTING MARKET AND FORECAST, 2012-2018 ($ MILLIONS) MOLECULAR DIAGNOSTICS 191 TABLE 93 MOLECULAR DIAGNOSTICS MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 20 MOLECULAR DIAGNOSTICS MARKET AND FORECAST, 2012-2018 ($ MILLIONS) CANCER BIOMARKER TESTS 192 CANCER DISEASE MANAGEMENT 192 PERSONALIZED CANCER TESTING 192 Cancer Testing Competitors 192 CIRCULATING TUMOR CELL MARKET - A NEW APPROACH 193 TABLE 94 CTC S - DIFFERENTIATING FEATURES 194 CTCs Advantages 194 THE CLINICAL DIAGNOSTICS MARKET 195 Market Opportunities 195 TABLE 95 STEM CELL MARKET OVERVIEW 196 TABLE 96 KEY COMPANIES SELLING STEM CELL RESEARCH PRODUCTS 196 CTC Testing 197 TABLE 97 CTC COMPANIES WITH PROMISING PRODUCTS 197 181 181 188 188 190 190 191 191

CellSearch CTC test 198 TABLE 98 CLINICAL USE OF CELLSEARCH SYSTEM 198 AdnaTest 198 CURRENT STATUS OF THE MARKET 198 TABLE 99 PRICING (DOLLARS) 199 TABLE 100 CELLSEARCH KIT 199 Updated Coding and Payment for Circulating Tumor Cell Testing 200 Global Market for Circulating Cancer Cells (CTCs) 200 TABLE 101 GLOBAL CIRCULATING TUMOR CELL TESTING MARKET SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 21 GLOBAL CIRCULATING TUMOR CELL TESTING MARKET SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) TABLE 102 GLOBAL CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 22 GLOBAL CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) TABLE 103 GLOBAL CIRCULATING TUMOR CELL MARKET FOR BREAST CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 23 GLOBAL CIRCULATING TUMOR CELL MARKET FOR BREAST CANCER - SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) TABLE 104 GLOBAL CIRCULATING TUMOR CELL MARKET FOR COLORECTAL CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) FIGURE 24 GLOBAL CIRCULATING TUMOR CELL MARKET FOR COLORECTAL CANCER -SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) United States Market for Circulating Cancer Cells (CTCs) 206 TABLE 105 U.S. CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 25 U.S. CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST, 2012-2018 ($ MILLIONS) TIMELINE 207 TABLE 106 U.S. CIRCULATING TUMOR CELL MARKET - BY INDICATION, SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 26 U.S. CIRCULATING TUMOR CELL MARKET - BY INDICATION SALES AND FORECAST, 2012-2018 ($ MILLIONS) Europe - Market for Circulating Cancer Cells (CTCs) 208 TABLE 107 EUROPEAN CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 27 EUROPEAN CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) TABLE 108 EUROPEAN CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) Rest of World Market for Circulating Cancer Cells (CTCs) 210 TABLE 109 REST OF WORLD CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 28 REST OF WORLD CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) Canada 211 TABLE 110 REST OF WORLD CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) FIGURE 29 REST OF WORLD CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, 2012-2018 ($ MILLIONS) 201 201 202 203 204 204 205 205 207 207 208 208 209 209 210 210 211 212 212

