New Multianalyte Assay with Algorithmic Analyses for Adenexal Mass

1. Risk of Ovarian Malignancy
Algorithm (ROMA)
Dr. Bikash Chaudhury
HOD Biochemistry

2. Outline of the Presentation
• Overview of Ovarian Cancer
• Current clinical tools to assess Ovarian Cancer
• Ca 125 & HE4
• MAAAs
• ROMA
• Summary

3. Ovarian Cancer is a Major Women's Health Problem
1ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
• High morbidity and mortality
• Appropriate treatment improves survival1
– Oncology specialists
– High volume centres
• Need better risk assessment tools

4. Epidemiology
• 5th leading cause of cancer deaths in women and affecting at
least 1 in 70 women
• 5-year survival rate is around 80-90%for patients with Stage I
disease and only 30%with Stage III and Stage IV
• In India, Ovary is the third leading site of cancer among women.
• The age adjusted incidence rates of ovarian cancer vary between
5.4 to 8.0 per 1,00,000 populations in different parts of the
country.

5. Ovarian Cancer: browsing through basics

6. Survival Rates for Ovarian Cancer Need to be Improved
Ovarian Cancer 5-yr Survival Rate by Stage
Stage Distribution
at Diagnosis
Survival Rate
Heintz APM, et al. FIGO Annual Report on the Results of Treatment in Gynecologic Cancers. 2000; 24 :107-138.
Holschneider CH, Berek JS. Semin Surg Oncol. 2000;19:3-10.
Stage I 20-27% 73-93%
Stage II 5-10% 45-70%
Stage III 52-58% 21-37%
Stage IV 11-17% 11-25%

7. Current Clinical Tools to Assess Risk of Ovarian Cancer
• History
• Physical exam
• Imaging (US, CT and MRI)
• Tumor markers (CA 125)

8. “Top Ten” Biomarkers for
Detection of Ovarian Cancer
• CA 125
• HE4
• CA 15-3
• CA 72-4
• B7-H4 (Ov-110)
• Transthyretin
• IGFBP-2
• SMRP (Mesomark™)
• HK6
• Cytokeratin 19
(CYFRA 21-1)

9. Ultrasound Assessment of Pelvic Mass
• Limitations of Ultrasound
– Not all morphologic variables are commonly reported or
measured
– User variability (tertiary care vs community)
– Ultrasound reporting is not standardized
– Quality and complexity of machine (e.g. Doppler)
– Complex algorithms
Moore RG et al. J Clin Oncol. 2007;25:4159-4161.

10. CA125 HAS BEEN THE MOST
COMMONLY
USED MARKER IN THE PREDICTION OF
OVARIAN CANCER FOR YEARS
TOGETHER……..BUT THE PARADIGM IS
NOW CHANGING, DUE TO THE
SHORTCOMINGS OF CA125 !!

11. Limitations of CA125 as a marker for ovarian cancer
Non specificity to ovarian cancer:
• Besides ovarian cancer, CA 125 levels are raised in
several other non-cancerous conditions like endometriosis,
pelvic inflammatory disease and benign ovarian cysts
• Elevated CA125 levels have also been commonly noted in
physiological states like menstruation and pregnancy.

12. Limitations of CA125 as a marker for ovarian cancer
Therefore, the rate of false positive results is
high, when CA 125 is used as a biomarker of
ovarian cancer.
Infact, this tendency towards false positivity is
further augmented when CA 125 is used for
detecting ovarian cancer in pre-menopausal
women.

13. Cannot be employed as a biomarker for early detection of
ovarian cancer:
• Less sensitive in detecting patients with early ovarian cancer.
Elevated levels of CA 125 are reported only in 50% of Stage 1
ovarian cancer cases
• This limits its use to only biomarker for monitoring therapeutic
efficacy in ovarian cancer.
Limitations of CA125 as a marker for ovarian cancer

14. HE4 (Human Epididymal Protein 4)
• Initially discovered to be over-expressed in
epididymal tissue and later in ovarian cancer tissue.
• Tumour expression is histologic dependent.
 Most Serous and Endometrioid tutors
 50% of Clear Cell Tumours
 0 % of Mucinous tumours.

