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A New Test for Assessing the Risk of Ovarian Cancer in Women with Adnexal Mass

PresenterPlaceDate

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Ovarian Cancer is a Major Women's Health Problem

• High morbidity and mortality

• Appropriate treatment improves survival1

– Oncology specialists– High volume centers

• Need better risk assessment tools

1ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.

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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% sensitive1

– 75% specific1

1FDI-03 Clinical Study Report.

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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

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ROMA™ Will Improve Treatment of Women with Adnexal Mass

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Agenda

• Ovarian Cancer Risk Assessment

• ROMA™ Development

• Multicenter Validation Trial

• Conclusion and Summary

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Ovarian Cancer Risk Assessment

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Need New Tools to Better Assess Ovarian Cancer Risk

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Ovarian Cancer is a Deadly Disease

• 204,499 new cases in 2008

• 124,860 deaths

• Leading cause of gynecologic cancer deaths

• 5th leading cause of cancer deaths in women

International Agency for Research on Cancer. Globocan 2002. http://www-dep.iarc.fr/

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1 in 5 Women will havea Pelvic Mass

• 20% of women will be diagnosed with an adnexal mass1

• 5 - 10% of women will have surgery for an ovarian neoplasm (100,000 to 200,000)2

• 13 - 21% of these masses will be malignant2

1Curtin JP. Gynecol Oncol. 1994;55:S42-S46. 2NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.

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Survival Rates for Ovarian Cancer Need to be Improved

Ovarian Cancer 5-yr Survival Rate by Stage

Stage Distribution at Diagnosis

Survival Rate

Stage I 20-27% 73-93%

Stage II 5-10% 45-70%

Stage III 52-58% 21-37%

Stage IV 11-17% 11-25%

Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138.Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.

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How can we Affect Ovarian Cancer Survival?

• Prevention

• Screening

• Early detection

• Surgery

• Chemotherapeutic agents

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Surgery can Impact Survival

• Cytoxan to Paclitaxel– 14 month survival advantage1

• Intravenous to Intraperitoneal– 16 month survival advantage2

• Surgery by gynecologic oncologist– 12 month survival advantage3,4

1McGuire WP et al. NEJM. 1996;334(1):1-6.2Armstrong DK et al. NEJM. 2006;354(1):34-43.3Engelen MJA et al. Cancer. 2006;106(3):589-598.4Bristow RE et al. J Clin Oncol. 2002;20(5):1248-1259

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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

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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

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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

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Oncology Specialist Most Likely to Perform Comprehensive Surgery

*Ovarian Cancer Surgery by: Surgeon

Surgeon SpecialtyRate of Comprehensive

Surgery

Gynecologic oncologist 75.7%

Obstetrician gynecologist 37.3%

General surgeon 38.5%

Goff BA et al. Cancer. 2007;109(10):2031-2042.

* South Carolina admissions

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High Volume Surgeons Most Likely to Perform Comprehensive Surgery

Ovarian Cancer Surgery by: Surgeon

Surgery VolumePercentage

of Cases

Rate of Comprehensive

Surgery

Very Low1 case/year

25.2% 55.2%

Low / Medium2-9 cases/year

22.7% 65.1%

High≥ 10 cases/year

52.1% 75.2%

Goff BA et al. Cancer. 2007;109(10):2031-2042.

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Less than Half of Ovarian Cancer Surgery is at High Volume Hospital

Ovarian Cancer Surgery by: Hospital

Surgery VolumePercentage

of Cases

Rate of Comprehensive

Surgery

Low1-9 cases/year

33.3% 57.4%

Medium10-19 cases/year

18.1% 69.5%

High≥ 20 cases/year

48.6% 73.7%

Goff BA et al. Cancer. 2007;109(10):2031-2042.

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Significantly Higher Survival Rates with Oncology Specialists

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Type of Surgeon Impacts Survival Rates

Type of Hospital Impacts Survival Rates

Paulsen T et al. Int J Gynecol Cancer. 2006;16(Suppl 1):11-17.

