THERAPIES AND DIAGNOSTICS FOR OVARIAN CANCER. HLC143A June Usha Nagavarapu Project Analyst ISBN: X

Transcription

1 THERAPIES AND DIAGNOSTICS FOR OVARIAN CANCER HLC143A June 2013 Usha Nagavarapu Project Analyst ISBN: X BCC Research 49 Walnut Park, Building 2 Wellesley, MA , Custom Reports: carol.laverty@bccresearch.com

2 TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 2 STUDY GOALS AND OBJECTIVES 2 REASONS FOR CONDUCTING THIS STUDY 2 INTENDED AUDIENCE 2 SCOPE OF THE STUDY 3 METHODOLOGY 3 INFORMATION SOURCES 3 ABOUT THE AUTHOR 4 RELATED BCC REPORTS 4 BCC ON-LINE SERVICES 4 DISCLAIMER 4 CHAPTER 2 SUMMARY 6 SUMMARY TABLE OVARIAN CANCER DRUGS AND DIAGNOSTICS-GLOBAL MARKETS, THROUGH 2018 ($ SUMMARY FIGURE OVARIAN CANCER DRUGS AND DIAGNOSTICS-GLOBAL MARKETS, ($ 7 7 CHAPTER 3 OVERVIEW 9 OVARIAN CANCERS 9 TABLE 1 OVARIAN CANCER FACTS 9 TABLE 2 TYPES OF OVARIAN CANCERS 10 EPITHELIAL TUMORS 10 GERM CELL TUMORS 10 STROMAL TUMORS 10 METASTASIS 10 TABLE 3 OVARIAN TUMORS METASTASIS 11 OVARIAN DISORDERS 11 RISK FACTORS 11 TABLE 4 MAIN RISK FACTORS FOR OVARIAN CANCER 12 TABLE 5 HIGH-RISK FACTORS 12 PREVENTION 13 TABLE 6 PREVENTIVE FACTORS 13 PREVENTIVE STRATEGIES FOR HIGH-RISK WOMEN 13 SYMPTOMS 14 TABLE 7 OVARIAN CANCER SYMPTOMS 14 SIGNS OF CANCER 15 DIAGNOSIS AND SYMPTOM PROGRESSION 15 Early Detection 16 DIAGNOSIS 16 TUMOR MARKERS 16 VITAMIN D AND OVARIAN CANCER 16 PROGNOSIS 17 PROGNOSIS BY STAGE 17 TREATMENT 17 CHEMOTHERAPY 18

3 TARGETED THERAPY 18 IMMUNOTHERAPY 18 RESEARCH AND NEW DEVELOPMENTS 18 CONCLUSIONS 19 CHAPTER 4 OVARIAN CANCER: BIOLOGY 21 OVERVIEW 21 REPRODUCTIVE BIOLOGY 21 TABLE 8 HOW OVARIAN CANCER CAN PROGRESS 21 TABLE 9 COMMON HISTOLOGICAL SUBTYPES OF OVARIAN CANCERS 22 TABLE 10 OVARIAN CANCER ORIGINS 23 BORDERLINE TUMORS OF THE OVARY 24 BIOMARKERS 24 MOLECULAR ANALYSIS IN OVARIAN CANCER 25 TABLE 11 MUTATED GENES IN HIGH-GRADE SEROUS OVARIAN CANCER 25 Mutations and Different Subtypes of Ovarian Cancer 26 Potential Biomarkers and Mutations for Ovarian Cancer 26 Biomarkers and Future 27 Ovarian Cancer Biomarkers: Potential Use 27 Combining CA-125 with Other Biomarkers 28 Prognostic Biomarkers 28 TABLE 12 GLOBAL PROGNOSTIC OVARIAN CANCER BIOMARKERS 28 Novel Biomarkers 29 TABLE 13 ACOG GUIDELINES UPDATED ACOG GUIDELINES 31 CA-125: A QUESTION OF USE 31 DIAGNOSTIC TESTS BASED ON BIOMARKERS 31 MODIFIED ACOG REFERRAL GUIDELINES 32 A PROMISING CANDIDATE 32 HE4 AND THE ALGORITHM FOR RISK OF OVARIAN MALIGNANCY 33 OVA1 VERSUS ROMA 33 OVARIAN CANCER AND STEM CELLS 34 TABLE 14 GENES IN TYPE I EPITHELIAL OVARIAN CANCER CELLS 34 CONCLUSIONS 35 CHAPTER 5 OVARIAN CANCER DIAGNOSIS 37 CURRENT PRACTICES 37 PREVENTION 37 SYMPTOMS AND DIAGNOSIS 37 TABLE 15 OVARIAN CANCER SYMPTOMS 38 DIAGNOSIS 38 TUMOR MARKERS 39 CA INITIAL SURGERY 39 EXPLORATORY LAPAROTOMY 39 PROGNOSIS 40 COMPLETE RESPONSE 40

