Topic-Driven Round Table on Ovarian Cancer: Everything You Need to Know About CA-125

Women with ovarian cancer joined Julie Larson, LCSW and peers via video or phone to talk about "Everything You Need to Know About CA-125"

1. CA125 October 2020 Melissa Frey M.D. Assistant Professor Division of Gynecologic Oncology   Weill Cornell Medicine Obstetrics and Gynecology  

2. Biomarker An indicator of disease “A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to a therapeutic intervention.” United States National Institutes of Health

3. CA125 Cancer Antigen 125 (CA125) Biomarker of epithelial ovarian cancer Glycoprotein on surface of ovarian cancer cells The 125 th experimental attempt! Normal value CA 125 ≤35 U/mL New England Journal of Medicine (1983)

4. Potential use of CA125 Monitor response of ovarian cancer to treatment Monitor women with history of ovarian cancer to detect recurrence Ovarian cancer screening in asymptomatic women Evaluate women with a pelvic mass planning for surgery

5. 1. Monitor response of ovarian cancer to treatment

6. Monitor response of ovarian cancer to treatment Ovarian cancer diagnosis Ovarian cancer remission CA125 measurements https://thenounproject.com

7. Monitor response of ovarian cancer to treatment Only FDA approved indication for CA125 Gynecologic Cancer Intergroup (GCIG) Criteria for CA 125 response: Criteria Response > 50% reduction of CA125 compared to pretreatment sample Progression > Doubling of CA125 from upper limit of normal or from nadir value

8. Monitor response of ovarian cancer to treatment CA125 Value https://thenounproject.com

9. 2. Monitor for ovarian cancer recurrence

10. Monitor for ovarian cancer recurrence Ovarian cancer Remission Ovarian cancer recurrence CA125 measurements https://thenounproject.com

11. Monitor for ovarian cancer recurrence Monitor women with prior history of ovarian cancer for recurrence of cancer CA125 obtained at time of each surveillance visit

12. Monitor for ovarian cancer recurrence Gynecologic Cancer Intergroup (GCIG) Criteria for disease progression Woman with elevated CA125 that normalized with treatment CA125 > 2x upper limit of normal on 2 occasions at least 1 week apart Woman with elevated CA125 that NEVER normalized with treatment CA125 > 2x lowest value on 2 occasions at least 1 week apart Woman with NO prior elevation in CA125 CA125 > 2x lowest value on 2 occasions at least 1 week apart

13. Monitor for ovarian cancer recurrence CT scan – recurrent ovarian cancer Completion of treatment (normal CA125) CA125

14. What are the advantages of monitoring CA125 for recurrence?

15. Reassurance (for the patient and the physician) Survey of women with gynecologic cancer* 85% of women felt it was important to know about CA125 72% of women felt safe when their most recent CA125 was normal * Mayerhofer K, et al. Anticancer Res 2000

16. Earlier diagnosis of ovarian cancer recurrence CA125 rises about 4.5 months before women experience symptoms Earlier treatment of recurrent disease can reduce inpatient care for cancer-related problems Ascites Bowel obstruction Opportunity for 2 nd surgery

17. Opportunity for secondary cytoreduction Study of women who had a secondary cytoreduction* Women who had shorter interval between rise in CA125 and surgery had better chance of successful surgery Successful cytoreduction – 5 weeks Unsuccessful (suboptimal) cytoreduction – 16 weeks Suggests that acting expeditiously upon a rising CA 125 level improve surgical outcomes *Fleming ND, et al. Gynecologic Oncology 2011 Controversy – does secondary cytoreduction improve survival? GOG 213 – No DESKTOP III - Yes

18. What are the disadvantages of monitoring CA125 for recurrence?

19. Normal results can be deceptive ~50% of early ovarian cancer is associated with normal CA125

20. CA125 can result in patient anxiety CA125 psychosis CA125 preoccupation independent predictor of distress and depressive symptoms Ovarian cancer Remission CA125 measurements Ovarian cancer Recurrence https://thenounproject.com

21. Benefit of e arly diagnosis of recurrence? Detecting recurrence by elevated CA125 results in… Early start to chemotherapy More time on chemotherapy Option for secondary surgery? Reduction in quality of life NO PROVEN BENEFIT IN OVERALL SURVIVAL!

22. MRC OV05/EORTC 55955 collaborative trial Ovarian cancer Remission CA125 checked every 3 months Early chemotherapy Chemotherapy within 28 days 2x upper limit of normal (~70) Delayed chemotherapy Treatment at time of clinical or symptomatic relapse *Rustin GJ. et al. Lancet. 2010.

23. MRC OV05/EORTC 55955 collaborative trial 1442 women registered for trial Women with unblinded CA125 started chemotherapy 5 months earlier Women with early chemotherapy had worse quality of life No difference in overall survival between groups from time of randomization Early chemotherapy – 26 months Delayed chemotherapy – 27 months *Rustin GJ. et al. Lancet. 2010.

24. MRC OV05/EORTC 55955 collaborative trial Recurrence diagnosed (CA125) Time on chemotherapy Recurrence diagnosed (symptoms/exam) Time on chemotherapy

25. Overall survival was the same! MRC OV05/EORTC 55955 collaborative trial Recurrence diagnosed (CA125) Time on chemotherapy Recurrence diagnosed (symptoms/exam) Time on chemotherapy

26. MRC OV05/EORTC 55955 collaborative trial Recurrence diagnosed (CA125) Time on chemotherapy Recurrence diagnosed (symptoms/exam) Time on chemotherapy Time off of treatment with no symptoms

27. Does knowing this information about CA125, recurrence and survival change the decision ovarian cancer patients make about monitoring?

