OVARIAN CANCER HAS ELUDED SCREENING AND EARLY DETECTION . SEVERAL BIOMARKERS ARE PROPOSED AND HERE IS A AN UPDATED REVIEW OF WHAT EXISTS IN THE CURRENT CLIMATE FOR THE SAME Ovarian carcinomas relate to highest death rate in gynecologic malignancies as absence of symptoms shield the disease in the early stage. Current evidences have been devoted to discovering early effective screening mechanism prior to the onset of clinical symptoms.Serum biomarkers may aid in the diagnosis of Early ovarian cancer Distinguish malignant from benign disease Prevent unnecessary surgery Improve rates of early detection. Prof Girija Wagh is the Head of the Department of OBG at Bharati University Medical College and Hospital and a well acknowledged teacher and a researcher.This overview will certainly help the learners to approach this condition with more promise

1. Diagnostic and
Prognostic Biomarkers
in ovarian cancer

2. INTRODUCTION
Ovarian carcinomas relate
to highest death rate in
gynecologic malignancies
as absence of symptoms
shield the disease in the
early stage.
Current evidences have
been devoted to
discovering early effective
screening mechanism
prior to the onset of
clinical symptoms

3. Definition: Biomarkers
Biomarker is any indicator of disease; a tumor maker is a biomarker specific
for malignancy.
A characteristic that is objectively measured and evaluated as an indicator of
normal biologic processes, pathogenic processes, or pharmacologic
response to a therapeutic intervention
EOC : abnormal findings on physical examination, imaging studies, or
laboratory tests (including serum biomarkers).
Biomarkers Definitions Working Group.. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69:89.

4. Epithelial ovarian cancer
(EOC)
Collective term used to describe primary
ovarian malignancies of
 Serous
 Endometrioid
 Clear cell
 Mucinous histologies.
Pathogenesis and clinical behavior may
differ, management strategies are
generally similar.
The high-grade serous carcinoma
histology :primary malignancies of the
fallopian tube and peritoneum :often
grouped collectively with primary epithelial
ovarian cancer.

5. Biomarkers
 Biologic markers (commonly
termed "biomarkers") that are
used to aid in the diagnosis
of EOC are an active area of
investigation
 Identified in serum, urine,
ovarian cyst fluid, ascites,
and other body fluids.
 Serum biomarkers.

6. USES OF BIOMARKERS
Serum biomarkers may aid
in the diagnosis of EOC :
Distinguish malignant from
benign disease
Prevent unnecessary
surgery
Improve rates of early
detection

7. EOC
presents
several
diagnostic
challenges:
While symptoms of EOC are usually present, they
are often nonspecific.
Difficult to differentiate between benign and
malignant adnexal masses on imaging.
Definitive diagnosis of EOC requires
histopathologic examination
Most EOCs are diagnosed at a late stage.
EOC is associated with poor prognosis

8. Biomarkers


9. Limitations of
biomarkers
 No biomarker can distinguish between the
various EOC subtypes
(ie, ovarian, fallopian tube, and peritoneal)
No serum biomarker is both highly
sensitive and specific for the diagnosis of
EOC.
Combining serum markers or using
multimodality strategies may improve
detection of malignancy.

10. The current situation
Transvaginal ultrasonography and
cancer antigen 125 (CA-125) are the
common methods for the detection of
ovarian cancer
Biomarkers as CA125, Human
epididymis protein 4 (HE4),
apolipoprotein A1, transthyretin,
transferrin, and β2-macroglobulin have
contributed to the Risk of Malignancy
index (RMI), Risk of Malignancy
Algorithm (ROMA), OVA1 algorithms
and International Ovarian Tumor
Analysis (IOTA) to distinguish benign
from malignant disease

11. Current clinical
practice
 Clinicians use all the available information
(eg, patient symptoms, imaging findings,
serum biomarker testing, menopausal status,
risk factors) to arrive at the degree of clinical
suspicion that a mass is malignant and to
decide whether the patient should undergo
diagnostic surgery or continued surveillance,
and whether referral to a gynaecologic
oncologist is appropriate.

12. CA 125 :
Cancer
antigen 125
Most widely used biomarker for
EOC, is approved by the USFDA :for
monitoring response to therapy in
patients with known EOC.
Off-label for evaluation of an adnexal
mass
Used alone or in combination with
other serum biomarkers and/or pelvic
ultrasound
510(k) Substantial Equivalence Determination Decision
Summary. US Food and Drug Administration. Available at:
http://www.accessdata.fda.gov/cdrh_docs/reviews/K042731.pd
f (Accessed on August 20, 2012)

13. CA 125 : INFO
 Gene and protein: The gene for CA 125 is called MUC16 . CA 125 antigen is a large transmembrane glycoprotein
derived from both coelomic (pericardium, pleura, peritoneum) and müllerian (fallopian tube, endometrial,
endocervical) epithelia
 The antigen complex contains two major domains, A and B.
 A portion of the extracellular domain includes repeat sequences that bind the OC125 and M11 monoclonal
antibodies.
 Assays : Many CA 125 assays in use, different test performance, clinically equivalent
 CA 125 (which reacts with OC125) and CA 125 II (which utilizes both the OC125 and M11 moieties
 While CA 125 II may be more specific, there are no data to support the superiority of one test over the other, and
both assays are widely accepted
 Serial tests should be done with the same assay, which usually means using the same laboratory.
 Normal values vary (eg, CA 125: ≤35 units/mL, CA 125 II: <20 units/mL)
 Absolute cutoffs remain clinically arbitrary, particularly for premenopausal patients.