4 RECURRENCE 41 MINIMALLY-INVASIVE PROCEDURE 41 ROUTINE OVARIAN CANCER SCREENING 41 STAGING 42 TABLE 16 STAGES OF OVARIAN CANCER 42 TABLE 17 STAGING OF OVARIAN CANCER 43 OVARIAN CANCER GRADING 43 OVARIAN CANCER DIAGNOSIS 44 PHYSICAL EXAM 44 PELVIC EXAM 44 TABLE 18 DIAGNOSTIC TESTS FOR OVARIAN CANCER 44 BLOOD TESTS 44 ULTRASOUND 44 BIOPSY 45 IMAGING STUDIES 45 ULTRASOUND 45 COMPUTED TOMOGRAPHY 46 BARIUM ENEMA X-RAY 46 MAGNETIC RESONANCE IMAGING 46 CHEST X-RAY 47 POSITRON EMISSION TOMOGRAPHY (PET SCAN) 47 OTHER TESTS 47 LAPAROSCOPY 47 COLONOSCOPY 47 BIOPSY 48 BIOMARKERS AND TESTS 48 RISK OF OVARIAN MALIGNANCY ALGORITHM 48 BLOOD TESTS 48 CA-125 BLOOD TEST 49 CA-125 Test to Monitor the Status of Ovarian Cancer 51 OTHER BIOMARKER-BASED BLOOD SCREENING TESTS FOR OVARIAN CANCER 51 TABLE 19 TUMOR BIOMARKER-BASED TESTS FOR OVARIAN CANCER DIAGNOSIS 51 HE4 BLOOD TEST 51 THE RISK OF OVARIAN MALIGNANCY ALGORITHM (ROMA) TEST 52 TABLE 20 TEST FEATURES OF ROMA 54 OVA1 TEST 55 OVADX 55 TABLE 21 OVADX FEATURES 56 GENETIC TESTING 56 NOVEL TEST PREDICTED PRESENCE OF BRCA MUTATIONS 57 SECOND TEST 57 Decision Tool for Women with BRCA Mutations 58 CURRENT SCREENING METHODS 58 NEED FOR A SCREENING STRATEGY 59 TO SCREEN OR NOT TO SCREEN 60 NEW DIAGNOSTIC TESTS 61

5 CHAPTER 6 TREATMENT STRATEGIES FOR OVARIAN CANCER 64 CURRENT TREATMENT PRACTICES 64 MAJOR MARKETED PRODUCTS 65 TABLE 22 DRUGS FOR OVARIAN CANCER 65 TABLE 23 OTHER MAJOR THERAPEUTIC AGENTS 65 SURGERY 66 TABLE 24 CURRENT TREATMENT STRATEGY: OVARIAN CANCER 66 CHEMOTHERAPY 67 Intraperitoneal Chemotherapy 69 TABLE 25 CHEMOTHERAPEUTIC DRUGS FOR OVARIAN CANCER 69 IV Chemotherapy 69 TABLE 26 CHEMOTHERAPY ADMINISTRATION 70 Side Effects 70 TARGETED THERAPY 70 IMMUNOTHERAPY 71 STAGING 71 TREATMENT OF OVARIAN EPITHELIAL CANCER 71 Stage I 71 TABLE 27 TREATMENT OPTIONS BY STAGE 72 Stage II 72 Stage III 72 Stage IV 72 RADIATION THERAPY 73 PALLIATIVE/SUPPORTIVE CARE 73 RECURRENT OVARIAN CANCER 73 METASTATIC OVARIAN CANCER 74 OVARIAN CANCER DRUGS PIPELINE 74 TABLE 28 PIPELINE DRUG CLASSES 74 TABLE 29 OVARIAN CANCER DRUGS: DELIVERY TECHNOLOGIES 75 SURVEILLANCE AFTER TREATMENT 75 TABLE 30 OPTIMAL SURVEILLANCE STRATEGY 75 RECURRENT OVARIAN EPITHELIAL CANCER 75 SECOND-LOOK SURGERY 76 TREATMENT OF RECURRENT CANCER 76 TABLE 31 TREATMENT PLAN FOR RECURRENT CANCER 76 MULTIDRUG RESISTANCE 77 TABLE 32 PLATINUM RESISTANCE 77 TABLE 33 REASONS FOR THE ONSET OF MDR 78 TREATMENT OF SENSITIVE CANCER 79 TREATMENT OF RESISTANT CANCER 79 SECONDARY-CHEMOTHERAPY DRUGS 80 TOPOTECAN 80 SINGLE-AGENT ETOPOSIDE 80 DOCETAXEL 81 GEMCITABINE 81 OXALIPLATIN 82 5-FU AND LEUCOVORIN 83