ASIA-PACIFIC SOLID TUMORS MARKET 212 FUTURE AND NEXT STEPS 213 CHAPTER 9 PATENTS 216 TABLE 111 CIRCULATING TUMOR CELL ASSAY CHARACTERISTICS 216 KEY PATENTS 216 TABLE 112 CTC PATENTS 217 VERIDEX 218 EpCAM Based Enrichment Using Magnetic Beads 218 MAGSWEEPER 218 EpCAM Based Magnetic Beads 218 SCRIPPS RESEARCH INSTITUTE (EPIC SCIENCES) 219 HD-CTC Technology 219 CELLPOINT DIAGNOSTICS 219 ON-Q-ITY 219 BIOFLUIDICA 219 ADNAGEN 220 Multiple Antibodies on Magnetic Beads 220 FILTINI 220 3D Parylene Membrane Filter for Isolation of CTC 220 IKONISYS 220 AVIVA BIOSCIENCES 221 Methods, Compositions, and Automated Systems for Separating Rare Cells TABLE 113 KEY PATENTS BY AVIVA BIOSCIENCES 221 HARVARD UNIVERSITY - MEHMET TONER, PHD 221 Microposts Coated with EpCAM 221 CELLECTIVE DX 222 Materal Displacement Obstacle Chip 222 JOHNS HOPKINS UNIVERSITY 222 Antibody-Coated Microfluidic Chip and Quantum Dots-Based Imaging 222 MEDICAL DISCOVERY PARTNERS 222 RBC Agglutination Followed by Filtration 222 CYNVENIO BIOSYSTEMS 222 Microfluidic Sheath Flow for Cell Isolation 222 SCREENCELL 223 BIOCEPT 223 Recovery of Rare Cells Using a Microchannel Apparatus with Patterned Posts CANOPUS BIOSCIENCE 223 Enrichment Technology Is Now Protected by Key Patents 223 ADVANCED CELL DIAGNOSTICS 224 221 223 CHAPTER 10 SELECTED COMPANY PROFILES 226 COMPANIES 226 KEY PLAYERS 226 TABLE 114 COMMERCIAL CIRCULATING TUMOR CELL TECHNOLOGY PLATFORMS 226 KEY COMPANY PROFILES 227

ADNAGEN 227 ADVANCED CELL DIAGNOSTICS 227 APOCELL 228 AVIVA BIOSCIENCES 228 BIOCEP LTD. 229 BIOCEPT INC. 229 BIOFLUIDICA MICROTECHNOLOGIES LLC 230 CANOPUS BIOSCIENCES 230 CELLTRAFIX INC. 230 CELULA 231 CLEARBRIDGE BIOMEDICS 231 CREATV MICROTECH INC 232 CYNVENIO BIOSYSTEMS, INC. 232 EPIC BIOSCIENCES 232 FILTINI INC. 233 FLUXION BIOSCIENCES 233 GREINER BIO-ONE GMBH 233 IKONISYS INC. 234 IVDIAGNOSTICS INC. 234 JANSSEN DIAGNOSTICS 234 MILTENYI BIOTECH 234 NANOSTRING TECHNOLOGIES INC. 235 NATURAL NANO INC. 235 ONCO VISTA 235 ON-Q-ITY 235 RARECELLS 236 SCREENCELL 236 SILICON BIOSYSTEMS USA 237 STEMCELL TECHNOLOGIES 237 SYNERGEX CORPORATION 237 SYSMEX CORPORATION 238 VERIDEX, LLC 238 VITATEX INC. 239 CHAPTER 11 REFERENCES 241

LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL MARKET SALES AND FORECAST FOR CIRCULATING TUMOR CELL TECHNOLOGY, THROUGH 2018 ($ MILLIONS) TABLE 1 CATEGORIES OF STEM CELLS 14 TABLE 2 PRODUCT CATEGORIES 15 TABLE 3 KEY FACTORS OF CTC S 16 TABLE 4 CIRCULATING TUMOR CELLS - FEATURES 18 TABLE 5 METASTATIC CASCADE 24 TABLE 6 EPCAM-BASED ASSAYS 26 TABLE 7 CTC DETECTION - ADVANTAGES 29 TABLE 8 CANCER - KEY FACTS 32 TABLE 9 CANCER CAUSES 33 TABLE 10 CANCER CAUSING FACTORS 34 TABLE 11 CANCER SCREENING METHODS 35 TABLE 12 NONCOMMUNICABLE DISEASES ACTION PLAN 36 TABLE 13 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 (MILLIONS) 37 TABLE 14 ESTIMATED GLOBAL CANCER INCIDENCE, 2008 (THOUSANDS) 38 TABLE 15 INCREASE IN CANCER BURDEN - FACTORS 41 TABLE 16 THE MAIN TYPES OF CANCER AND ASSOCIATED MORTALITY 