Is This Ovary Malignant?Separating the Olives from the Pits

Frederick R. Ueland, M.D.

Associate Professor Gynecologic Oncology

University of Kentucky Markey Cancer Center

Siena, ItalySettled 900-400 BC

Walled city by 12th century1st Palio race in 1656

Il Palio di Siena

Outline■ The challenge of ovarian tumors■ Value of specialists in ovarian cancer■ Essentials in preoperative evaluation

Examination Imaging Biomarkers

■ Algorithms ACOG RMI

■ Summary

Challenge of Ovarian Tumors

There are 155 million women in United States ~125 million women 13 years of age or older

90 million are between 13 and 50 years of age 30 million are over age 50

How common are ovarian tumors? Premenopausal

14% annual incidence (13 million), 30% prevalence (27 million) Postmenopausal

5% annual incidence (1.5 million), 16% prevalence (5 million) Resolution: 70% of unilocular, 55% of complex tumors

Millions of ovarian tumors, 22,000 cancers annually Which tumors need removal and by whom?

United States Census Bureau, 2008; Data from University of Kentucky Ovarian Cancer Screening Program, 2009 (N=27,000)

Many tumors, few cancers Low prevalence

15% of ovarian neoplasms are malignant Germ cell tumors Borderline tumors Epithelial cancers

Benign ovarian tumors 70% functional cysts 20% neoplastic 10% endometriomas

Other Inflammatory

Few tumors, many cancers High prevalence

50% of ovarian neoplasms are malignant Epithelial ovarian cancer Metastatic cancer Granulosa cell tumors

Benign ovarian tumors Cystadenoma Fibroma Thecoma

Ovarian Tumors

Premenopausal Postmenopausal

Cancer Mortality1930-2003

Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006

1930

1940

1950

1960

1970

1980

1990

1998

2000

2002

0

10

20

30

40

Colon & rectum

UterusStomach

Ovary

Rate Per 100,000

NIH Consensus Statement1994

“Women with ovarian masses identified preoperatively as having a significant risk of cancer should be given the option of surgery

performed by a gynecologic oncologist”

Value of Specialists

Meta-analysis of 18 studies concluded marked benefit with gynecologic oncologist (Giede 2005) Complete surgical staging with early disease Optimal cytoreductive surgery with advanced disease Improved median and overall survival

Involvement of GO supported by: NCCN guidelines SGO, ACOG SOGC clinical practice guidelines NIH London Medical Advisory statement

Preoperative Evaluation

Physical examination Pelvic, abdominal, and lymph node survey

Imaging study Transvaginal ultrasonography CT scan

Biomarkers CA125

Not FDA-cleared as a diagnostic test Low sensitivity and specificity

Pelvic ExaminationDetecting ovarian tumors

Ovarian palpation is difficult in older women, obese women, and when the uterus is large

Ueland et al. Gyn Oncol, 2005

Pelvic Exam

Ultrasound P-value

Age ≥ 55 0.30 0.74 < 0.001

Patient wt ≥ 200 lb 0.09 0.73 < 0.001

Uterine wt ≥ 200 g 0.16 0.80 < 0.001

UltrasoundOvarian tumors

Unilateral Simple, unilocular Septated (MI < 5) No ascites Resolution

Bilateral Complex (MI ≥ 5)

Solid wall abnormalities Internal papillations

Ascites Persistence or growth

Benign Malignant

When Cysts are NOT Malignant

Unilocular cysts

Septated ovarian cysts

Saunders B. et al. Risk of Sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol 118: 278-282, 2010.

Modesitt et al. Risk of malignancy in unilocular ovarian cystic tumors. Gynecol Oncol 102:594-599, 2003

UltrasoundKentucky Morphology Index

Ueland et al. Gynecol Oncol, 2003

Ascites

Kentucky Morphology Index

5 6 7 8 9 100

10

20

30

40

50

60

70

80

90

100

High Risk 5-10

% Benign % Cancer

2032

38

92 77 83

Ueland et al. Gynecol Oncol, 2003

Sensitivity 0.98

Specificity 0.81

PPV 0.41

NPV 0.99

Ovarian Tumor Ultrasound

Definition of (+) US varied with each author

Author N Prevalence Sens (%) Spec (%) PPV (%) PPV (20%)

Kobayashi, 1976 406 15 70 73 31 39

Hermann, 1987 241 21 82 93 75 73

Finkler, 1988 102 36 62 95 88 75

Benacerraf, 1990 100 30 80 87 72 62

Granberg, 1990 180 22 82 92 74 73

Sassone, 1991 143 10 100 83 37 59

Ueland, 2003 442 12 98 81 41 56

CA125 HE4 CEA CA19-9

■ LDH■ β-hCG■ AFP■ OVA1

Ovarian Biomarkers

CA125 Antigen derived from:

Coelomic epithelium (pericardium, pleura, peritoneum) Mullerian epithelium (tubal, endometrial, endocervical)