TH: Teaching hospitalNTH: Nonteaching hospital

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Significantly Higher Survival Rates with Oncology Specialists

StudyGynecologic Oncologists

Gynecologists/General

Surgeonsp value

Eisenkop 1992 35 months 17 months <0.001

Junor 1999 18 months 13 months <0.005

Carney 2002 26 months 15 months <0.01

Tingulstad 2003 21 months 12 months 0.01

Eisenkop SM et al. Gynecol Oncol. 1992;47(2):203-209.Junor EJ et al. Br J Obstet Gynaecol. 1999;106(11):1130-1136.Carney ME et al. Gynecol Oncol. 2002;84:36-42.Tingulstad S et al. Obstet Gynecol. 2003;102(3):499-505.

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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):1248-1259.

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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 centers1

• 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 cancer2

1Goff BA et al. Cancer. 2007;109(10):2031-2042.2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.

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Current Clinical Tools to Assess Risk of Ovarian Cancer

• History

• Physical exam

• Imaging (US, CT and MRI)

• Tumor markers (CA 125)

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We can Improve the Care for Ovarian Cancer Patients

• Better risk assessment

• Improved patient care and management

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

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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

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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.

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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.

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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.

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Pivotal Trial Enrollment

• 566 patients enrolled

• 530 evaluable patients– 246 premenopausal– 284 postmenopausal

• 94% of patients were evaluable

FDI-03 Clinical Study Report.

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Study Cohort Disease Distribution: Enriched for EOC

Pivotal Trial: Pathology Distribution for All Cases

Pathology Premenopausal(N)

Postmenopausal(N)

All Patients(N)

Benign 200 151 351 (66%)

Invasive EOC 18 111 129 (24%)

LMP Tumors 16 6 22 (4%)

Non EOC 6 0 6 (1%)

Metastatic 5 9 14 (3%)

Other Gyn 1 7 8 (2%)

Total 246 284 530

FDI-03 Clinical Study Report.

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Spectrum of Benign Disease as Expected

Pathology Pre Post All %Serous cystadenoma/Cystadenoma 25 53 78 22.2

Endometriosis 42 2 44 12.5

Simple/Paratubal 34 21 55 15.7

Teratoma 18 11 29 8.3

Adenofibroma/Cystadenofibroma 6 16 22 6.3

Mucinous Cystadenoma 9 13 22 6.3

Leiomyoma 16 3 19 5.4

Fibroma/Fibrothecoma 3 15 18 5.1

Tubo-ovarian abscess/Hydrosalpinx 8 6 14 4.0

Functional cyst/Hemorrhagic cyst 14 0 14 4.0

Normal 3 2 5 1.4

Other 22 9 31 8.8

Total 200 151 351 100Data on file, FDI.

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Stage Distribution forEOC as Expected

InvasiveEOC

Premenopausal(N)

Postmenopausal(N)

All Patients(N)

Stage I 4 13 17 (13%)

Stage II 3 15 18 (14%)

Stage III 8 76 84 (65%)

Stage IV 1 5 6 (5%)

Unstaged 2 2 4 (3%)

Total 18 111 129

Data on file, FDI.

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Most Ovarian Cancers Correctly Classified

All Patients: Distribution of Benign vs EOC + LMP Tumors

DiseaseLow Risk(N)

High Risk

(N)

All(N)

Sensitivity Specificity PPV NPV

Benign 262 89 351

89% 75% 60% 94%EOC + LMP

17 134 151

Total 279 223 502

FDI-03 Clinical Study Report.

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Age GroupsLMP

EOC Stage% EOC

incorrectly classified

% EOC correctly classified

I IIIII & IV

NotStaged

Postmenopausal(n=111) 3 1 3 1 1 5% 95%

Premenopausal(n=18) 6 1 - - 1 11% 89%

All Ages(n=129) 9 2 3 1 2 6% 94%

Most Ovarian Cancers Correctly Classified

FDI-03 Clinical Study Report.

