1. Identifying Ovarian Tumors at High Risk for Ovarian Cancer Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology Vice Chairman, Department of Obstetrics and Gynecology University of Kentucky Markey Cancer Center

2. Ovarian Cancer Epidemiology ● Fifth leading cause of female cancer death in the United States ● Approximately 21,500 new cases of ovarian cancer and 14,600 deaths in 2009 ● Median age at diagnosis: 63 years ● Incidence: 13.1 per 100,000 women ● Prevalence: 176,000 women alive with a history of ovarian cancer (2006) ● Lifetime risk: 1/71 (1.4%) American Cancer Society, 2007 Surveillance, Epidemiology, and End Results (SEER) Program: National Cancer Institute, 2008

3. Cancer Incidence Rates 1975-2003 Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006 Colon and rectum Rate Per 100,000 Uterine Corpus Ovary

4. Cancer Mortality Rates 1930-2003 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 Colon & rectum Uterus Stomach Ovary Rate Per 100,000

5. Background Advanced stage presentation common (70%) Poor prognosis (50% 5-year survival) Slowly improving outcomes –Annual mortality change: –1.4% (2002-2006) Treatment –Comprehensive surgical staging for early disease –Cytoreduction for advanced disease –Combination chemotherapy –Clinical trials American Cancer Society: Facts & Figures, 2009. Atlanta. www. Cancer.org Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of Gynecologic Oncology, 4 th ed. Philadelphia: Lippincott Williams & Wilkins: 919-922, 2006

6. Stage and Outcome StagePercentSurvival I2495% II665% III5515-30% IV150-20% Overall50% American Cancer Society

7. Ovarian Cancer Symptoms Symptom awareness –95% report symptoms prior to diagnosis –> 12 times monthly –Pelvic and abdominal pain (77%) –Bloating, early satiety, GI symptoms (70%) –Pelvic (26%) and urinary symptoms (34%) Physician evaluation –Avoid diagnostic delay –Examination, imaging, laboratory testing as indicated –Sensitivity 57% for early stage 80% for advanced stage –Specificity 90% if > 50yo 86% for premenopausal women Goff B, et al. JAMA. 291:2705-12:2068-75, 2004 Olson S, et al. Obstet Gynecol. 98:212-7, 2001

8. 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 40 million women are Baby Boomers (age 41-59) How common are ovarian tumors? –Premenopausal women 14% annual incidence (13 million) 30% prevalence (27 million) –Postmenopausal women 5% annual incidence (1.5 million) 16% prevalence (5 million) –30% of unilocular and 45% of complex tumors typically persist Annually, there are tens of millions of ovarian cystic tumors, but only 22,000 ovarian cancers diagnosed United States Census Bureau, 2008 Data from University of Kentucky Ovarian Cancer Screening Program, 2009 (N=27,000)

9. Ovarian Tumors Premenopausal Women 15% of ovarian neoplasms in premenopausal women are malignant Non-inflammatory ovarian tumors – 70% functional cysts – 20% neoplastic – 10% endometriomas Other – Inflammatory process, bowel

10. Ovarian Tumors Postmenopausal Women 50% of ovarian neoplasms in postmenopausal women are malignant Benign epithelial tumor Stromal tumor – Granulosa cell – Fibroma – Thecoma Epithelial ovarian cancer Metastatic cancer

11. Guidelines and Algorithms NIH Consensus Statement, 1994 –“Women with ovarian masses identified preoperatively having a significant risk of cancer should be given the option of surgery performed by a gynecologic oncologist” Clinical algorithms –Examination, imaging, patient history, and laboratory tests –Infrequently utilized, not standardized –Challenging to evaluate

12. Biopsy of Ovarian Tumors Percutaneous FNA cytology of cystic ovarian tumors has low cancer sensitivity, ranging from 25% to 82 % Approximately 25-50% of ovarian cystic tumors aspirated in perimenopausal women will recur within 1 year Aspiration of a malignant cystic tumor may disseminate the cancer, increase the stage and worsen the prognosis ACOG Practice Bulletin no 83, 2006. Mizuno M, et al. Oncology. 65:29, 2003 Sainz de la Cuesta R, et al. Obstet Gyn. 84:1, 1994

13. Evaluation Physical examination –Pelvic, abdominal, and lymph node survey Imaging study –Transvaginal ultrasonography –CT scan CA-125 –Not FDA-approved as a diagnostic test –Low sensitivity and specificity