6 LIPOSOMAL DOXORUBICIN 83 HIGH-DOSE CHEMOTHERAPY 84 DRUGS APPROVED FOR OVARIAN CANCER 84 TABLE 34 DRUGS APPROVED FOR OVARIAN CANCER 84 PROMISING NEW THERAPIES 85 AVASTIN 85 TABLE 35 NEW OVARIAN CANCER DRUGS 85 DRUG THERAPIES IN CLINICAL TRIALS 86 TABLE 36 OVARIAN CANCER DRUGS IN CLINICAL TRIALS 86 BEVACIZUMAB AND RECURRENT OVARIAN CANCER 87 Combining Chemotherapy with Bevacizumab Improves Outcomes for Ovarian Cancer Patients PARP INHIBITORS 88 FUTURE TACTICS: THE ROLE OF BIOMARKERS 88 MOLECULAR THERAPEUTICS PROGRAM 89 BRCA1/2 ONCOGENES 89 VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) 90 The EGFR/ErbB Family of Receptor Tyrosine Kinases 90 MUCIN 16 (MUC16) 91 LEWIS X MUCIN DETERMINANT (OVX1) 91 IL-6R-JAK-STAT3 AXIS AND NUCLEAR FACTOR KAPPA-B (NF-KB) 91 PI3K/AKT/MTOR CELL-SIGNALING PATHWAY 93 ATP-BINDING CASSETTE (ABC) DRUG TRANSPORTERS 93 TABLE 37 OVARIAN CANCER: BIOMARKERS AS DRUG CANDIDATES 94 OUTLOOK CHAPTER 7 OVARIAN CANCER INCIDENCE 99 CANCER AND ITS GLOBAL IMPACT 99 TABLE 38 GLOBAL CANCER INCIDENCE 100 TABLE 39 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 ( 100 FIGURE 1 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 ( 101 TABLE 40 CANCER KEY FACTS 103 THE FUTURE OF CANCER 103 TABLE 41 INCREASE IN CANCER BURDEN: FACTORS 104 OVARIAN CANCER INCIDENCE 105 TABLE 42 OVARIAN CANCER INCIDENCE BY REGION, FIGURE 2 OVARIAN CANCER INCIDENCE BY REGION, TABLE 43 GLOBAL OVARIAN CANCER INCIDENCE, TABLE 44 ESTIMATED GLOBAL OVARIAN CANCER INCIDENCE, FIGURE 3 ESTIMATED GLOBAL OVARIAN CANCER INCIDENCE, TABLE 45 OVARIAN CANCER INCIDENCE BY LOCATION, 2008 (NUMBER OF CASES) 108 FIGURE 4 OVARIAN CANCER INCIDENCE BY LOCATION, 2008 (NUMBER OF CASES) 108 NORTH AMERICA 109 TABLE 46 ESTIMATED OVARIAN CANCER INCIDENCE IN NORTH AMERICA, FIGURE 5 ESTIMATED OVARIAN CANCER INCIDENCE IN NORTH AMERICA, OVARIAN CANCER INCIDENCE IN UNITED STATES

7 TABLE 47 OVARIAN CANCER - U.S. INCIDENCE, TABLE 48 NEW CASES AND DEATHS FROM OVARIAN CANCER IN THE U. S., FIGURE 6 NEW CASES AND DEATHS FROM OVARIAN CANCER IN THE U.S., TABLE 49 ESTIMATED OVARIAN CANCER INCIDENCE IN THE U.S., FIGURE 7 ESTIMATED OVARIAN CANCER INCIDENCE IN THE U.S TABLE 50 OVARIAN CANCER: INCIDENCE AND MORTALITY IN UNITED STATES, FIGURE 8 OVARIAN CANCER: INCIDENCE AND MORTALITY IN U.S., TABLE 51 OVARIAN CANCER SURVIVAL RATES COMPARED TO OTHER CANCERS 113 Survival and Stage 113 TABLE 52 STAGE DISTRIBUTION AND FIVE-YEAR RELATIVE SURVIVAL BY STAGE AT DIAGNOSIS, (%) EUROPE AND OVARIAN CANCER 114 TABLE 53 OVARIAN CANCER - EUROPEAN AGE-STANDARDIZED INCIDENCE RATES IN EU-27 COUNTRIES, 2008 ESTIMATES FIGURE 9 OVARIAN CANCER EUROPEAN AGE-STANDARDIZED INCIDENCE IN EU-27 COUNTRIES, 2008 ESTIMATES TABLE 54 ESTIMATED OVARIAN CANCER INCIDENCE IN EUROPE, FIGURE 10 ESTIMATED OVARIAN CANCER: INCIDENCE IN EUROPE TABLE 55 ESTIMATED INCIDENCE, MORTALITY AND PREVALENCE IN EUROPEAN UNION, 2008 OVARIAN CANCER IN UK 119 TABLE 56 HOW MANY WOMEN DIE FROM OVARIAN CANCER? 119 TABLE 57 OVARIAN CANCER - NUMBER OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 TABLE 58 GYNECOLOGICAL CANCERS - NUMBER OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 FIGURE 11 GYNECOLOGICAL CANCERS - NUMBERS OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 Trends 121 TABLE 59 OVARIAN CANCER STATISTICS IN THE U.K., FIGURE 12 OVARIAN CANCER STATISTICS IN THE U.K., THE MIDDLE EAST AND OVARIAN CANCER 122 OVARIAN CANCER AND CHINA 122 OVARIAN CANCER AND AUSTRALIA 122 OVARIAN CANCER AND INDIA 123 TYPES OF OVARIAN CANCERS AND INCIDENCE 124 PRIMARY PERITONEAL AND PRIMARY FALLOPIAN TUBE CANCERS 125 OVARIAN EPITHELIAL CANCER 125 TABLE 60 PROGNOSIS FOR OVARIAN CANCER 126 OVARIAN GERM CELL TUMORS 126 DYSGERMINOMAS 126 OVARIAN TUMORS OF LOW MALIGNANT POTENTIAL 126 SUMMARY CHAPTER 8 MARKET 129 GLOBAL IVD MARKET 129 OVARIAN CANCER: DIAGNOSTIC TESTS 130

