C- 1 A New Test for Assessing the Risk of Ovarian Cancer in Women with Adnexal Mass Presenter Place Date

C- 2 Ovarian Cancer is a Major Women's Health Problem High morbidity and mortality Appropriate treatment improves survival 1 –Oncology specialists –High volume centers Need better risk assessment tools 1 ACOG Practice Bulletin. Obstet Gynecol. 2007;110:

C- 3 ROMA™: A Novel Ovarian Cancer Risk Assessment Tool Evaluated 15 biomarkers including HE4, which is: –Putative protease inhibitor –CE-Marked and available for clinical use Assess Risk of ovarian cancer in patients with Pelvic Mass Monitor patients with ovarian cancer –Expressed in reproductive, respiratory tissues –Complementary to CA 125 Developed ROMA™ –89% sensitive 1 –75% specific 1 1 FDI-03 Clinical Study Report.

C- 4 ROMA™: A Novel Ovarian Cancer Risk Assessment Tool Stratify risk of ovarian cancer Ensure treatment by right surgeon/right facility Used in conjunction with other Dx methods Not intended for detection or screening

C- 5 ROMA™ Will Improve Treatment of Women with Adnexal Mass

C- 6 Agenda Ovarian Cancer Risk Assessment ROMA™ Development Multicenter Validation Trial Conclusion and Summary

C- 7 Ovarian Cancer Risk Assessment

C- 8 Need New Tools to Better Assess Ovarian Cancer Risk

C- 9 Ovarian Cancer is a Deadly Disease 204,499 new cases in ,860 deaths Leading cause of gynecologic cancer deaths 5th leading cause of cancer deaths in women International Agency for Research on Cancer. Globocan

C in 5 Women will have a Pelvic Mass 20% of women will be diagnosed with an adnexal mass % of women will have surgery for an ovarian neoplasm (100,000 to 200,000) % of these masses will be malignant 2 1 Curtin JP. Gynecol Oncol. 1994;55:S42-S46. 2 NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.

C- 11 Survival Rates for Ovarian Cancer Need to be Improved Ovarian Cancer 5-yr Survival Rate by Stage Stage Distribution at Diagnosis Survival Rate Stage I20-27%73-93% Stage II5-10%45-70% Stage III52-58%21-37% Stage IV11-17%11-25% Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 : Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.

C- 12 How can we Affect Ovarian Cancer Survival? Prevention Screening Early detection Surgery Chemotherapeutic agents

C- 13 Surgery can Impact Survival Cytoxan to Paclitaxel –14 month survival advantage 1 Intravenous to Intraperitoneal –16 month survival advantage 2 Surgery by gynecologic oncologist –12 month survival advantage 3,4 1 McGuire WP et al. NEJM. 1996;334(1): Armstrong DK et al. NEJM. 2006;354(1): Engelen MJA et al. Cancer. 2006;106(3): Bristow RE et al. J Clin Oncol. 2002;20(5):

C- 14 The Optimal Care for Ovarian Cancer Cytoreductive surgery with complete surgical staging Rationale for surgical staging: –Define the extent of disease –Determine the need for adjuvant treatment –Provide prognosis –Outline a plan of care

C- 15 Surgical Debulking Increases Survival for Ovarian Cancer Optimal surgical debulking can include: Hysterectomy Removal of ovaries Bowel resection Peritoneal stripping Diaphragmatic stripping Lymph node debulking

C- 16 Gynecologic Oncologists are Ovarian Cancer Specialists Gynecologic oncologist –Recognized sub-specialty in US Residency in Obstetrics and Gynecology (4 yrs) Fellowship in Gynecologic Oncology (3-4 yrs) –Outside US Gynecologists with high oncology surgical volume Experienced in: –Surgical care –Medical management –Chemotherapy –Natural history

C- 17 Oncology Specialist Most Likely to Perform Comprehensive Surgery *Ovarian Cancer Surgery by: Surgeon Surgeon Specialty Rate of Comprehensive Surgery Gynecologic oncologist75.7% Obstetrician gynecologist37.3% General surgeon38.5% Goff BA et al. Cancer. 2007;109(10): * South Carolina admissions

C- 18 High Volume Surgeons Most Likely to Perform Comprehensive Surgery Ovarian Cancer Surgery by: Surgeon Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Very Low 1 case/year 25.2%55.2% Low / Medium 2-9 cases/year 22.7%65.1% High ≥ 10 cases/year 52.1%75.2% Goff BA et al. Cancer. 2007;109(10):