Two different assays Assay I < 35 U/ml; Assay II < 20 U/ml

Expressed by 80% non-mucinous EOC Low sensitivity (false negatives)

50% sensitivity in early stage ovarian cancers 20-25% false negatives in advanced stage cancers

Mucinous, clear cell cancers, mixed mullerian tumors

FDA-cleared to monitor cancer treatment Neither a screening nor a diagnostic test

CA125Non-specific

Benign ovarian cysts Uterine leiomyomata Pelvic inflammatory

disease Endometriosis Adenomyosis Pregnancy Menstruation Ascites

Heart failure Liver failure Renal failure Peritoneal tuberculosis Diverticulitis Pancreatitis Recent abdominal or

thoracic surgery Other malignancies

1. Quest Diagnostics Website www.questdiagnostics.com2. He4 Product Insert, Fujirebio Diagnostics, Inc.

Antigen derived from: Human epididymis protein

Product of the WFDC2 (HE4) gene that is over-expressed in patients with ovarian carcinoma1

FDA-cleared to monitor cancer treatment with other clinical methods

HE4 not for monitoring mucinous or germ cell ovarian cancers 2

■Neither a screening nor a diagnostic test

HE4

Risk of Malignancy Algorithm

CA125 and HE4 Accrual from tertiary centers

Moore R, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 2009;112:40-46.

All Subjects(N= 503)

Premenopausal(N= 236)

Postmenopausal(N= 267)

Sensitivity 89 76 92

Specificity 75 75 75

PPV 60 34 74

NPV 94 95 93

Prevalence= 34%

CEA Mucinous neoplasms

CA19-9 Gastrointestinal (pancreatic)

LDH* Dysgerminoma

*Most beneficial in young women with solid tumors

■ β-hCG*■ Pregnancy■ Trophoblastic disease■ Choriocarcinoma

■ AFP*■ Hepatic neoplasms■ Endodermal sinus tumors

Other Ovarian Biomarkers

FDA NEWS RELEASE

For Immediate Release: Sept. 11, 2009

Media Inquiries: Peper Long, 301-796-4671, mary.long@fda.hhs.govConsumer Inquiries: 888-INFO-FDA

FDA Clears a Test for Ovarian CancerTest can help identify potential malignancies, guide surgical decisions

The U.S. Food and Drug Administration today cleared a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test, called OVA1, helps patients and health care professionals decide what type of surgery should be done and by whom.

OVA1 Panel: CA125-II, transthyretin, apolipoprotein

A1, beta 2 microglobulin, transferrin

Sensitivity EOC 99%, nonEOC 78%, borderline 75%,

metastases 94% Stage I 90%, stage II-IV 100%

Range 0-10 Premenopausal Postmenopausal

Low Risk < 5.0 < 4.4

High Risk ≥ 5.0 ≥ 4.4

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG Referral Guidelines

CA125 >200 U/mL

Ascites Evidence of abdominal or

distant metastases Family history one or

more first-degree relatives with ovarian or breast cancer

CA125 >35 U/mL Nodular or fixed mass Ascites Evidence of abdominal or

distant metastases Family history one or

more first-degree relatives with ovarian or breast cancer

Premenopausal Women Postmenopausal Women

ACOG Committee Opinion: number 280, December 2002. Obstet Gynecol 2002;100:1413-6

ACOG Validation Im, 2005

Chart review 1035 patients, 7 tertiary centers 95%- imaging, 68%- CA125, 24%- both “SGO and ACOG referral guidelines effectively

separate women with pelvic masses into two risk categories for malignancy”

Dearking, 2007 Prospective, single-institutional trial, 837 patients Guidelines performed well in predicting advanced-

stage disease, but “poorly” in early-stage disease, and premenopausal women

“Need a more sensitive biomarker” Recommended modifications:

CA-125 >67 U/mL (pre); exclude FH of breast, ovarian cancer

OVA1 Trial

27 sites throughout United States 516 patients,161 malignancies 52% from primary care providers

Preoperative evaluation Physician assessment Imaging, serum

Biomarker assays- Quest laboratories Johns Hopkins Biomarker Discovery Center Specialty Laboratories

Independent data analysis Applied Clinical Intelligence

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG Performance

All Subjects(N= 516)

Premenopausal(N= 235)

Postmenopausal(N= 281)

ACOGModified ACOG

ACOGModified ACOG

ACOGModified ACOG

Sensitivity 77 80 58 76 84 81

95% CI 70 to 83 73 to 85 43 to 71 61 to 86 77 to 90 73 to 87

Specificity 68 71 77 70 56 71

95% CI 63 to 72 66 to 75 71 to 83 64 to 77 49 to 64 64 to 77

PPV 52 55 38 38 58 66

95% CI 46 to 58 49 to 61 27 to 50 28 to 48 50 to 65 58 to 74

NPV 87 88 89 92 84 84

95% CI 82 to 90 84 to 92 83 to 92 87 to 96 76 to 90 77 to 89

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG PerformancePremenopausal women