43 TABLE 17 GENERAL GLOBAL CANCER INCIDENCE BY TYPE 43 TABLE 18 GLOBAL INCIDENCE OF CANCER BY TYPE, 2008 (THOUSANDS/%) 44 TABLE 19 CANCER INCIDENCE IN MEN, 2008 (THOUSANDS/%) 45 TABLE 20 CANCER INCIDENCE IN WOMEN, 2008 (THOUSANDS/%) 46 TABLE 21 GLOBAL INCIDENCE OF CANCER IN DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000, 2008 TABLE 22 GLOBAL INCIDENCE OF CANCER IN MEN - DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000 (WORLD), 2008 TABLE 23 GLOBAL INCIDENCE OF CANCER IN WOMEN - DEVELOPED COUNTRIES AGE-STANDARDIZED RATE PER 100,000 (WORLD), 2008 TABLE 24 UNITED STATES - COMMON TYPE OF CANCER ESTIMATES, 2013 50 TABLE 25 GLOBAL BREAST CANCER FACTS 51 TABLE 26 BREAST CANCER IN THE UNITED STATES 52 TABLE 27 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF COLORECTAL CANCER IN MEN, 2008 TABLE 28 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF COLORECTAL CANCER IN WOMEN, 2008 TABLE 29 UNITED STATES - COLORECTAL CANCER INCIDENCE ESTIMATES, 2013 55 TABLE 30 TOP 20 COUNTRIES WITH THE HIGHEST INCIDENCE OF PROSTATE CANCER, 2008 TABLE 31 PROSTATE CANCER INCIDENCE AND MORTALITY WORLDWIDE, 2008 (THOUSANDS) TABLE 32 GLOBAL ESTIMATED PROSTATE CANCER DEATHS AND AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 TABLE 33 GLOBAL ESTIMATED NEW CASES OF PROSTATE CANCER, 2008 2030 TABLE 34 PROSTATE CANCER CASES AND DEATHS IN THE U.S. 2008-2011 63 TABLE 35 ESTIMATED NEW CASES OF PROSTATE CANCER IN THE U.S., 2012-2030 TABLE 36 PROSTATE CANCER INCIDENCE RATES IN THE U.S. BY RACE, 2005-2009 (PER 100,000 MEN) 8 47 48 49 54 55 56 58 60 62 64 65

TABLE HEADING TABLE 37 ESTIMATED PROSTATE CANCER CASES IN THE U S., 2020 AND 2030 TABLE 38 MORTALITY RATES BY RACE IN U.S., 2005-2009 66 TABLE 39 ESTIMATED PROSTATE CANCER IN CANADA, 2012 67 TABLE 40 EUROPEAN (EU27 COUNTRIES) ESTIMATED PROSTATE CANCER MORTALITY - AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATION, 2008 TABLE 41 PROSTATE CANCER DEATHS IN THE U.K., 2010 (RATE PER 100,000 POPULATION) TABLE 42 POTENTIAL APPLICATIONS OF CTC-BASED DIAGNOSTICS 74 TABLE 43 CLINICAL RELEVANCE OF CTC 78 TABLE 44 CTC ENRICHMENT METHODS 78 TABLE 45 TECHNIQUES USED FOR CIRCULATING TUMOR CELL (CTC) ENRICHMENT 80 TABLE 46 TECHNIQUES USED FOR CIRCULATING TUMOR CELL (CTC) ANALYSIS 84 TABLE 47 ENUMERATION TECHNIQUES 86 TABLE 48 FUNCTIONAL ASSAYS 90 TABLE 49 KEY FACTS ABOUT CIRCULATING TUMOR CELLS 97 TABLE 50 MICRO-COUNT FEATURES A NEW TECHNOLOGY 98 TABLE 51 CTC ASSAY PRE-ANALYTICAL VALIDATION CONSIDERATIONS 102 TABLE 52 CTC ASSAY ANALYTICAL VALIDATION CONSIDERATIONS 102 TABLE 53 CTC ASSAY POST-ANALYTICAL VALIDATION CONSIDERATIONS 103 TABLE 54 CURRENT ENRICHMENT ASSAYS FOR CTCS 105 TABLE 55 CTC ENUMERATION ASSAYS 108 TABLE 56 CHARACTERIZATION ASSAYS FOR CTCS 111 TABLE 57 KEY FEATURES-IVD CTC TESTS 112 TABLE 58 TUMOR TYPES: PROJECTED NEW CASES AND ESTIMATED DEATHS, 2010 112 TABLE 59 PROSTATE CANCER DIAGNOSIS AND ROLE OF CTC'S 115 TABLE 60 CURRENT DIAGNOSTIC METHODS 115 TABLE 61 APOSTREAM KEY FEATURES 116 TABLE 62 CANOPUS BIOSCIENCE