14. Pelvic Examination Detecting Ovarian Tumors 1. Ovarian detection on pelvic examination is infrequent in women ≥ 55 years old (30%) 2. Ovarian detection is exceedingly difficult in women weighing at least 200 lb (9%) 3. A large uterus (weight ≥ 200 g) makes ovarian palpation unlikely (16%) Ueland et al. Gyn Oncol, 2005

15. Pelvic Exam vs. Ultrasound Pelvic ExamUltrasoundP value Age ≥ 550.300.74< 0.001 Patient wt ≥ 200 lb 0.090.73< 0.001 Uterine wt ≥ 200 g 0.160.80< 0.001 Ueland et al. Gyn Oncol, 2005

16. Sonographic Characteristics Ovarian 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

17. Ovarian Tumor Imaging Type of CystPatients% Regressed under observation20572 Required exploratory laparotomy 8128 Ovarian neoplasms4616 Benign epithelial3211 Benign teratoma93 Malignant epithelial41.4 Dysgerminoma10.3 Endometriosis2810 Para-ovarian cyst41.4 Hydrosalpinx31 Functional cysts00 Spanos W. Am J Obstet Gynecol, 1973

18. Ovarian Tumor Imaging Modesitt et al, Gyn Oncol, 2003 Type of CystPatients% Resolution226169% Cyst + septum53717% Persistent cyst2207% Cyst + solid area1805% Solid mass210.7% Removed by surgery401.3% Total3259100%

19. Kentucky Morphology Index MI Score = 6 Ueland et al. Gyn Oncol, 2003 Ascites 

20. Kentucky Morphology Index High Risk Score (5-10) 20 32 38 92 77 83 Ueland et al. Gyn Oncol, 2003

21. Morphology Index Predicting Malignancy Sensitivity0.98 Specificity0.81 Positive predictive value0.41 Negative predictive value0.99 Accuracy0.83 Ueland et al. Gyn Oncol, 2003

22. Ovarian Tumor Ultrasound Definition of (+) US varied with each author AuthorNumberPrevalenceSens(%)Spec (%)PPV(%) PPV (at 20%) Kobayashi, 1976 4061570733139 Hermann, 1987 2412182937573 Finkler, 1988 1023662958875 Benacerraf, 1990 1003080877262 Granberg, 1990 1802282927473 Sassone, 1991 14310100833759 Ueland, 2003 4421298814156

23. CA-125 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 FDA-approved to monitor cancer treatment – Neither a screening nor a diagnostic test False negative CA-125 values (low sensitivity) – 50% of early stage ovarian cancers – 20-25% of advanced stage ovarian cancers – Mixed mullerian tumors, clear cell cancers

24. CA-125 Non-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

25. Role Surgery Proper staging for early disease –Determine adjuvant therapy Cytoreduction for advanced disease –Radical surgery as indicated –“Optimal” ≤ 1cm Reassessment laparotomy Secondary debulking

26. Staging by Specialty Women with early stage ovarian cancer – 291 subjects Complete surgical staging performed: – 97% gynecologic oncologists – 52% general obstetrician/gynecologists – 35% general surgeons McGowan L, et al. Obstet Gynecol;65:568-72, 1985

27. Surgical Cytoreduction Advanced Stage Ovarian Cancer Slide courtesy of Gynecologic Cancer Foundation

28. Surgical Cytoreduction Advanced Stage Ovarian Cancer Meta-analysis of 53 studies –6,885 stage III/IV patients Cytoreduction –High volume centers have higher rates of “optimal” surgery –“Optimal” improved survival by 11 months (50% increase) –Each 10% increment in cytoreduction = 5.5% improvement in survival % Cytoreduction Median Survival (months) Bristow, J Clin Oncol 20:1248, 2002

29. Improved Survival Utah Cancer Registry –848 new ovarian cancers, 1992-1998 Only 39% were ever seen by a gyn onc Patients with advanced disease had significant survival advantage when managed by gynecologic oncologist –median survival 26 mo vs. 15 mo, p < 0.01 Carney ME, et al. Gynecol Oncol;84:36-42, 2002

30. Improved Survival Medicare claims by physician specialty –SEER database –65 years or older –3067 surgeries for ovarian cancer Only 33% of patients with ovarian cancer were treated by gynecologic oncologist Improved outcomes and overall survival when managed by gynecologic oncologist Earle C.C, et al. JNCI 98:3, 2006