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Most Early Stage EOC Correctly Classified

Correctly Identified

Total Cases

Percentage correctly Identified

Stage I & II 30 35 86%

Stage III & IV 89 90 99%

All Invasive EOC*

121 129 94%

*All EOC including unstaged EOC

FDI-03 Clinical Study Report.

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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; 97:992-929.

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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

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ROMA™ has Increased Sensitivity Compared with RMI

Pre & PostMenopausal

Benign (n=315) vs EOC (n=124)

Sensitivity* (95% CI) Specificity (95% CI)

RMI 85% (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=0.0129CI: Confidence Interval

Data on file, FDI.

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ROMA™ has Increased Sensitivity vs RMI for Early Stage Cancer

Pre & PostMenopausal

Benign (n=315) vs Stage I-II EOC (n=35)

Sensitivity* (95% CI) Specificity (95% CI)

RMI 66% (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=0.0510CI: Confidence Interval

Data on file, FDI.

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ROMA™ DemonstratesSuperior 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.

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Additional Slides

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Ovarian Cancer Epidemiology

• Age adjusted incidence is 2 to 15 cases per 100,000 women

• Incidence ratesare stable orslowly increasing

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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 cancerwill have an adequate staging or cytoreductive surgery1,2. Gynecologic Oncologists are trained in staging of ovarian cancer.

1Carney ME et al. Gynecol Oncol. 2002;84:36-42.2McGowan L et al. Obstet Gynecol. 1985;65(4):568-572.

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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

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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)

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CA 125• “Gold Standard” biomarker in ovarian cancer• Elevated CA 125 in 50% of Stage I disease and 80% of epithelial

ovarian cancers1

• Elevated in the pre-clinical asymptomatic phase of the disease

Limitations – Elevated levels in benign gynecological disease1,2

– 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

1NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.

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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

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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;25:4159-4161.

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Preoperative Differentiation of Benign and MalignantPelvic 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

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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;110:201-213.

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Surgical Staging

Surgical Staging by Specialty

Study Gynecologic Oncologist

Gynecologist General surgeon

Earle 200660% (nodes)

118/198

36% (nodes)

146/409

16% (nodes)

23/144

Engelen 200661% (nodes)

40/65

30% (nodes)

41/135-

Grossi 200247%

(ext staging)

15%

(ext staging)

0%

(ext staging)

Earle CC et al. J Ntl Cancer Inst. 2006;25:172-180.Engelen MJA et al. Cancer. 2006;106:589-598.

Grossi M et al. MJA..2002;177:11-16.

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Ultrasound and CA125

RMIScore

Sensitivity(%)

Specificity(%)

Likelihood ratio for malignancyif result is:

Positive Negative

25 100 62.2 2.7 0.00

50 95.1 76.5 4.1 0.06

75 92.7 84.7 6.1 0.09

100 85.4 87.8 7.0 0.17

150 85.4 93.9 14.0 0.16

200 85.4 96.9 42.1 0.15

250 78.0 99.0 76.9 0.22

Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.

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Adequacy of Surgical Staging

Results of repeat staging in apparent early stage ovarian cancers

Initial Stage # of Patients % Upstaged

IA 37 16

IB 10 30

IC 2 0

IIA 4 100

IIB 38 39

IIC 9 33

Total 100 31

Young RC et al. JAMA.1983;250(22):3072-3076.

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Ultrasound Evaluation of a Pelvic MassUltrasound Evaluation of a Pelvic Mass

Study ScoreSensitivity

(%)Specificity

(%)PPV(%)

NPV(%)

Ferrazzi 1997 9 87 67 41 95

Granberg 1990 2 87 49 31 93

Sassone 1991 9 74 65 36 90

DePriest 1993 5 88 40 28 93

Lerner 1994 4 87 59 36 95

Ferrazzi E et al. Ultrasound Obstet Gynecol.1997;10:192-197.

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Pivotal Trial Referral Patterns

Gastroenterologist0%

Self-referred1%

Other10%

Gynecologist69%

Family Practitioner9%

Surgeon2%

Internist9%

N=524 of the 566 trial population Data on File, FDI.

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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;110:201-213.