14. CA 125: Diagnostic Performance
Limited and has a low sensitivity and a low overall specificity.
In a meta-analysis including 77 studies assessing the diagnostic performance of CA 125 for preoperative
identification of an adnexal mass suspicious for ovarian malignancy, an elevated CA 125 (defined as >35 units/mL)
had a sensitivity of 78 % and a specificity of 78 ~%
REASONS :
Not consistently produced by some histologic types of EOC, including mucinous, clear cell, and mixed müllerian
ovarian tumors
May be affected by disease stage.
Lower in early-stage compared with late-stage disease with studies reporting a wide range of sensitivities
Stage I: range 25 to 75 %
Stage II: 61 to 96 %

15. CA 125 is associated
with many conditions
other than EOC
 Premenopausal status
 Higher body mass index
(BMI)
 Prior hysterectomy
 Cigarette smoking
 Menstruation

16. CA 125 ? PREDICTION ??
CA 125 may predict ovarian cancer, but its usefulness is
hampered by its limited specificity and very low positive
predictive value (PPV).
Asymptomatic postmenopausal women :elevated CA 125
(≥30 Units/mL) was a predictor of subsequent ovarian
cancer risk
[RR] 35.9 at one year and 14.3 at five years
PLCO Cancer Screening Trial, 74% of the CA 125-
detected ovarian cancers were at an advanced stage
(stage IIIC or IV)

17. Human
epididymis
protein 4:
HE4
HE4 is approved by the FDA for monitoring of recurrent
or progressive disease in patients with EOC
May be particularly useful in detecting disease
recurrence in patients with a non-elevated CA 125
levels at time of diagnosis
Prognostic implications: In a cohort study with over
300 patients (mean age 62 y) with newly diagnosed
EOC undergoing surgical management, a preoperative
HE4 >277 pM was associated with increased mortality
(adjusted hazard ratio 1.9, 95% CI 1.1-3.3), particularly
in patients with serous histology

18. HE 4 : INFO
Gene and protein :HE4 is an antigen
derived from human epididymis protein,
a product of the WFDC2 gene that is
overexpressed in patients with serous
and endometrioid ovarian carcinoma
Assays :The laboratory reference range
of HE4 is ≤150 pM; this value represents
the upper 95th percentile for both
premenopausal and postmenopausal
patients.
Limitations : Serum HE4 may be
affected by pregnancy and age.

19. Carcinoembryoni
c antigen : CEA
Protein normally found in embryonic or
fetal tissue.
Serum levels disappear almost
completely after birth, but small amounts
may be present in the colon.
In adults, CEA may be elevated in
malignancies that produce the protein,
particularly mucinous cancers associated
with the gastrointestinal tract or ovary.

20. CEA : INFO
Assays – Individual laboratory assays vary
slightly, but the typical upper limit of normal for
CEA in nonsmokers is 3.8 micrograms per liter
(mcg/L). Smokers : 5.5 mcg/L
Limitations – CEA may also be elevated in
patients without EOC and any of the following
• Malignancy (eg, gastrointestinal [particularly colon], breast,
pancreas, thyroid, and lung carcinoma).
• Benign conditions (eg, mucinous cystadenoma of the ovary
or appendix, cholecystitis, liver cirrhosis, diverticulitis,
inflammatory bowel disease, pancreatitis, pulmonary
infections).
• Pseudomyxoma peritonei, whether the cause is of a benign
or malignant etiology.
• Cigarette smoking.

21. Ratio of CA
125 to CEA
Diagnostic implications.
In a retrospective study including 640
patients undergoing evaluation for a
pelvic mass, when CEA levels were >5
ng/mL, 68 % were found to have
nonovarian malignancies.
CA 125/CEA ratio >25, a primary
ovarian cancer was found in 82 %

22. Cancer
antigen 19-9
Mucin protein that may be elevated in
EOC but is used sparingly in ovarian
cancer management
Used to monitor disease response to
therapy or detect cancer recurrence in
patients with a documented gastric
cancer, pancreatic cancer, gallbladder
cancer, cholangiocarcinoma, or
adenocarcinoma of the ampulla of Vater.

