- Ovarian cancer is the 4th leading cause of cancer death in women in the US, with a 5-year survival rate of only 35% for advanced cases. Most cases are diagnosed at an advanced stage due to non-specific early symptoms. - There is no consensus on screening guidelines due to a lack of evidence that screening reduces mortality. Current screening methods like ultrasound and CA-125 lack sensitivity and specificity. - Several large trials are underway to evaluate new screening strategies using ultrasound, tumor markers, and genetic testing to enable earlier detection when treatment is most effective. Improved screening methods are needed to reduce ovarian cancer mortality rates.

1. Ovarian Cancer Screening Mati Zolti M.D. Department of Obstetrics & Gynaecology Sheba Medical Center Tel Hashomer, Israel

2. Ovarian Cancer: Burden of suffering 4 th leading cause of cancer death in women in the U.S. (after lung, breast and colon) Overall 5-year survival rate is 35% The “silent killer”: asymptomatic in early stages 75% diagnosed with advanced stage disease; 5-year survival only 10-28% Woman’s lifetime risk of dying from ovarian cancer is 1.1%

3. Ovarian Cancer in Israel New Cases : 220 Death : 95 Median age : 51 (2XXX)

4. Ovarian Cancer Symptoms of ovarian cancer : asymptomatic Lower abdominal pain/pressure mass Abdominal enlargement Vaginal bleeding Urinary/bowel symptoms

5. Types of Ovarian Tumors Functional Follicle cyst Corpus luteum cyst Theca lutein cyst Inflammatory Tubo-ovarian abscess Benign tumors/cysts * Endometriotic cyst Brenner tumor Benign teratoma (dermoid cyst) Fibroma *Rare or very rare potential for malignancy Malignant (or malignant potential) Malignant teratoma Endometrioid carcinoma Dygerminoma Secondary ovarian tumor Cystadenoma, cystadenocarcinoma (>50% for serous, ~5% for mucinous) Granulosa cell tumor (15-20%) Arrhenoblastoma (<20%) Theca cell tumor (<1%)

6. Epithelial Ovarian Cancer Overall 5-year survival rate is 75-95% if cancer confined to ovaries; decreases to 10-17% if distant metastases Survival improved when cancer detected in early stage Only 25% diagnosed in Stage I

7. Early Detection and Mortality No direct evidence that women with early stage cancer found on screening have lower mortality than women with more advanced disease Indirect evidence supports benefits of early detection: Most important prognostic factor in patients with advanced ovarian cancer is tumor burden after initial debulking Surgical debulking and chemo more effective when cancer detected early

8. The challenge Natural history of ovarian cancer not well understood No well-defined precursor lesion Length of time from localized tumor to dissemination is unknown Multiple efforts underway to develop effective screening method for early detection

9. Risk factors The majority of women with ovarian cancer have no known risk factors Most significant risk factor is genetic predisposition

10. Risk factors: Heredity Up to 10% of epithelial ovarian cancer cases are familial 3 familial syndromes familial breast-ovarian cancer syndrome site-specific ovarian cancer cancer family syndrome (Lynch type II) Familial breast-ovarian cancer and site-specific ovarian cancer syndromes both associated with mutations of the BRCA1 suppressor gene; account for 90% of familial ovarian cancers Rollins,G. Ann Int Med 2000;133:1021-1024

11. Additional Risk Factors Age Women over age 50 account for ~80% of all cases (ave. age at dx is 61) Reproductive history early menarche, nulliparity or age >30 at first child-bearing, and late menopause Fertility drugs prolonged use of Clomid, especially without achieving pregnancy Personal history of breast cancer Hormone replacement therapy > 10 years May be associated with 30% increased risk Talcum powder Some studies have shown slightly increased risk in women who use talc powder on genital area American Cancer Society, 2001

12. Protective factors Multiparity: First pregnancy before age 30 Oral contraceptives: 5 years of use cuts risk nearly in half Tubal ligation Hysterectomy Lactation Bilateral oopherectomy

13. Delays in Diagnosis Lack of severity and specificity of early symptoms Early signs/symptoms may include bloating, gas, indigestion, abdominal fullness or discomfort, constipation, pelvic pressure, urinary frequency, abnormal vaginal bleeding, fatigue, back pain, leg pain Early stage tumors difficult to detect on pelvic exam