TECHNOLOGY - BENEFITS 118 TABLE 63 CELLOPTICS' CANCER APPLICATION 118 TABLE 64 CELLOPTICS' KEY FEATURES - ENRICHMENT 119 TABLE 65 CELLOPTICS' KEY FEATURES - LABELING 119 TABLE 66 CELLOPTICS' KEY FEATURES - DETECTION 120 TABLE 67 ISET TEST - SPECIFICATIONS 120 TABLE 68 CTC TECHNOLOGIES FOR CLINICAL MANAGEMENT 137 TABLE 69 CTC TECHNOLOGIES FOR CLINICAL MANAGEMENT 142 TABLE 70 EPISPOT: CLINICAL TRIALS FOR DETECTION OF CTC S 148 TABLE 71 OUTCOME MEASUREMENTS NCT01596790 TRIAL 149 TABLE 72 CTC ASSAY CLINICAL READINESS EVALUATION 155 TABLE 73 CTC ASSAY ANALYTICAL VALIDATION CONSIDERATIONS 156 TABLE 74 CTC QUALIFICATION STUDIES 158 TABLE 75 GLOBAL CANCER INCIDENCE - ESTIMATES, 2008-2030 (MILLIONS) 167 TABLE 76 GLOBAL CANCER SURVIVORS, 2008 (MILLIONS) 169 TABLE 77 UNITED STATES CANCER SURVIVORS, 2008-2022 (MILLIONS) 169 TABLE 78 MALE CANCER SURVIVORS (%) 170 TABLE 79 FEMALE CANCER SURVIVORS (%) 170 TABLE 80 MAJOR PLAYERS 172 65 68 70

TABLE HEADING TABLE 81 GLOBAL CANCER DRUG MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 82 DRUGS APPROVED IN 2013 175 TABLE 83 CANCER FORECAST IN U.S., 2020 - KEY FACTS 176 TABLE 84 CANCER CARE COST IN U.S., 2010 AND 2020 ($ BILLIONS) 177 TABLE 85 GLOBAL IN VITRO DIAGNOSTICS MARKET SALES AND FORECAST THROUGH 2018 ($ MILLIONS) TABLE 86 CANCER TESTING MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) 183 TABLE 87 KEY PLAYERS 184 TABLE 88 SIGNIFICANT DEVELOPMENTS IN CANCER FOLLOW-UP 187 TABLE 89 CANCER TESTS AND LIMITATIONS - THE CASE AGAINST DEVELOPMENT OF A UNIVERSAL TEST TABLE 90 GLOBAL BIOMARKER MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 91 THE KEY PLAYERS 189 TABLE 92 U.S. BIOMARKER CANCER TESTING MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 93 MOLECULAR DIAGNOSTICS MARKET AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 94 CTC S - DIFFERENTIATING FEATURES 194 TABLE 95 STEM CELL MARKET OVERVIEW 196 TABLE 96 KEY COMPANIES SELLING STEM CELL RESEARCH PRODUCTS 196 TABLE 97 CTC COMPANIES WITH PROMISING PRODUCTS 197 TABLE 98 CLINICAL USE OF CELLSEARCH SYSTEM 198 TABLE 99 PRICING (DOLLARS) 199 TABLE 100 CELLSEARCH KIT 199 TABLE 101 GLOBAL CIRCULATING TUMOR CELL TESTING MARKET SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 102 GLOBAL CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 103 GLOBAL CIRCULATING TUMOR CELL MARKET FOR BREAST CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 104 GLOBAL CIRCULATING TUMOR CELL MARKET FOR COLORECTAL CANCER - SALES AND FORECAST BY REGION, THROUGH 2018 ($ MILLIONS) TABLE 105 U.S. CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 106 U.S. CIRCULATING TUMOR CELL MARKET - BY INDICATION, SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 107 EUROPEAN CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 108 EUROPEAN CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 109 REST OF WORLD CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 110 REST OF WORLD CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, THROUGH 2018 ($ MILLIONS) TABLE 111 CIRCULATING TUMOR CELL ASSAY CHARACTERISTICS 216 TABLE 112 CTC PATENTS 217 TABLE 113 KEY PATENTS BY AVIVA BIOSCIENCES 221 TABLE 114 COMMERCIAL CIRCULATING TUMOR CELL TECHNOLOGY PLATFORMS 226 173 181 188 188 190 191 201 202 204 205 207 208 209 210 210 212

LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL MARKET SALES AND FORECAST FOR CIRCULATING TUMOR CELL TECHNOLOGY, 2012-2018 ($ MILLIONS) FIGURE 1 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 (MILLIONS) 37 FIGURE 2 UNITED STATES - COMMON TYPE OF CANCER ESTIMATES, 2013 50 FIGURE 3 UNITED STATES - COLORECTAL CANCER INCIDENCE ESTIMATES, 2013 56 FIGURE 4 PROSTATE CANCER INCIDENCE AND MORTALITY WORLDWIDE, 2008 (THOUSANDS) FIGURE 5 GLOBAL ESTIMATED PROSTATE CANCER DEATHS AND AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 FIGURE 6 GLOBAL ESTIMATED NEW CASES OF PROSTATE CANCER 2008-2030 FIGURE 7 PROSTATE CANCER CASES AND DEATHS IN THE U.S., 2008-2011 63 FIGURE 8 ESTIMATED NEW CASES OF PROSTATE CANCER IN THE U.S., 2012-2030 FIGURE 9 ESTIMATED PROSTATE CANCER CASES IN THE U.S., 2020 AND 2030 FIGURE 10 EUROPEAN (EU27 COUNTRIES) ESTIMATED PROSTATE CANCER MORTALITY - AGE-STANDARDIZED MORTALITY RATES PER 100,000 POPULATIONS, 2008 FIGURE 11 PROSTATE CANCER DEATHS IN THE U.K., 2010 (RATE PER 100,000 POPULATION) FIGURE 12 TUMOR TYPES - PROJECTED NEW CASES AND ESTIMATED DEATHS, 2010 113 FIGURE 13 GLOBAL CANCER INCIDENCE - ESTIMATES, 2008-2030 (MILLIONS) 167 FIGURE 14 GLOBAL CANCER SURVIVORS 2008 (MILLIONS) 169 FIGURE 15 GLOBAL CANCER DRUG MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 16 GLOBAL IN VITRO DIAGNOSTICS MARKET SALES AND FORECAST 2012-2018 ($ MILLIONS) FIGURE 17 CANCER TESTING MARKET AND FORECAST, 2012-2018 ($ MILLIONS) 183 FIGURE 18 GLOBAL BIOMARKER MARKET AND FORECAST, 2012-2018 ($ MILLIONS) 188 FIGURE 19 U.S. BIOMARKER CANCER TESTING MARKET AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 20 MOLECULAR DIAGNOSTICS MARKET AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 21 GLOBAL CIRCULATING TUMOR CELL TESTING MARKET SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) FIGURE 22 GLOBAL CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) FIGURE 23 GLOBAL CIRCULATING TUMOR CELL MARKET FOR BREAST CANCER - SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) FIGURE 24 GLOBAL CIRCULATING TUMOR CELL MARKET FOR COLORECTAL CANCER -SALES AND FORECAST BY REGION, 2012-2018 ($ MILLIONS) FIGURE 25 U.S. CIRCULATING TUMOR CELL MARKET FOR PROSTATE CANCER - SALES AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 26 U.S. CIRCULATING TUMOR CELL MARKET - BY INDICATION SALES AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 27 EUROPEAN CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) FIGURE 28 REST OF WORLD CIRCULATING TUMOR CELL MARKET SALES AND FORECAST, 2012-2018 ($ MILLIONS) 8 58 61 62 64 66 68 71 173 181 190 191 201 203 204 205 207 208 209 211

FIGURE TITLE FIGURE 29 REST OF WORLD CIRCULATING TUMOR CELL MARKET BY CANCER TYPE - SALES AND FORECAST, 2012-2018 ($ MILLIONS) 212