8 TABLE 61 GLOBAL OVARIAN CANCER DIAGNOSTIC TESTS AND MARKET SALES AND FORECAST, THROUGH 2018 ($ FIGURE 13 OVARIAN CANCER DIAGNOSTIC TESTS AND MARKET SALES AND FORECAST, ($ GENETIC TESTING 131 SURGICAL BIOPSY 131 OVARIAN CANCER: CURRENT SCREENING PRACTICES 131 TABLE 62 OVARIAN ABNORMALITIES 131 THE FUTURE OF OVARIAN CANCER SCREENING 131 CURRENT BIOMARKER-BASED TESTS 132 TRANSVAGINAL SONOGRAPHY 132 Drawbacks 133 TABLE 63 GLOBAL MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, THROUGH 2018 ($ FIGURE 14 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, ($ TABLE 64 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, THROUGH 2018 ($ FIGURE 15 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, ($ SERUM CA-125 IN COMBINATION WITH TRANSVAGINAL ULTRASOUND 135 PROTEOMICS 135 IMAGING TECHNIQUES 136 TABLE 65 IMAGING TESTS 136 BLOOD TESTS AND MARKET 136 TABLE 66 OVARIAN CANCER - RISK TYPES 136 TABLE 67 OVARIAN CANCER WOMEN WITH INCREASED RISK 137 TABLE 68 OVARIAN CANCER: INHERITED RISK DUE TO KNOWN GENETIC MUTATIONS OVARIAN CANCER TESTS AND MARKET DYNAMICS 138 TABLE 69 GLOBAL MARKET FOR LAB TESTS FOR OVARIAN CANCER, THROUGH 2018 ($ FIGURE 16 GLOBAL MARKET FOR LAB TESTS FOR OVARIAN CANCER, ($ TABLE 70 U.S. MARKET FOR LAB TESTS FOR OVARIAN CANCER, THROUGH 2018 ($ FIGURE 17 U.S. MARKET FOR LAB TESTS FOR OVARIAN CANCER, ($ CA-125 TEST MARKET 140 TABLE 71 ELEVATED CA-125 LEVEL 141 TABLE 72 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, THROUGH 2018 ($ FIGURE 18 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, ($ TABLE 73 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, THROUGH 2018 ($ FIGURE 19 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, ($ HE4 TEST MARKET

9 TABLE 74 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, THROUGH 2018 ($ FIGURE 20 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, TABLE 75 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, THROUGH 2018 ($ FIGURE 21 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, ($ WHY THE HE4 TEST AND CA-125 COMBINED? 145 TABLE 76 WHY HE4 AND CA-125 COMBINED? 146 TABLE 77 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, THROUGH 2018 ($ FIGURE 22 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, ($ TABLE 78 UNITED STATES OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, THROUGH 2018 ($ FIGURE 23 UNITED STATES OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, ($ OVA1 BLOOD TEST AND MARKET 149 TABLE 79 GLOBAL OVA1 MARKET, THROUGH 2018 ($ 149 FIGURE 24 GLOBAL OVA1 MARKET, ($ 150 Why OVA1? 151 OvaSure 151 OvaCheck 151 Onko-Sure 152 New Test 152 RECOMMENDATIONS FOR OVARIAN CANCER SCREENING 153 MOLECULAR DIAGNOSTICS MARKET 154 TABLE 80 GLOBAL MOLECULAR DIAGNOSTICS MARKET, THROUGH 2018 ($ FIGURE 25 GLOBAL MOLECULAR DIAGNOSTICS MARKET, ($ 154 ARRAYIT'S EARLY OVARIAN CANCER DIAGNOSTICTEST 155 TABLE 81 GLOBAL MARKET FOR OVADX, THROUGH 2018 ($ 155 FIGURE 26 GLOBAL MARKET FOR OVADX, ($ 156 TABLE 82 U.S. MARKET FOR OVADX, THROUGH 2018 ($ 156 FIGURE 27 U.S. MARKET FOR OVADX - SALES AND FORECAST ($ PAP TESTS AND OVARIAN CANCERS 157 SURGERY MARKET 157 TABLE 83 GLOBAL OVARIAN CANCER SURGERY MARKET, THROUGH 2018 ($ FIGURE 28 GLOBAL OVARIAN CANCER SURGERY MARKET, ($ 159 TABLE 84 U.S. OVARIAN CANCER SURGERY MARKET, THROUGH 2018 ($ 159 FIGURE 29 U.S. OVARIAN CANCER SURGERY MARKET, ($ 160 COMPUTED TOMOGRAPHY 160 TABLE 85 GLOBAL COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, THROUGH 2018 ($ FIGURE 30 GLOBAL COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, ($