C- 19 Less than Half of Ovarian Cancer Surgery is at High Volume Hospital Ovarian Cancer Surgery by: Hospital Surgery Volume Percentage of Cases Rate of Comprehensive Surgery Low 1-9 cases/year 33.3%57.4% Medium cases/year 18.1%69.5% High ≥ 20 cases/year 48.6%73.7% Goff BA et al. Cancer. 2007;109(10):

C- 20 Significantly Higher Survival Rates with Oncology Specialists Type of Surgeon Impacts Survival Rates Type of Hospital Impacts Survival Rates Paulsen T et al. Int J Gynecol Cancer. 2006;16(Suppl 1): TH: Teaching hospital NTH: Nonteaching hospital

C- 21 Significantly Higher Survival Rates with Oncology Specialists Study Gynecologic Oncologists Gynecologists/ General Surgeons p value Eisenkop months17 months<0.001 Junor months13 months<0.005 Carney months15 months<0.01 Tingulstad months12 months0.01 Eisenkop SM et al. Gynecol Oncol. 1992;47(2): Junor EJ et al. Br J Obstet Gynaecol. 1999;106(11): Carney ME et al. Gynecol Oncol. 2002;84: Tingulstad S et al. Obstet Gynecol. 2003;102(3):

C- 22 Cytoreductive Surgery Increases Survival for Ovarian Cancer Patients Multiple studies and large meta-analyses have shown residual disease following surgery is the most significant prognostic factor: 53 studies, 6,885 patients Optimal cytoreduction  survival from 22.7 to 33.9 months (50%  ) Bristow RE et al. J Clin Oncol. 2002;20(5):

C- 23 Current Practice is Sub-Optimal for Ovarian Cancer Patients In the US only 50% of women with ovarian cancer are operated on by high volume surgeons or at high volume centers 1 Studies around the world show that survival rates are improved when patients have surgery by surgeons and at centers experienced in the management of ovarian cancer 2 1 Goff BA et al. Cancer. 2007;109(10): ACOG Practice Bulletin. Obstet Gynecol. 2007;110:

C- 24 Current Clinical Tools to Assess Risk of Ovarian Cancer History Physical exam Imaging (US, CT and MRI) Tumor markers (CA 125)

C- 25 We can Improve the Care for Ovarian Cancer Patients Better risk assessment Improved patient care and management

C- 26 Validation of ROMA™ as a Risk Assessment Tool and Patient Benefit

C- 27 Development and Validation of ROMA™ Two pilot studies combined to generate ROMA™ –Patients enrolled from: Women and Infants’ Hospital, Providence RI Massachusetts General Hospital, Boston MA Pivotal trial (FDI-03) to validate ROMA™ –National trial –New patient cohort for validation

C- 28 Primary Objective of Pivotal Trial To validate a predictive model utilizing a dual marker assay of HE4 and CA 125 to assess the risk for epithelial ovarian cancer including borderline/low malignant potential tumors in women with a pelvic mass FDI-03 Clinical Study Report.

C- 29 Pivotal Trial Study Sites Chosen to Enrich Ovarian Cancer Population 14 geographically dispersed sites across the US Divisions of Gynecologic Oncology, within Departments of Obstetrics and Gynecology Sites chosen to enrich study population FDI-03 Clinical Study Report.

C- 30 Pivotal Trial Methods Prospective double-blind multicenter trial Eligibility criteria: –≥18 years of age –Ovarian cyst or a pelvic mass –Planned surgical intervention All EOC patients to be surgically staged All blood samples obtained preoperatively Central pathology review FDI-03 Clinical Study Report.

C- 31 Pivotal Trial Enrollment 566 patients enrolled 530 evaluable patients –246 premenopausal –284 postmenopausal 94% of patients were evaluable FDI-03 Clinical Study Report.

C- 32 Study Cohort Disease Distribution: Enriched for EOC Pivotal Trial: Pathology Distribution for All Cases PathologyPremenopausal (N) Postmenopausal (N) All Patients (N) Benign (66%) Invasive EOC (24%) LMP Tumors16622 (4%) Non EOC606 (1%) Metastatic5914 (3%) Other Gyn178 (2%) Total FDI-03 Clinical Study Report.

