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 125th experimental attempt!
• Normal value
• CA 125 ≤35 U/mL
New England Journal of Medicine
(1983)

4. Potential use of CA125
1. Monitor response of ovarian cancer to treatment
2. Monitor women with history of ovarian cancer to detect recurrence
3. Ovarian cancer screening in asymptomatic women
4. 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
0
500
1000
1500
2000
2500
Pretreatment Chemotherapy
#1
Chemotherapy
#2
Chemotherapy
#3
Chemotherapy
#4
CA125Value
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. 0
100
200
300
400
500
600
700
800
900
Pretreatment Completion
of treatment
12 months 15 months 18 months 21 months 24 months
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 2nd 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 early 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 ovarian 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
- Colon, 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
1. Monitor response of ovarian cancer to treatment
2. Monitor women with history of ovarian cancer to detect recurrence
3. Ovarian cancer screening in asymptomatic women
4. Evaluate women with a pelvic mass planning for surgery

40. Potential use of CA125
1. Monitor response of ovarian cancer to treatment
2. Monitor women with history of ovarian cancer to detect recurrence
3. Ovarian cancer screening in asymptomatic women
4. 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