10 TABLE 86 U.S. COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, THROUGH 2018 ($ FIGURE 31 U.S. COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, ($ MOLECULAR DIAGNOSTICS 162 CONCLUSIONS CHAPTER 9 GLOBAL OVARIAN CANCER TREATMENT MARKET 165 OVARIAN CANCER: CURRENT SCENARIO 165 TABLE 87 KEY HIGHLIGHTS OF THE THERAPEUTIC MARKET 165 GLOBAL SPENDING ON MEDICINES 165 GLOBAL TREATMENTS AND FUTURE TRENDS 166 MARKET DYNAMICS 166 TABLE 88 NEW LAUNCHES IN CANCER TREATMENT MARKET 167 CANCER THERAPY: GOOD AND BAD 168 TABLE 89 MAJOR PLAYERS 168 CYTOTOXIC THERAPIES MARKET 169 TABLE 90 CYTOTOXIC THERAPIES MARKET INDICATIONS 169 TABLE 91 GLOBAL CYTOTHERAPEUTICS MARKET, 2010 AND 2017 ($ 169 FIGURE 32 GLOBAL CYTOTHERAPEUTICS MARKET, 2010 AND 2017 ($ 169 TABLE 92 U.S. CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 170 FIGURE 33 U.S. CYTOTHERAPEUTICS MARKET, ($ 170 TABLE 93 EUROPEAN CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 171 FIGURE 34 EUROPEAN CYTOTHERAPEUTICS MARKET, ($ 172 TABLE 94 JAPANESE CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 172 FIGURE 35 JAPANESE CYTOTHERAPEUTICS MARKET, ($ 173 GLOBAL OVARIAN CHEMOTHERAPY CANCER MARKET 173 TABLE 95 GLOBAL OVARIAN CANCER CHEMOTHERAPY MARKET, THROUGH 2018 ($ FIGURE 36 GLOBAL OVARIAN CANCER CHEMOTHERAPY MARKET, ($ TABLE 96 OVARIAN CANCER CHEMOTHERAPY MARKET IN KEY COUNTRIES THROUGH 2018 ($ FIGURE 37 OVARIAN CANCER CHEMOTHERAPY MARKET IN KEY COUNTRIES, ($ OVARIAN CANCER TREATMENT STRATEGIES: CURRENT TRENDS 175 CURRENT TREATMENT PRACTICES FOR OVARIAN CANCER: IMPACT ON THE MARKET TABLE 97 STANDARD INITIAL CHEMOTHERAPY 176 TABLE 98 DRUGS FOR RECURRENT OVARIAN CANCER 177 TABLE 99 HORMONAL THERAPY DRUGS 177 CHEMOTHERAPY AND DRAWBACKS 177 Drugs Used in Chemotherapy 178 Paclitaxel 178 TABLE 100 KEY OVARIAN CANCER DRUGS- SALES, 2010 ($ Carboplatin 178 TABLE 101 CARBOPLATIN: SALES, THROUGH 2012 ($ 179 Doxil 179

11 Taxotere/Docetaxel 179 TABLE 102 TAXOTERE GLOBAL SALES AND FORECAST ($ 180 Cisplatin 180 Gemzar 180 TABLE 103 GEMZAR REVENUE, 2010 AND 2011 ($ 181 Future for Gemcitabine 181 Hycamtin 182 Navelbine 182 Carboplatin 182 TREATMENT OPTIONS FOR RELAPSED OR REFRACTORY OVARIAN CANCER: MARKET ANALYSIS TABLE 104 DRUGS FOR REFRACTORY OVARIAN CANCER 182 TABLE 105 HORMONAL THERAPY DRUGS 183 RADIATION THERAPY 183 CURRENT COMPETITION IN OVARIAN CANCER DRUGS 183 NEW MOLECULES 184 TABLE 106 PROMISING MOLECULES 184 Avastin 184 TABLE 107 AVASTIN REVENUES, THROUGH 2013 ($ 185 TABLE 108 AVASTIN-OVARIAN CANCER MARKET FORECAST BY REGION, THROUGH 2018 ($ Abagovomab 186 TABLE 109 NEW MOLECULES - ESTIMATED SALES, 2018 ($ 187 Pazopanib 187 Nintedanib 188 Opt Paclical (Paclitaxel) 188 Opaxio 188 AMG Vintafolide (EC145) 188 Karenitecin 189 Farletuzumab 189 FUTURE FOR OVARIAN CANCER MARKET 189 TABLE 110 PROMISING BIOLOGIC DRUG TREATMENTS 190 OVARIAN CANCER - COSTS AND MARKET OUTLOOK 190 MARKET OVERVIEW - GLOBAL PERSPECTIVES 191 THE PIPELINE - NEW RESEARCH AREAS 192 TABLE 111 DRUG CATEGORIES IN DEVELOPMENT MOLECULES IN THE PIPELINE 192 CONCLUSIONS: UNMET NEEDS CHAPTER 10 PATENT LANDSCAPE 195 TABLE 112 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 113 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 114 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 115 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, GLOBAL IMPACT OF PATENT EXPIRIES 197 PATENT LANDSCAPE 198 GEMZAR 199