15. Why HE4 ???
HE4 overcomes some of the drawbacks of
CA125 as a biomarker for ovarian cancer

16. HE4 as a biomarker for ovarian cancer
• Detects ovarian cancer with a 67% sensitivity at a specificity
level of 96%. Therefore, false positivity is significantly lower as
compared to CA125 testing
• Differentiates between ovarian cancer and benign ovarian
Conditions
• Elevated HE4 levels are expressed in early stage ovarian
cancer and hence HE4 testing can detect Stage I disease

17. HE4 as a biomarker for ovarian cancer
• Can be effectively employed for therapeutic monitoring and
recurrence estimations. Recent clinical evidence testifies that
levels elevate at least 5-8 months prior to relapse of ovarian
cancer
• The positive predictive value of HE4 as a biomarker is higher
as HE4 predictions have shown a significantly greater positive
correlation with PET/CT results

18. Should HE4 completely replace CA 125?
Is it time to totally abandon CA 125 as a
marker for ovarian cancer?
“NO”……………….
Lets explore what recent clinical
evidence recommends !!

19. HE4+CA125: In conjunction with each other
• Clinical evidence recommends that HE4 testing
should be combined with CA 125 measurements.
• The diagnostic accuracy and sensitivity of the
combination of HE4 and CA125 is significantly
higher than either of the biomarkers used alone.

20. Snapshots of Clinical Evidence:HE4+CA125
Hamed et al; 2013

21. Snapshots of Clinical Evidence:HE4+CA125
Li et al; 2009

22. Snapshots of Clinical Evidence:HE4+CA125
Moore et al; 2009

23. We can Improve the Care for Ovarian Cancer Patients
• Better risk assessment
• Improved patient care and management

24. Need New Tools to Better Assess Ovarian
Cancer Risk

25. Multianalyte Assays with Algorithmic Analyses
(MAAAs)
• Multianalyte Assays with Algorithmic Analyses (MAAAs) are
procedures that utilize multiple results derived various assays
• The individual component procedures are not reported
separately.
• MAAAs are then used in algorithmic analyses to derive a single
result, reported typically as a numeric score or probability.
• MAAAs are typically unique to a single vendor.

26. ROMA Will Improve Treatment of
Women with Adnexal Mass

27. What is ROMA?
• Current clinical evidence recommends combining HE4 with
CA125 for screening, monitoring and prognostication of ovarian
cancer.
• Risk of ovarian malignancy algorithm (ROMA) as the name
suggests, is a US-FDA approved risk stratification tool for
ovarian cancer.

28. How does ROMA work?
Under the ROMA stratification, 3 patient variables are used:
1. HE4 levels
2. CA125 levels
3. Patient’s menopausal status
Based on these variables, a numerical score is derived for each
individual patient by using an established formula
The score determines the risk of malignancy in an individual
patient, classified as either high or low.

29. How to Calculate ROMATM

30. Interpretation (in the current set-up):
• Pre-menopausal : 11.4 %
– < 11.4 % : Low risk of finding epithelial ovarian cancer
– ≥ 11.4 % : High risk of finding epithelial ovarian cancer
• Post-menopausal : 29.9 %
– < 29.9 % : Low risk of finding epithelial ovarian cancer
– ≥ 29.9 % : High risk of finding epithelial ovarian cancer

31. ROMA score is intended for use in women who
meet the following criteria :
• Are over 18 years of Age
• Have an ovarian mass
• Surgery is planned
• Not yet referred to an oncologist

32. Caution for use of ROMA Score :
• The test is not intended as screening or stand alone diagnostic
assay for ovarian cancer.
• ROMA has not been validated for following groups :
– Women previously treated for malignancy
– Women Currently being treated with chemotherapy
– Pregnant women
– Women < 18 years of age.
• ROMA should not be used without an independent clinical /
radiological evaluation and is not intended to be a screening test or
to determine whether a patient should proceed to surgery.

33. Snapshots of Clinical Evidence: ROMA
Kim et al; 2011

34. Snapshots of Clinical Evidence: ROMA

36. ROMA Demonstrates Superior Performance
• Correctly identifies 94% of Epithelial Ovarian
Carcinomas
• Performs better than other markers individually
• Simple and easy to use
• Quantitative test
• No subjective data
• Assigns a risk for malignancy