32. Value of Specialists Meta-analysis (18 studies) concluded marked benefit with gynecologic oncologist (Giede 2005) – Complete surgical staging with early stage disease – Optimal cytoreductive surgery with advanced disease – Improved median and overall survival Others supporting GO involvement: – NCCN guidelines – SGO, ACOG – SOGC clinical practice guidelines – NIH consensus statement – London Medical Advisory statement

33. 33 NCCN Guidelines ● Cytoreductive surgery ● all patients with stage II, III or IV ovarian cancer ● “optimal” cytoreduction (no residual disease > 1 cm) ● Gynecologic oncologist ● perform the initial surgical procedure ● Improved overall survival ● Category I recommendation ● Combination adjuvant chemotherapy ● Most patients (>70%) relapse after 1 st line therapy ● Clinical trials NCCN Clinical Practice Guidelines in Oncology, 2008 Ozols et al. J Clin Oncol. 21: 3194-3200, 2003

34. 34 Ovarian Cancer Dilemma ● Ovarian tumors are very common, particularly in young women ● Women with benign tumors prefer to have their surgery close to home with their established gynecologist ● Women with ovarian cancer are best managed by a gynecologic oncologist ● Current methods are unreliable in differentiating benign from malignant ovarian tumors, particularly in young women and early stage disease

35. 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 WomenPostmenopausal Women

36. Validation of Guidelines Im, 2005 –Chart review with 7 tertiary centers: 1035 patients –95% had imaging, 68% had preop CA-125, 24% had 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 –Recommended modifications: CA-125 <67 U/mL (pre), exclude FH of breast, ovarian cancer

37. A Multi-institutional Evaluation of ACOG and SGO Referral Guidelines for an Ovarian Mass Rachel Ware, Alan Smith, Chris Desimone, Leigh Seamon, Scott Goodrich, Iwona Podzielinski, Lori Sokoll, Joseph Santoso, J.R. van Nagell Jr., Zhen Zhang, Frederick Ueland. Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

38. Results ACOG Criteria Modified ACOG Criteria Sensitivity, %7780 95% CI70 to 8373 to 85 Specificity, %6871 95% CI63 to 7266 to 75 PPV, %5255 95% CI46 to 5849 to 61 NPV, %8788 95% CI82 to 9084 to 92

39. ACOG Results Premenopausal (N= 235) Postmenopausal (N= 281) ACOG Criteria Modified ACOG Criteria ACOG Criteria Modified ACOG Criteria Sensitivity, %58768481 95% CI43 to 7161 to 8677 to 9073 to 87 Specificity, %77705671 95% CI71 to 8364 to 7749 to 6464 to 77 PPV, %38 5866 95% CI27 to 5028 to 4850 to 6558 to 74 NPV, %899284 95% CI83 to 9287 to 9676 to 9077 to 89

40. ACOG Results ACOG Criteria Premenopausal women Cancer Stage EarlyLate Sensitivity, %47100 95% CI26 to 6972 to 100 Specificity, %77 95% CI71 to 83 PPV, %1619 95% CI8 to 2811 to 31 NPV, %94100 95% CI89 to 9798 to 100

41. FDA NEWS RELEASE For Immediate Release: Sept. 11, 2009 Media Inquiries: Peper Long, 301-796-4671, mary.long@fda.hhs.gov Consumer Inquiries: 888-INFO-FDA FDA Clears a Test for Ovarian Cancer Test 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.

42. The OVA1 Test Biomarker panel –CA125, transthyretin (prealbumin), apolipoprotein A1,beta 2 microglobulin, transferrin OvaCalc software algorithm OVA1 risk index, range 0-10 PremenopausalPostmenopausal Low Risk < 5.0< 4.4 High Risk ≥ 5.0≥ 4.4

43. OVA1 Indications Known pelvic mass or ovarian tumor Complete physician assessment –Examination, imaging, history, labs Decision for surgery OVA1 –Low risk OVA1 reassuring –High risk OVA1 referred to gyn oncologist

44. The OVA1 Test Improves the Preoperative Assessment of Ovarian Tumors Frederick Ueland, Chris Desimone, Leigh Seamon, Rachel Ware, Scott Goodrich, Iwona Podzielinski, Lori Sokoll, Alan Smith, Joseph Santoso, J.R. van Nagell Jr., Zhen Zhang. Presented at the Society of Gynecologic Oncology Annual Meeting, 2010