12 TABLE 116 OVARIAN CANCER CHEMOTHERAPY DRUGS: PATENT EXPIRY 199 DOXIL 199 CISPLATIN 200 CHAPTER 11 LATEST NEWS AND DEVELOPMENTS 202 LILLY'S EARLY ONCOLOGY PIPELINE 202 LPATH AND DIAGNOSTICS 202 ROCHE 203 EARLY STAGE OVARIAN CANCER DIAGNOSTIC 204 NEW CHEMOTHERAPY STRATEGY EMERGES IN OVARIAN CANCER 204 Court Reaffirms Right of Myriad Genetics to Patent Genes 205 NANOTECHED RNA DRUG REDUCES OVARIAN CANCER TUMORS 206 VERASTEM LAUNCHES OVARIAN CANCER TRIAL 207 WORK ON GENETIC CAUSES OF PROSTATE, BREAST AND OVARIAN CANCER OVARIAN CANCER VACCINE 208 NOVOTTF THERAPY CHAPTER 12 SELECTED COMPANIES 210 ABBOTT LABORATORIES 210 AMGEN 210 APP PHARMACEUTICALS 210 ARRAYIT CORP. 211 ASTRAZENECA 211 BIONUMERIK PHARMACEUTICALS 211 BOEHRINGER INGELHEIM GMBH 212 BRISTOL-MYERS SQUIBB 212 CELL THERAPEUTICS, INC. 212 CHUGAI PHARMACEUTICAL 213 EISAI INC. 213 ELI LILLY AND COMPANY 213 ENDOCYTE 214 FUJIREBIO DIAGNOSTICS 214 GE HEALTHCARE 214 GLAXOSMITHKLINE 215 GOLD STANDARD DIAGNOSTICS 216 JOHNSON & JOHNSON 216 LPATH 217 MENARINI GROUP 217 MYRIAD GENETICS 217 NOVOCURE 218 OASMIA PHARMACEUTICAL 218 OPTIMER PHARMACEUTICALS 218 PFIZER 219 PROVISTA DIAGNOSTICS 219 RADIENT PHARMACEUTICALS 220 ROCHE DIAGNOSTICS 220 SANOFI 220

13 TAJ PHARMACEUTICALS 221 TELIK, INC. 221 TEVA PHARMACEUTICAL INDUSTRIES LTD. 221 VERMILLION 222 CHAPTER 13 REFERENCES 224

14 LIST OF TABLES TABLE HEADING SUMMARY TABLE OVARIAN CANCER DRUGS AND DIAGNOSTICS-GLOBAL MARKETS, THROUGH 2018 ($ TABLE 1 OVARIAN CANCER FACTS 9 TABLE 2 TYPES OF OVARIAN CANCERS 10 TABLE 3 OVARIAN TUMORS METASTASIS 11 TABLE 4 MAIN RISK FACTORS FOR OVARIAN CANCER 12 TABLE 5 HIGH-RISK FACTORS 12 TABLE 6 PREVENTIVE FACTORS 13 TABLE 7 OVARIAN CANCER SYMPTOMS 14 TABLE 8 HOW OVARIAN CANCER CAN PROGRESS 21 TABLE 9 COMMON HISTOLOGICAL SUBTYPES OF OVARIAN CANCERS 22 TABLE 10 OVARIAN CANCER ORIGINS 23 TABLE 11 MUTATED GENES IN HIGH-GRADE SEROUS OVARIAN CANCER 25 TABLE 12 GLOBAL PROGNOSTIC OVARIAN CANCER BIOMARKERS 28 TABLE 13 ACOG GUIDELINES TABLE 14 GENES IN TYPE I EPITHELIAL OVARIAN CANCER CELLS 34 TABLE 15 OVARIAN CANCER SYMPTOMS 38 TABLE 16 STAGES OF OVARIAN CANCER 42 TABLE 17 STAGING OF OVARIAN CANCER 43 TABLE 18 DIAGNOSTIC TESTS FOR OVARIAN CANCER 44 TABLE 19 TUMOR BIOMARKER-BASED TESTS FOR OVARIAN CANCER DIAGNOSIS 51 TABLE 20 TEST FEATURES OF ROMA 54 TABLE 21 OVADX FEATURES 56 TABLE 22 DRUGS FOR OVARIAN CANCER 65 TABLE 23 OTHER MAJOR THERAPEUTIC AGENTS 65 TABLE 24 CURRENT TREATMENT STRATEGY: OVARIAN CANCER 66 TABLE 25 CHEMOTHERAPEUTIC DRUGS FOR OVARIAN CANCER 69 TABLE 26 CHEMOTHERAPY ADMINISTRATION 70 TABLE 27 TREATMENT OPTIONS BY STAGE 72 TABLE 28 PIPELINE DRUG CLASSES 74 TABLE 29 OVARIAN CANCER DRUGS: DELIVERY TECHNOLOGIES 75 TABLE 30 OPTIMAL SURVEILLANCE STRATEGY 75 TABLE 31 TREATMENT PLAN FOR RECURRENT CANCER 76 TABLE 32 PLATINUM RESISTANCE 77 TABLE 33 REASONS FOR THE ONSET OF MDR 78 TABLE 34 DRUGS APPROVED FOR OVARIAN CANCER 84 TABLE 35 NEW OVARIAN CANCER DRUGS 85 TABLE 36 OVARIAN CANCER DRUGS IN CLINICAL TRIALS 86 TABLE 37 OVARIAN CANCER: BIOMARKERS AS DRUG CANDIDATES 94 TABLE 38 GLOBAL CANCER INCIDENCE 100 TABLE 39 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 ( 100 TABLE 40 CANCER KEY FACTS 103 TABLE 41 INCREASE IN CANCER BURDEN: FACTORS 104 TABLE 42 OVARIAN CANCER INCIDENCE BY REGION, TABLE 43 GLOBAL OVARIAN CANCER INCIDENCE, TABLE 44 ESTIMATED GLOBAL OVARIAN CANCER INCIDENCE, TABLE 45 OVARIAN CANCER INCIDENCE BY LOCATION, 2008 (NUMBER OF CASES) 108 7