14. Diagnostic tools History Pelvic Exam (including rectal) Transvaginal Ultrasound – detection of masses and mass characteristics Tumor markers – CA-125, LPA (plasma lysophosphatidic acid) CT – assess spread to LN, pelvic and abdominal structures MRI – best for distinguishing malignant from benign tumors

15. Work-up of Adnexal Mass Age Size of mass Unilateral vs. bilateral CA-125 levels Ultrasound configuration Color-flow Doppler flow Presence of symptoms Must first categorize as functional, benign neoplastic or potentially malignant Diagnostic approach depends on:

16. Diagnostic approach If premenopausal and asymptomatic, with unilateral, mobile, simple cystic mass <8-10cm and no family history, can observe for 4-6 weeks and then repeat TVUS and pelvic exam. If resolved, no further work-up necessary If larger or unchanged, or if character of mass has changed on TVUS, surgical evaluation required

17. Diagnostic Approach If postmenopausal and asymptomatic, with unilateral simple cyst <5cm AND normal CA-125, can follow closely with repeat TVUS All other postmenopausal women with ovarian mass require surgical evaluation

18. Surgical Evaluation Refer to Gyn-Onc specialist Exploratory laparotomy has been the gold standard and includes: Peritoneal washings for cytology Evaluation of frozen section Complete staging procedure if borderline or malignant tumor on frozen section

19. Surgical Evaluation Laparoscopy can be considered in premenopausal woman with ovarian mass small enough to remove via laparoscopic approach; not recommended if high suspicion for malignancy

20. Stages Ia, Ib, Ic

21. Stages IIa, IIb, IIc

22. Stages IIIa, IIIb, IIIc

23. Stage IV

24. Treatment Depends on staging, tumor type, age, desire for future fertility Can include surgery, chemotherapy and/or radiation therapy Clinical trials are ongoing

25. Surgical treatment Primary debulking and cytoreduction; may include: Bilateral salpingo-oopherectomy Hysterectomy Lymphadenectomy (para-aortic, inguinal) Omentectomy “brushing” of diaphragm, examination of liver

26. Chemotherapy and Radiation Usually 6 cycles of chemotherapy Cisplatin (or Carboplatin) plus Paclitaxel most commonly used combination therapy XRT

27. Why screening for ovarian cancer is so difficult? Anatomic location of the ovary, not easily accesible Lack well defined precursor lesion and has poorly defined natural history Low prevalence, need exquisite specificity to avoid unnecessary intervention Lack of a good method

28. Screening Strategies Ultrasound (transvaginal vs transabdominal) Color-flow doppler CA-125 Other tumor markers

29. Ultrasound Both tranabdominal and transvaginal techniques identify enlarged ovaries or abnormal morphology; TVUS has better resolution One large study of TVUS underway has reported sensivity of 81% and specificity of 98.9% Major limitations are poor PPV in asymptomatic women and inability to detect malignances when ovaries are normal size Allows earlier stage detection

30. Color-flow Doppler Used in conjunction with TVUS Measures resistance in blood vessels supplying the ovaries May provide additional information to help distinguish malignant from benign masses

31. CA-125 Sustained elevation in 82% of women with advanced ovarian cancer, but fewer than 1% of healthy women Poor sensitivity (elevated in only 50% of women with Stage I disease) Poor specificity (elevated in many gynecologic and non-gynecologic malignancies as well as benign conditions)

32. CA-125 Malignant conditions Cervical CA Fallopian tube CA Endometrial CA Pancreatic CA Colon CA Breast CA Lymphoma Mesothelioma Benign conditions Endometriosis/Menses Uterine fibroids PID Pregnancy Diverticulitis Pancreatitis Liver disease Renal failure Appendicitis IBD

33. Lysophosphatidic acid (LPA) Tumor marker being investigated for screening Phospholipid with mitogenic and growth factor-like actions In 1 small study LPA was detected in 9 of 10 patients with Stage I ovarian CA, 24/24 with advanced cancer, and 14/14 with recurrent cancer. Only 28 of 47 pts had elevated CA-125, including 2 of 9 with Stage I disease

34. Current Screening Guidelines “ Routine screening for ovarian cancer by ultrasound, the measurement of serum tumor markers, or pelvic examination is not recommended. There is insufficient evidence to recommend for or against the screening of asymptomatic women at increased risk of developing ovarian cancer.”

35. Screening Guidelines– cont’d NIH Consensus Conference (1994) women with presumed hereditary cancer syndrome should undergo annual pelvic exams, CA-125 measurements, and TVUS until childbearing is complete or at age 35, at which time prophylactic bilateral oopherectomy is recommended. ACP counsel high risk women about potential harms and benefits of screening

36. Screening, cont’d American Cancer Society, AAFP and ACOG do not recommend screening for ovarian cancer in the general population Canadian Task Force on Periodic Health Examination “insufficient evidence to recommend for or against screening in high-risk women”

37. Where do we go from here? Several strategies for screening currently under investigation TVUS as primary screening method Multimodal strategy using CA-125 as initial indicator and if elevated, TVUS used for secondary testing LPA (phospholipid with mitogenic and GF-like actions) may be more sensitive than CA-125 in detecting early stage cancers

38. Ovarian Cancer Screening Trials The United Kingdom Collaborative Trial of Ovarian Cancer Screening: will compare TVUS and multimodal screening to control The European Study: RCT to screen women with TVUS at 18-month or 3-year intervals The NIH Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: 10-year study using multimodal strategy

39. Take home points Screening not indicated at this time ASK about family history of cancers LISTEN when women present with non-specific GI complaints; include OC in DDx DO perform careful bimanual exam and rectal exam as part of pelvic exam Refer women with + Family Hx to GynOnc

40. Marker Updates - Ca 125 • Approved marker to test for recurrence • Remains the single most sensitive and specific marker for ovarian cancer to date • Addition of other markers might improve sensitivity and specificity • Longitudinal assessment may also improve sensitivity and specificity

41. ROCA: Risk of Ovarian Cancer Algorithm

42. Marker Updates—OvaCheck In 2002, a paper in Lancet described an approach to ovarian cancer screening using mass spectrometry to create protein patterns from blood and computer software to find patterns associated with disease. In 2003, the software developer announced it would market a test called OvaCheck for screening high risk populations. The test would be offered as a “homebrew” diagnostic circumventing the need for premarket review. In July 2004, the FDA ruled that the computer software was, in fact, a medical device and would require review. In 2004 and 2005, the developer announces partnerships with several hospitals to further validate the assay and patents “A process for distinguishing between biological states based upon hidden patterns from biological data.”

43. Marker Updates—Ciphergen Panel Collaborating with several academic centers, Ciphergen has sought to combine mass spectrometry with Protein Chip arrays including some antibody-based chips In 2004, a paper in Cancer Research identified three biomarkers:Apoliporotein A1 and transthyretin (both downregulated), and a fragment of inter-α-trypsin (up-regulated) in ovarian cancer. The three markers plus CA 125 had a sensitivity of 74% for early stage disease and specificity of 97%. An update in 2006 CEBP, found somewhat lower sensitivity and specificity when benign disease included. Testing is underway on a panel of 7 markers.

44. Marker Updates - Yale’s Panel In a paper in PNAS in 2004, a group led by Yale investigators used antibody microarrays to identify four proteins that distinguished ovarian cancer: leptin, prolactin, osteopontin, and insulin-like growth factor II. The combination had a sensitivity of 95% and specificityof 95% for distinguishing ovarian cancer, all stages. In 2006, Yale announced it would partner with a Chinese diagnostics company to develop this panel as a screening test for ovarian cancer.

45. Marker Updates - Luminex Panel In an AACR abstract, Lokshin et al from the Univ. of Pittsburgh used the “bead-based” Luminex system for multiplexing many antibody-based assays to distinguish ovarian cancer cases from controls. Eight biomarkers had the highest diagnostic power including: CA 125, CA 19-9, EGFR, G-CSF, Eotaxin, IL-2r, cVCAM, and MIF. For postmenopausal ovarian cancer the sensitivity was 100% at a specificity of 98.6%. Has partnered with Pittsburgh biostatisticians to develop an algorithm to combine the markers.