45. Methods 27 primary care, specialty sites throughout U.S. Preoperative evaluation –imaging to confirm ovarian tumor –serum collection for CA125 –physician assessment (Is it malignant? “yes or no”) Centralized assay at Quest Diagnostics Validation assays –Johns Hopkins Biomarker Discovery Center –Specialty Laboratories Independent data analysis –Applied Clinical Intelligence

46. Study Population All Subjects Non-GO Physicians GO Physicians Patients516269247 Mean age, yr (sd)52 (14)50 (14)55 (14) Median age, yr524854 Range (min, max)18 to 9219 to 9018 to 92 Menopausal Status, n (%) Pre235 (46%)144 (54%)91 (37%) Post281 (54%)125 (46%)156 (63%) Pathology Diagnosis, n (%) Benign ovarian condition355 (69%)197 (73%)158 (64%) Epithelial ovarian cancer (EOC)96 (19%)45 (17%)51 (21%) Other primary ovarian malignancy9 (2%)5 (2%)4 (2%) Low malignant potential (borderline)28 (5%)12 (4%)16 (6%) Non-primary ovarian malignancy with involvement of the ovaries 18 (4%)5 (2%)13 (5%) Non-primary ovarian malignancies with no involvement of ovaries 10 (2%)5 (2%) OVA1 Trial

47. OVA1 Test Alone Sensitivity92% Specificity43% PPV42% NPV93%

48. OVA1 Sensitivity Tumor subtypeCancer stage I90% II100% III100% IV100% Epithelial OC99% Non EOC78% LMP75% Metastases94%

49. PremenopausalPostmenopausal Performance Preoperative assessment Preoperative assessment plus OVA1 Preoperative assessment Preoperative assessment plus OVA1 Sensitivity, %60898198 95% CI46 to 7376 to 9573 to 8794 to 100 Specificity, %83407428 95% CI77 to 8834 to 4867 to 8122 to 35 PPV, %46266949 95% CI34 to 5820 to 3461 to 7643 to 55 NPV, %90948596 95% CI84 to 9386 to 9778 to 9086 to 99 Negative Likelihood Ratio 0.480.270.250.06 95% CI0.33 to 0.690.12 to 0.640.17 to 0.370.02 to 0.25 Prevalence19% (45/235)41% (116/281) OVA1 Results

50. non-GO physiciansGO physicians Performance Preoperative assessment Preoperative assessment plus OVA1 Preoperative assessment Preoperative assessment plus OVA1 Sensitivity, %72927899 95% CI61 to 8183 to 9668 to 8594 to 100 Specificity, %83427526 95% CI77 to 8735 to 4967 to 8120 to 33 PPV, %60366343 95% CI50 to 7030 to 4454 to 7236 to 50 NPV, %89938698 95% CI84 to 9386 to 9779 to 9088 to 100 Negative Likelihood Ratio 0.340.200.300.04 95% CI0.23 to 0.490.09 to 0.440.20 to 0.450.01 to 0.31 Prevalence27% (72/269)36% (89/247) OVA1 Results

51. OVA1 Clinical Utility 1.The OVA1 test successfully classifies patients into high or low probability of malignancy. 2.OVA1 has high sensitivity in pre- and postmenopausal women, all stages of EOC. 3.OVA1 outperforms the ACOG criteria and physician assessment. 4.When combined with other clinical information, the OVA1 test can help determine the risk of malignancy for an ovarian tumor before surgery, and facilitate decisions about referral to a gynecologic oncologist.

52. Simplified Algorithm Ovarian Tumor Physician Assessment Local surgery High RiskLow Risk Referral to GYO for Surgery OVA1 Blood Test

53. Summary Ovarian tumors are exceedingly common, particularly in premenopausal women 5-10% of American women will undergo surgery to evaluate ovarian mass in their life-time Ovarian cancer is infrequent but often fatal in advanced stages Current algorithms (which combine symptoms, imaging, physical examination, and CA-125) are useful for identifying advanced stage cancer but of limited utility in detecting early stage disease

54. Summary OVA1 is the only FDA-approved blood test for ovarian tumors to assist physicians in making preoperative referral decisions Appropriate referral to a gynecologic oncologist for women at high risk for ovarian cancer may lead to improved survival