15 TABLE HEADING TABLE 46 ESTIMATED OVARIAN CANCER INCIDENCE IN NORTH AMERICA, TABLE 47 OVARIAN CANCER - U.S. INCIDENCE, TABLE 48 NEW CASES AND DEATHS FROM OVARIAN CANCER IN THE U. S., TABLE 49 ESTIMATED OVARIAN CANCER INCIDENCE IN THE U.S., TABLE 50 OVARIAN CANCER: INCIDENCE AND MORTALITY IN UNITED STATES, TABLE 51 OVARIAN CANCER SURVIVAL RATES COMPARED TO OTHER CANCERS 113 TABLE 52 STAGE DISTRIBUTION AND FIVE-YEAR RELATIVE SURVIVAL BY STAGE AT DIAGNOSIS, (%) TABLE 53 OVARIAN CANCER - EUROPEAN AGE-STANDARDIZED INCIDENCE RATES IN EU-27 COUNTRIES, 2008 ESTIMATES TABLE 54 ESTIMATED OVARIAN CANCER INCIDENCE IN EUROPE, TABLE 55 ESTIMATED INCIDENCE, MORTALITY AND PREVALENCE IN EUROPEAN UNION, 2008 TABLE 56 HOW MANY WOMEN DIE FROM OVARIAN CANCER? 119 TABLE 57 OVARIAN CANCER - NUMBER OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 TABLE 58 GYNECOLOGICAL CANCERS - NUMBER OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 TABLE 59 OVARIAN CANCER STATISTICS IN THE U.K., TABLE 60 PROGNOSIS FOR OVARIAN CANCER 126 TABLE 61 GLOBAL OVARIAN CANCER DIAGNOSTIC TESTS AND MARKET SALES AND FORECAST, THROUGH 2018 ($ TABLE 62 OVARIAN ABNORMALITIES 131 TABLE 63 GLOBAL MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, THROUGH 2018 ($ TABLE 64 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, THROUGH 2018 ($ TABLE 65 IMAGING TESTS 136 TABLE 66 OVARIAN CANCER - RISK TYPES 136 TABLE 67 OVARIAN CANCER WOMEN WITH INCREASED RISK 137 TABLE 68 OVARIAN CANCER: INHERITED RISK DUE TO KNOWN GENETIC MUTATIONS 137 TABLE 69 GLOBAL MARKET FOR LAB TESTS FOR OVARIAN CANCER, THROUGH 2018 ($ TABLE 70 U.S. MARKET FOR LAB TESTS FOR OVARIAN CANCER, THROUGH 2018 ($ TABLE 71 ELEVATED CA-125 LEVEL 141 TABLE 72 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, THROUGH 2018 ($ TABLE 73 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, THROUGH 2018 ($ TABLE 74 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, THROUGH 2018 ($ TABLE 75 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, THROUGH 2018 ($ TABLE 76 WHY HE4 AND CA-125 COMBINED? 146 TABLE 77 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, THROUGH 2018 ($ TABLE 78 UNITED STATES OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, THROUGH 2018 ($ TABLE 79 GLOBAL OVA1 MARKET, THROUGH 2018 ($

16 TABLE HEADING TABLE 80 GLOBAL MOLECULAR DIAGNOSTICS MARKET, THROUGH 2018 ($ 154 TABLE 81 GLOBAL MARKET FOR OVADX, THROUGH 2018 ($ 155 TABLE 82 U.S. MARKET FOR OVADX, THROUGH 2018 ($ 156 TABLE 83 GLOBAL OVARIAN CANCER SURGERY MARKET, THROUGH 2018 ($ TABLE 84 U.S. OVARIAN CANCER SURGERY MARKET, THROUGH 2018 ($ 159 TABLE 85 GLOBAL COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, THROUGH 2018 ($ TABLE 86 U.S. COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, THROUGH 2018 ($ TABLE 87 KEY HIGHLIGHTS OF THE THERAPEUTIC MARKET 165 TABLE 88 NEW LAUNCHES IN TABLE 89 MAJOR PLAYERS 168 TABLE 90 CYTOTOXIC THERAPIES MARKET INDICATIONS 169 TABLE 91 GLOBAL CYTOTHERAPEUTICS MARKET, 2010 AND 2017 ($ 169 TABLE 92 U.S. CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 170 TABLE 93 EUROPEAN CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 171 TABLE 94 JAPANESE CYTOTHERAPEUTICS MARKET, THROUGH 2018 ($ 172 TABLE 95 GLOBAL OVARIAN CANCER CHEMOTHERAPY MARKET, THROUGH 2018 ($ TABLE 96 OVARIAN CANCER CHEMOTHERAPY MARKET IN KEY COUNTRIES THROUGH 2018 ($ TABLE 97 STANDARD INITIAL CHEMOTHERAPY 176 TABLE 98 DRUGS FOR RECURRENT OVARIAN CANCER 177 TABLE 99 HORMONAL THERAPY DRUGS 177 TABLE 100 KEY OVARIAN CANCER DRUGS- SALES, 2010 ($ 178 TABLE 101 CARBOPLATIN: SALES, THROUGH 2012 ($ 179 TABLE 102 TAXOTERE GLOBAL SALES AND FORECAST ($ 180 TABLE 103 GEMZAR REVENUE, 2010 AND 2011 ($ 181 TABLE 104 DRUGS FOR REFRACTORY OVARIAN CANCER 182 TABLE 105 HORMONAL THERAPY DRUGS 183 TABLE 106 PROMISING MOLECULES 184 TABLE 107 AVASTIN REVENUES, THROUGH 2013 ($ 185 TABLE 108 AVASTIN-OVARIAN CANCER MARKET FORECAST BY REGION, THROUGH 2018 ($ TABLE 109 NEW MOLECULES - ESTIMATED SALES, 2018 ($ 187 TABLE 110 PROMISING BIOLOGIC DRUG TREATMENTS 190 TABLE 111 DRUG CATEGORIES IN DEVELOPMENT MOLECULES IN THE PIPELINE 192 TABLE 112 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 113 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 114 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 115 DRUGS SCHEDULED TO LOSE U.S. MARKET PROTECTION, TABLE 116 OVARIAN CANCER CHEMOTHERAPY DRUGS: PATENT EXPIRY