23. Biomarkers
under
investigation
Osteopontin
Mesothelin
Lysophosphatidic acid (LPA)
Haptoglobin transthyretin
Apolipoprotein A1
Serum c-reactive protein and
OVX1

24. Biomarker panels

25. OVA 1
 Sensitivity of OVA1 for EOC, when combined with
clinical assessment, was 96%
 OVA1 correctly predicted ovarian malignancy in 92
% of patients with early-stage disease and had a
NPV 97 %.
 Risk of malignancy also increases with rising OVA
1 scores.
 1110 patients with an adnexal mass, the likelihood
for malignancy was higher for patients with higher
OVA scores and those with a high-risk versus low-
risk ovarian imaging score

26. OVERA /OVA 2

27. OVERA :
493 banked serum patient samples from the
OVA500 trial:
Overa had a sensitivity and specificity of
91& 69 %, & NPV & PPV : 97&30 %
Combined with clinician assessment, Overa
detected 75 %of malignancies that were
missed by clinician assessment alone.
Combination of imaging and Overa
improves the preoperative assessment of an
adnexal mass.

30. The risk of malignancy index (RMI) is a
multimodal approach that combines pelvic
ultrasound ("U"), menopausal status ("M"), and
serum CA 125 into an index score ("I"; I = U x M
x CA 125) to predict the risk of ovarian cancer in
patients with an adnexal mass
"U" – The ultrasound result is scored 1 point for
each of the following characteristics: multilocular
cyst, solid areas, metastases, ascites, and
bilateral masses. U = 0 for an ultrasound score of
0 points, U = 1 for an ultrasound score of 1 point,
and U = 3 for an ultrasound score of 2 to 5
points.
"M" – Menopausal status is scored as 1 =
premenopausal and 3 = postmenopausal.
"Postmenopausal" is defined as no menses for
more than one year or a patient over 50 years of
age who has had a hysterectomy.
CA 125 – Serum CA 125 is measured in
units/mL.
A number of modifications to the RMI have since been proposed
(the versions are referred to as RMI I through IV), which involve
assigning different values to each variable
Patients with an RMI index score of ≥250 are referred to a specialist
RMI I and II (using a cutoff score of 200) had the best diagnostic performance (RMI I: sensitivity 78 and specificity 87
percent; RMI II: sensitivity 79 and specificity 81 percent)

31. ADNEX model
The adnexa (ADNEX) model is unique in that
it is intended to predict not only whether an
adnexal mass is malignant, but also identify
other outcomes: benign, borderline, stage I
invasive, stage II to IV invasive, and
secondary metastatic adnexal tumors .
Assessment of Different Neoplasias in the Adnexa

33. The ADNEX model combines three clinical and six
ultrasound predictors:
●Age
●Serum CA 125
●Type of center (ie, oncology centers [defined as tertiary referral centers with a specific gynecologic oncology unit], other hospitals)
●Ultrasound features:
•Maximum diameter of lesion
•Proportion of solid tissue (maximum diameter of the largest solid component divided by the maximum diameter of the lesion)
•>10 cyst locules
•Number of papillary projections (0, 1, 2, 3, >3)
•Acoustic shadows
•Ascites

34. Conclusion
Use of serum biomarkers for the
diagnosis of epithelial ovarian
cancer (EOC) is an active area of
investigation.
Biomarkers or panels of biomarkers
are generally used in combination
with each other or with imaging to
arrive at the degree of clinical
suspicion that an adnexal mass is
benign or malignant and whether
referral to a gynecologic oncologist
is appropriate.
No biomarker can distinguish
between the various EOC subtypes
(ie, ovarian, fallopian tube, and
peritoneal) and no serum biomarker
is both highly sensitive and specific
for the diagnosis of EOC

35. Serum
biomarkers
CA 125 – CA 125 is approved for monitoring response to therapy in
patients with known EOC; it is also the most used biomarker for the
evaluation of adnexal masses for EOC, although it is not approved for
this indication. CA 125 has a low sensitivity, particularly for early-stage
ovarian cancer, and low specificity, particularly in premenopausal
patients.
HE4 – HE4 is approved for monitoring for recurrent or progressive
disease in patients with EOC and may be particularly useful in detecting
disease recurrence in patients with a nonelevated CA 125 levels at time
of diagnosis.
CEA – CEA may be elevated in malignancies associated with the
gastrointestinal tract or ovary; the ratio of CA 125 to CEA has diagnostic
implications with higher levels being associated with primary ovarian
malignancies.
CA 19-9 –may be elevated in EOC but is used sparingly in ovarian
cancer management

36. PANELS
Commercially available biomarker
panels, including OVA1, Overa, Risk of
Malignancy Algorithm (ROMA), Risk of
Malignancy Index (RMI), and the
Assessment of Different Neoplasias in
the Adnexa (ADNEX) model are used
to assess the likelihood of malignancy
in patients in whom surgery for an
adnexal mass is planned.
These tests should not be used alone
to decide whether to proceed with
surgical exploration for an adnexal
mass.
These tests have not been studied for
ovarian cancer screening.