Cancer Stage

Early Late

Sensitivity 47 100

95% CI 26 to 69 72 to 100

Specificity 77 77

95% CI 71 to 83 71 to 83

PPV 16 19

95% CI 8 to 28 11 to 31

NPV 94 100

95% CI 89 to 97 98 to 100

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG Revisited OVA1 replacing CA125

All subjectsN=516

PremenopausalN= 235

PostmenopausalN= 281

Sensitivity 94 91 95

95% CI 89 to 97 79 to 97 89 to 98

Specificity 35 43 26

95% CI 30 to 40 36 to 50 19 to 33

PPV 40 28 47

95% CI 35 to 45 21 to 35 41 to 54

NPV 93 95 88

95% CI 87 to 96 89 to 98 75 to 94

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG PerformanceUnivariate comparison

ACOG Criteria Modified ACOG CriteriaOdds Ratio (95% CI)

P Value Odds Ratio (95% CI)

P Value

Menopausal status 3.0 <.001 3.0 <.001

CA125-II level 11.6 <.001 9.3 <.001

Ascites 7.8 <.001 7.8 <.001

Evidence of metastasis 11.7 <.001 11.7 <.001

Nodular or fixed mass 3.3 <.001 -- --

FH of breast cancer 1.9 0.036 -- --

FH of ovarian cancer 1.5 0.332 -- --

Presented at SGO Annual Meeting, San Francisco, CA March, 2010

ACOG Simplified*

1. OVA1 (+)

2. Nodular or fixed mass

3. Ascites

4. Metastases

 *presence of any criterion warrants referral to a gynecologic

oncologist

Sensitivity93%

Specificity40%

PPV41%

NPV93%.

Risk of Malignancy IndexU x M x CA125

US Meno Size CA125 HR Score

RMI 1 Jacobs 1990 0, 1, 3 1, 3 NA U/mL >200

RMI 2 Tingulstad 1996 1, 4 1, 4 NA U/mL >125

RMI 3 Tingulstad 1999 1, 3 1, 3 NA U/mL >200

RMI 4 Yamamoto 2006 1, 4 1, 4 1, 2* U/mL >450

RMI 5 Lee 2010 ? ? NA U/mL ?

*<7 cm or ≥7 cm

Risk of Malignancy IndexCutoff = 200

Manjunath et al. Gynecol Oncol 81:225-229, 2001.

Sens Spec PPV NPV0

10

20

30

40

50

60

70

80

90

100

73

91 93

67

RMI 1RMI 2RMI 3

Ultrasound with Biomarker

US* with OVA1 US* with CA125

n/N Sensitivity 95% CI n/N Sensitivity 95% CIAll stages3

102/105 97 92 to 99 82/105 78 69 to 85

Stage I 28/31 90 75 to 97 16/31 52 35 to 68

Stage II 18/18 100 82 to 100 14/18 78 55 to 91 Early stage (I & II) 46/49 94 84 to 98 30/49 61 47 to 74 Late stage (III & IV) 54/54 100 93.4 to 100 52/54 96 88 to 99Premenopausal women

Early stage (I & II) 14/17 82 59 to 94 5/17 29 13 to 53

Late stage (III & IV) 10/10 100 72 to 100 9/10 90 60 to 98Postmenopausal women

Early stage (I & II) 32/32 100 89 to 100 25/32 78 61 to 89

Late stage (III & IV) 44/44 100 92 to 100 43/44 98 88 to 100

*US= solid, papillary projections, ascites onlyData from OVA1 trial presented at SGO, 2010

Correlation of OVA1 and Cancer

High risk imaging Low risk imaging

OVA1 score % Malignant Odds Ratio % Malignant Odds Ratio

4.4 as cut-off 50.5 8.8 16.7 5.2

5.0 as cut-off 51.7 4.9 16.3 3.3

6.0 as cut-off 66.1 8.4 24.4 4.9

7.0 as cut-off 79.5 13.4 31.6 5.4

8.0 as cut-off 82.5 12.0 50.0 10.6

9.0 as cut-off 84.8 10.9 100.0 NC

Evaluation of an ovarian tumor

Unilocular/septate Complex morphology1

US surveillanceevery 3-4 months

CA125 (or OVA1; RMI; ACOG)

Surgery with gynecologist

Surgery with gynecologic oncologist

US surveillanceevery 6 months

persistent low risk high risk2

*Perform tumor morphology indexing (MI)1Complex morphology: solid or papillary areas, ascites, metastases, or MI ≥ 52High risk: CA125 > 200 U/mL (pre), >35 U/mL (post), OVA1 (+), RMI > 200, or per ACOG guidelines

Ovarian tumorultrasound*

complex

low risk

Patient Referrals

Specificity doesn’t correlate with referral decisions

Ovarian cancer prevalence for GYO 20-40%

OVA1 trial 72% of all benign tumors referred to GYO for surgery 45% referred despite a NEGATIVE physician

assessment Physicians lack confidence in impression Non-medical factors