17 LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE OVARIAN CANCER DRUGS AND DIAGNOSTICS-GLOBAL MARKETS, ($ FIGURE 1 GLOBAL CANCER INCIDENCE ESTIMATES, 2008 AND 2030 ( 101 FIGURE 2 OVARIAN CANCER INCIDENCE BY REGION, FIGURE 3 ESTIMATED GLOBAL OVARIAN CANCER INCIDENCE, FIGURE 4 OVARIAN CANCER INCIDENCE BY LOCATION, 2008 (NUMBER OF CASES) 108 FIGURE 5 ESTIMATED OVARIAN CANCER INCIDENCE IN NORTH AMERICA, FIGURE 6 NEW CASES AND DEATHS FROM OVARIAN CANCER IN THE U.S., FIGURE 7 ESTIMATED OVARIAN CANCER INCIDENCE IN THE U.S FIGURE 8 OVARIAN CANCER: INCIDENCE AND MORTALITY IN U.S., FIGURE 9 OVARIAN CANCER EUROPEAN AGE-STANDARDIZED INCIDENCE IN EU-27 COUNTRIES, 2008 ESTIMATES FIGURE 10 ESTIMATED OVARIAN CANCER: INCIDENCE IN EUROPE FIGURE 11 GYNECOLOGICAL CANCERS - NUMBERS OF NEW CASES PER 100,000 POPULATION IN THE U.K., 2008 FIGURE 12 OVARIAN CANCER STATISTICS IN THE U.K., FIGURE 13 OVARIAN CANCER DIAGNOSTIC TESTS AND MARKET SALES AND FORECAST, ($ FIGURE 14 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, ($ FIGURE 15 U.S. MARKET FOR TRANSVAGINAL ULTRASOUND IN OVARIAN CANCER, ($ FIGURE 16 GLOBAL MARKET FOR LAB TESTS FOR OVARIAN CANCER, ($ FIGURE 17 U.S. MARKET FOR LAB TESTS FOR OVARIAN CANCER, ($ FIGURE 18 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, ($ FIGURE 19 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR CA-125, ($ FIGURE 20 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, FIGURE 21 U.S. OVARIAN CANCER DIAGNOSTIC MARKET FOR THE HE4 TEST, ($ FIGURE 22 GLOBAL OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, ($ FIGURE 23 UNITED STATES OVARIAN CANCER DIAGNOSTIC MARKET FOR THE ROMA TEST, ($ FIGURE 24 GLOBAL OVA1 MARKET, ($ 150 FIGURE 25 GLOBAL MOLECULAR DIAGNOSTICS MARKET, ($ 154 FIGURE 26 GLOBAL MARKET FOR OVADX, ($ 156 FIGURE 27 U.S. MARKET FOR OVADX - SALES AND FORECAST ($ FIGURE 28 GLOBAL OVARIAN CANCER SURGERY MARKET, ($ 159 FIGURE 29 U.S. OVARIAN CANCER SURGERY MARKET, ($ 160 FIGURE 30 GLOBAL COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, ($ FIGURE 31 U.S. COMPUTED TOMOGRAPHY IMAGING MARKET FOR OVARIAN CANCER, ($ FIGURE 32 GLOBAL CYTOTHERAPEUTICS MARKET, 2010 AND 2017 ($

18 FIGURE TITLE FIGURE 33 U.S. CYTOTHERAPEUTICS MARKET, ($ 170 FIGURE 34 EUROPEAN CYTOTHERAPEUTICS MARKET, ($ 172 FIGURE 35 JAPANESE CYTOTHERAPEUTICS MARKET, ($ 173 FIGURE 36 GLOBAL OVARIAN CANCER CHEMOTHERAPY MARKET, ($ FIGURE 37 OVARIAN CANCER CHEMOTHERAPY MARKET IN KEY COUNTRIES, ($