C- 33 Spectrum of Benign Disease as Expected PathologyPrePostAll% Serous cystadenoma/Cystadenoma Endometriosis Simple/Paratubal Teratoma Adenofibroma/Cystadenofibroma Mucinous Cystadenoma Leiomyoma Fibroma/Fibrothecoma Tubo-ovarian abscess/Hydrosalpinx Functional cyst/Hemorrhagic cyst Normal Other Total Data on file, FDI.

C- 34 Stage Distribution for EOC as Expected Invasive EOC Premenopausal (N) Postmenopausal (N) All Patients (N) Stage I41317 (13%) Stage II31518 (14%) Stage III87684 (65%) Stage IV156 (5%) Unstaged224 (3%) Total Data on file, FDI.

C- 35 Most Ovarian Cancers Correctly Classified All Patients: Distribution of Benign vs EOC + LMP Tumors Disease Low Risk (N) High Risk (N) All (N) SensitivitySpecificityPPVNPV Benign %75%60%94% EOC + LMP Total FDI-03 Clinical Study Report.

C- 36 Age Groups LMP EOC Stage % EOC incorrectly classified % EOC correctly classified III III & IV Not Staged Postmenopausal (n=111) %95% Premenopausal (n=18) %89% All Ages (n=129) %94% Most Ovarian Cancers Correctly Classified FDI-03 Clinical Study Report.

C- 37 Most Early Stage EOC Correctly Classified Correctly Identified Total Cases Percentage correctly Identified Stage I & II303586% Stage III & IV899099% All Invasive EOC* % *All EOC including unstaged EOC FDI-03 Clinical Study Report.

C- 38 ROMA™ vs RMI Risk of Malignancy Index (RMI) RMI = U x M x serum CA 125 level U= 0 for imaging score of 0 = 1 for imaging score of 1 = 3 for imaging score of 2-5 M= 1 if premenopausal = 3 if postmenopausal Jacobs I et al. Br J Obstet Gynecol.1990; 97:

C- 39 Secondary Analysis of ROMA™ vs RMI Able to calculate an RMI for 80% of patients Utilized US, CT scans and MRI results for RMI imaging scores

C- 40 ROMA™ has Increased Sensitivity Compared with RMI Pre & Post Menopausal Benign (n=315) vs EOC (n=124) Sensitivity* (95% CI) Specificity (95% CI) RMI85% (77% to 90%) 75% (70% to 80%) ROMA™94% (89% to 98%) 75% (70% to 80%) Benign and EOC: All Stages *Two Sample Test of Equality of Proportions p= CI: Confidence Interval Data on file, FDI.

C- 41 ROMA™ has Increased Sensitivity vs RMI for Early Stage Cancer Pre & Post Menopausal Benign (n=315) vs Stage I-II EOC (n=35) Sensitivity* (95% CI) Specificity (95% CI) RMI66% (48% to 81%) 75% (70% to 80%) ROMA™86% (70% to 95%) 75% (70% to 80%) Benign and EOC: Stage I & II *Two Sample Test of Equality of Proportions p= CI: Confidence Interval Data on file, FDI.

C- 42 ROMA™ Demonstrates Superior Performance Correctly identifies 94% of EOC1 Performs better than RMI Simple and easy to use Quantitative test No subjective data Assigns a risk for malignancy Data on file, FDI.

C- 43 Additional Slides

C- 44 Ovarian Cancer Epidemiology Age adjusted incidence is 2 to 15 cases per 100,000 women Incidence rates are stable or slowly increasing

C- 45 Surgical Staging The current standard of care for ovarian cancer is cytoreductive surgery with complete surgical staging. Complete surgical staging includes: –Laparotomy –Hysterectomy –Bilateral salpingo-oophorectomy –Careful evaluation of all peritoneal surfaces –Multiple washings for cytology –Multiple peritoneal biopsies –Hepatic and diaphragmatic cytology –Omentectomy –Pelvic and periaortic lymphadenectomy Less than 50% of women undergoing surgery for an ovarian cancer will have an adequate staging or cytoreductive surgery 1,2. Gynecologic Oncologists are trained in staging of ovarian cancer. 1 Carney ME et al. Gynecol Oncol. 2002;84: McGowan L et al. Obstet Gynecol. 1985;65(4):

C- 46 Ovarian Cancer Age at presentation is bimodal with peaks at age 40 and 60 years old Symptoms often are nonspecific: –Abdominal bloating –Pelvic pressure –GI symptoms –Respiratory –Constitutional