28. Monitoring CA125 – audit after OVO5/EORTC 55955 trial Patients counseled about results and given option for CA125 surveillance 80% of patients selected not to have routine CA125 assessment 20% of patients selected to have routine CA125 assessment 3% selected not to be informed of results Conclusion: If patients are given sufficient information about the role of routine CA125 measurements during follow-up, the majority decide against CA125 monitoring and hence, avoid these blood tests * Krell D. et al. Int J Gynecol Cancer. 2017.

29. 3. Ovarian cancer screening

30. Ovarian cancer screening CA125 is not a good screening test due to low sensitivity and low specificity Low sensitivity Many women with ovarian cancer will have normal CA125 Only ~ 50% of patients with stage I ovarian cancer have elevated CA125 Low specificity Many women with elevated CA125 will NOT have ovarian cancer Many other benign and malignant disease can cause an elevated CA125

31. Causes of elevated CA125 Benign (non-cancerous) Leiomyomas (fibroids) Endometriosis Pelvic inflammatory disease Pregnancy Hemorrhagic ovarian cyst Liver disease Pancreatic disease Diverticulitis Malignant Colon cancer Breast cancer Pancreatic cancer Bladder cancer Liver cancer Lung cancer Endometrial cancer

32. U.S. Preventive Services Task Force statement on ovarian cancer screening (2018) Major trials of promising ovarian cancer screening tools have null findings to date among healthy average-risk women, and there are considerable harms associated with screening. CA125 ovarian cancer screening – General population Prostate, Lung, Colon, Ovarian cancer screening trial (PLCO) and The U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) Evaluation of women with concurrent sonograms and CA125 No difference in ovarian cancer mortality in women on screening arm 74% of CA125-detected ovarian cancers were stage IIIC/IV Harms of ovarian cancer screening Unnecessary surgery following false-positive test Unnecessary removal of one or both ovaries Major surgical complications

33. CA125 o varian cancer screening – high risk population Women with hereditary ovarian cancer syndromes BRCA1/2 mutations Lynch syndrome BRIP1 mutation RAD51C mutation RAD51D mutations National Comprehensive Cancer Network Guidelines: Transvaginal sonogram combined with CA125 for ovarian cancer screening, although uncertain benefit, may be considered at the clinician’s discretion started at age 30-35 years

34. United Kingdom Familial Ovarian Cancer Screen Study (UK FOCSS) 3,500 women at increased ovarian cancer risk Annual CA125 and pelvic sonogram Percentage of women diagnosed ovarian cancer with >= Stage IIIC Screened within 1 year of diagnosis – 26.1% Not screening within 1 year of diagnosis – 85.7% *Rosenthal AN. et al. J Clin Oncol. 2013. Detection of lower-stage disease in women who adhered to screening has led to a decision to decrease the screening interval to four months for the next phase of the study

35. UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)  Sequential testing Annual CA125 Pelvic sonogram if CA125 abnormal as determined by an computer algorithm Screening resulted in higher likelihood of detecting early stage cancer Screening group – 39% No screening group – 26% Menon U. et al. J Clin Oncol. 2005. Jacobs IJ. Lancet. 2016. A mortality benefit was suggested for average-risk women screened with annual CA 125, followed by TVUS if the CA 125 result was abnormal as determined by an algorithmic guideline

36. 4. Pre-surgical evaluation for a pelvic mass

37. Pre-surgical evaluation for a pelvic mass Marker CA125 American College of Obstetricians and Gynecologists - Postmenopausal + Adnexal mass + CA125 > 35  refer to gynecologic oncologist - No cut off for premenopausal women HE4 Better option for premenopausal patients? CEA Cancers - C olon, breast, pancreas, thyroid, lung Non-cancers - Cigarette smoking, benign mucinous ovarian/ appendiceal tumors, cholecystitis, liver cirrhosis, diverticulitis, inflammatory bowel disease, pancreatitis, pulmonary infections CA19-9 Cancers – gastric, pancreatic, gallbladder

38. Pre-surgical evaluation pelvic mass - Biomarker panels OVA1 FDA approved 2009 5 serum biomarkers - CA 125 II, beta 2 macroglobulin, transferrin, transthyretin, apolipoprotein A1 ROMA (risk of malignancy algorithm) FDA approved 2011 2 serum biomarkers (CA125, HE4) + menopausal status

39. Potential use of CA125 Monitor response of ovarian cancer to treatment Monitor women with history of ovarian cancer to detect recurrence Ovarian cancer screening in asymptomatic women Evaluate women with a pelvic mass planning for surgery

40. Potential use of CA125 Monitor response of ovarian cancer to treatment Monitor women with history of ovarian cancer to detect recurrence Ovarian cancer screening in asymptomatic women Evaluate women with a pelvic mass planning for surgery

41. CA125 during a pandemic? Weighing risk of exposure to COVID-19 with benefit of CA125 result Survey of 603 women with ovarian cancer March 30, 2019 – April 13, 2019 24% of patients reported delay in oncology physician appointment 15% of patients reported delay in cancer-related labs

42. CA125 during a pandemic? Option to collect CA125 at convenient outpatient facilities Avoiding travel Maintaining social distancing Using telemedicine / video visits for discussion of results

43. CA125 October 2020 Melissa Frey M.D. Assistant Professor Division of Gynecologic Oncology   Weill Cornell Medicine Obstetrics and Gynecology