C- 47 EDRN “Top Ten” Biomarkers for Detection of Ovarian Cancer CA 125 HE4 CA 15-3 CA 72-4 B7-H4 (Ov- 110) Transthyretin IGFBP-2 SMRP (Mesomark™) HK6 Cytokeratin 19 (CYFRA 21-1)

C- 48 CA 125 “Gold Standard” biomarker in ovarian cancer Elevated CA 125 in 50% of Stage I disease and 80% of epithelial ovarian cancers 1 Elevated in the pre-clinical asymptomatic phase of the disease Limitations –Elevated levels in benign gynecological disease 1,2 –Low sensitivity in Stage I ovarian cancer –CA 125 alone is not a sensitive marker HE4 A commonly up-regulated biomarker in ovarian cancer Serum HE4 is a useful biomarker in the early diagnosis of ovarian cancer Biomarkers for Ovarian Cancer 1 NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14. 2 ACOG Practice Bulletin. Obstet Gynecol. 2007;110:

C- 49 Concordance between change in HE4 levels and clinical status Progression Total Upper 95% Limit 98.3 Estimate 93.1 Lower 95% Limit Change in Disease State ProgressionNo ProgressionTotal Change in HE4 >25% < 25% Total HE4 FDA-cleared for monitoring of recurrent ovarian cancer Longitudinal Performance of HE4 FDI HE4 Clinical Study Report.

C- 50 Genetic Risk Factors for Ovarian Cancer BRCA 1 (17q21) BRCA 2 (13q12) P53 (17q13) PTEN (10q24) HNPCC –MLH 1 (3p21) –MSH 2 (2p16) –PMS 1 (2q31) –PMS 2 (7p22) Only 10% of ovarian cancers are inherited

C- 51 Ultrasound Assessment of Pelvic Mass Limitations of Ultrasound –Not all morphologic variables are commonly reported or measured –User variability (tertiary care vs community) –Ultrasound reporting is not standardized –Quality and complexity of machine (e.g. Doppler) –Complex algorithms Moore RG et al. J Clin Oncol. 2007;25:

C- 52 Preoperative Differentiation of Benign and Malignant Pelvic Masses To evaluate the risk of a malignancy To determine the need for surgery To triage patients To Improve the quality of care for patients –Allow patients to stay in their community –Appropriate patients referred to specialists Medical-legal implications

C- 53 Epidemiologic Risk Factors for Ovarian Cancer Age Early age at menarche Late age at menopause Nulliparity Infertility Caucasian race History of endometriosis ACOG Practice Bulletin. Obstet Gynecol. 2007;110:

C- 54 Surgical Staging Surgical Staging by Specialty Study Gynecologic Oncologist GynecologistGeneral surgeon Earle % (nodes) 118/198 36% (nodes) 146/409 16% (nodes) 23/144 Engelen % (nodes) 40/65 30% (nodes) 41/135 - Grossi % (ext staging) 15% (ext staging) 0% (ext staging) Earle CC et al. J Ntl Cancer Inst. 2006;25: Engelen MJA et al. Cancer. 2006;106: Grossi M et al. MJA..2002;177:11-16.

C- 55 Ultrasound and CA125 RMI Score Sensitivity (%) Specificity (%) Likelihood ratio for malignancy if result is: Positive Negative Jacobs I et al. Br J Obstet Gynecol.1990; 97:

C- 56 Adequacy of Surgical Staging Results of repeat staging in apparent early stage ovarian cancers Initial Stage# of Patients% Upstaged IA3716 IB1030 IC20 IIA4100 IIB3839 IIC933 Total10031 Young RC et al. JAMA.1983;250(22):

C- 57 Ultrasound Evaluation of a Pelvic Mass StudyScore Sensitivity (%) Specificity (%) PPV (%) NPV (%) Ferrazzi Granberg Sassone DePriest Lerner Ferrazzi E et al. Ultrasound Obstet Gynecol.1997;10:

C- 58 Pivotal Trial Referral Patterns N=524 of the 566 trial population Data on File, FDI.

C- 59 ACOG Referral Guidelines Premenopausal –CA125 > 200 –Ascites –Evidence of metastasis –Family history of breast or ovarian cancer Postmenopausal –CA125 >35 –Ascites –Fixed or nodular mass –Evidence of metastasis –Family history of breast or ovarian cancer ACOG Practice Bulletin. Obstet Gynecol. 2007;110: