Ovarian Cancer

Screening

DR SUJATA DHANUKA Associate Vice President- Medico-Marketing

METROPOLIS HEALTHCARE LTD

Ovarian cancer accounts for nearly 4% of all cancers among women

Fifth most common cause of cancer related death in women

Age adjusted incidence is 2 to 15 cases per 100,000 women

Ovarian cancer is commonly referred to as the ‘silent killer’ as it

causes vague symptoms and can be confused with other conditions

Most women present with advanced disease which are difficult to treat,

resulting in poor survival rate (5 year survival rate less than 35%)

Therefore diagnosing ovarian cancer in early stages becomes crucial

where tumor markers may play an important role. If ovarian cancer

is detected early, 5 year survival is dramatically improved (86%)

Facts form NICE Guidelines for Ovarian Cancer 2011

Introduction

Who should be screened?

• Women at average risk

(relative risk less than 3

times the relative risk of the

general population)

– A history of breast cancer

diagnosed at age 41 or older

and no family history of

breast or ovarian

– A history of infertility and/or

use of assisted reproductive

therapies, such as in vitro

fertilization (IVF).

– A history of endometriosis

– A history of hormone

replacement use for the

management of symptoms

related to menopause.

• Women at increased

risk (relative risk 3 to 6

times greater than that

of the general

population)

– A first degree relative

with ovarian cancer.

– A personal history of

breast cancer prior to

age 40 or A personal

history of breast cancer

in one or more close

relatives diagnosed

with breast or ovarian

cancer at any age.

• Women at inherited

increased risk

(relative risk > 6

times that of the

general population)

- Presence of a BRCA1 or

BRCA2 mutation.

- Presence of a mismatch

repair gene mutation

associated with a

hereditary cancer

syndrome known as

Hereditary Non-

Polyposis Colon

Cancer (HNPCC)

/Lynch syndrome.

3 types of patient groups:

Primary ovarian cancer markers Ovarian tumour Traditional markers

Epithelial tumours Ca-125, CEA, Ca 19.9

CA 72-4/TAG 72

Germ cell tumours

-fetoprotein,

- HCG,

Serum PLAP & LDH

Sex cord stromal tumours

Estradiol, testosterone &

inhibin

Tumour Markers Produced by Epithelial Ovarian Tumours

TUMOUR PERCENT OF TUMOURS

PRODUCING MARKERS

CA125 CA19-9 CEA PLAP

SEROUS: -

Benign

Borderline

Malignant

80

98

99

6

87

40

0

6

17

83

93

84

MUCINOUS: - Benign Borderline Malignant

0

12.5 16

73 87 86

45 87 97

0 0 0

ENDOMETROID CA 66 64 25 66

CLEAR CELL CA 75 70 15 0

UNDIFFERENTIATED 82 52 23 57

MIXED MULLERIAN tumour 80 80 40 33

CA-125 It is the most widely used tumor marker in diagnosis & prognosis of

Epithelial ovarian cancer

CA-125 as a screening test was initiated by the fact that about 83% of

patients with epithelial ovarian cancers have elevated levels

Also found in other tissues such as mesothelial cells of the pleura,

peritoneum, pericardium

However, it lacks sensitivity and specificity

In only 50% of symptomatic stage I cases are serum levels of CA 125

found to be elevated, as compared with the levels in 80% of

advanced-stage cases.

Lack of specificity Elevated in • Benign gynaecology – Endometriosis, Fibroids, Pelvic Inflammatory Disease • Other peritoneal inflammation • Cyclical variations in pre-menopausal age group • Benign conditions- Urinary retention, Chronic renal failure, Pancreatitis • Other malignant disease – gastric and lung

Lack of sensitivity

• Ca 125 not raised in 30% of women with ovarian cancer – early stage disease

Ca 125 levels U/mL Sensitivity % Specificity %

65 and greater 79 82

150 69 93

190 63 95

RMI (Risk of Malignancy Index)

It is a correlation of Clinical, USG findings and CA-125 levels

Feature RMI 1 Score RMI 2 Score

Ultrasound features:

•Multilocular cyst

•solid areas

•bilateral lesions

• Ascites

•intra-abdominal

metastases

0= none

1= one abnormality

3= two or more

abnormalities

0= none

1= one abnormality

4= two or more

abnormalities

Premenopausal 1 1

Postmenopausal 3 4

CA125 U/ml U/ml

RMI score = ultrasound score x menopausal score x CA125 level in U/ml.

The RMI 2 score was more sensitive than the RMI 1 system with results of 74 to 80% at a specificity of 89 to 92% and positive predictive values around 80%

RMI (Risk of Malignancy Index)

Jacobs I et al. Br J Obstet Gynecol.1990; 97:992-929.

RMI

Score

Sensitivity

(%)

Specificity

(%)

Likelihood ratio for

malignancy if

result is

Positive Negative

25 100 62.2 2.7 0.00

50 95.1 76.5 4.1 0.06

75 92.7 84.7 6.1 0.09

100 85.4 87.8 7.0 0.17

150 85.4 93.9 14.0 0.16

200 85.4 96.9 42.1 0.15

250 78.0 99.0 76.9 0.22

The RMI scoring system is the method of choice for predicting whether or not an

ovarian mass is likely to be malignant.

Women with an RMI score >200 should be referred to a center with experience in

ovarian cancer surgery.

HE4

Human Epididymis Protein 4 (HE4) is a relatively new marker for ovarian cancer

HE4 is over expressed in patients with ovarian cancers whereas normal ovarian

tissue has minimal production of HE4

Data suggests that HE4 and CA-125 have comparable sensitivities and

specificities; however HE4 is a better marker in the detection of early stages of

ovarian cancer

Also, HE4 has a better ability to discriminate cancer from benign disease based

on its sensitivity in this patient population

HE4 + CA-125

Recent investigations revealed that adding HE4 to CA-125 resulted in an

increased sensitivity and specificity than either marker alone

HE4 in combination with CA 125 is a more accurate tool for differential diagnosis

of ovarian cancer from a benign ovarian cyst or endometriosis (another benign

condition)

HE4 – Clinical Studies

HE4 – Clinical Studies

HE4 – Clinical Studies

ROMA (Risk of Ovarian Malignancy Algorithm)

ROMA is a risk stratification tool that combines CA 125 and HE4 levels and uses

an algorithm to compute malignancy risk in a patient with pelvic mass

ROMA correctly classifies 89% of epithelial ovarian cancers (EOC) and low

malignant potential tumors as high risk and 75% of benign disease as low risk

The negative predictive value for the combined population was 93.9%, meaning

that there was a false negative rate of only 6%

The use of this combination assay will help to ensure that patients are given

optimal care by stratifying those at high risk to tertiary care centers that

specialize in ovarian cancer

ROMA vs RMI

ROMA has an increased sensitivity compared with RMI

At a specificity of 75%, the ROMA had a sensitivity of 94%, compared to the RMI, which

achieved a sensitivity of 85%.

This difference was found to be statistically significant.

Pre & Post Menopausal

Benign (n=315) vs EOC, All stages (n=124)

Sensitivity (95% CI) Specificity (95% CI)

RMI 85% (77% to 90%) 75% (70% to 80%)

ROMA™ 94% (89% to 98%) 75% (70% to 80%)

CI: Confidence Interval

ROMA vs RMI

When you look at early stage I & II invasive EOC patients, the ROMA achieved a

sensitivity of 86%, compared with a sensitivity of only 66% for the RMI.

This difference approached statistical significance with a p value of 0.05.

Pre & Post Menopausal

Benign (n=315) vs Stage I-II EOC (n=35)

Sensitivity (95% CI) Specificity (95% CI)

RMI 66% (48% to 81%) 75% (70% to 80%)

ROMA™ 86% (70% to 95%) 75% (70% to 80%)

CI: Confidence Interval

ROMA report

The results are expressed as a percentage

Classifies patients as being high risk or low risk for epithelial ovarian cancer

Two cut-off values; one for pre-menopausal women and another for post-

menopausal women

Premenopausal ROMA > 7.4% = High Risk for epithelial ovarian cancer ROMA < 7.4% = Low Risk for epithelial ovarian cancer

Postmenopausal ROMA > 25.3% = High Risk for epithelial ovarian cancer

ROMA < % = Low Risk for epithelial ovarian cancer

HE4 @ Metropolis

LIMITATIONS –

- HE4 serum concentrations in healthy individuals were related to

age with significantly higher concentrations in postmenopausal

women.

- Renal failure and effusions were the most important sources of

false positive HE4 serum concentrations. HE4 must be

interpreted carefully in patients with renal failure.

HE4- Limitations

Summary

HE4 levels are elevated in more than 50% of tumors that do not express

CA125

Combination assay results in a higher sensitivity and specificity than the

currently accepted Risk of Malignancy Index (RMI), with 87.4% sensitivity

and 56.8% specificity

CA125 + HE4 or HE4 alone have been shown to have greater sensitivity in

patients with early stage disease than CA125 alone

The combination of CA125 + HE4 is an accurate tool to stratify women

with a pelvic mass at risk for ovarian cancer.

Ovplex

The Ovplex is a diagnostic test for ovarian cancer, based on the presence of 5 biomarkers:

CA-125 C-Reactive Protein (CRP) Serum Amyloid A (SSA) Interleukin 6 (IL 6) Interleukin 8 (IL 8)

An algorithm is used to analyze the plasma concentrations of the above biomarkers and the results are expressed as the ‘Ovplex Index’ or the probability that the woman has ovarian cancer

Ovplex targets symptomatic women and is statistically significantly better than CA 125 alone in the detection of ovarian cancer

OvPlex™ outperforms CA125 for the detection of ovarian cancer in all stages of the disease - particularly, early stage

The OvPlex™ test reports a value between 0 and 1

OvPlex™ values of greater than 0.30 are indicative of a higher than normal risk of

ovarian cancer and it is recommended that the patient be referred to a gynaec-

oncologist for further assessment. OvPlex™ values below 0.30 and CA125 < 35 U/ml is

indicative of a low risk of ovarian cancer

Based upon the analysis of Receiver Operator Characteristic (ROC) Curves, at a cut-

off threshold of 0.45, for the detection of all ovarian cancer, OvPlex™ delivers 94%

specificity and 94% sensitivity. For early stage disease only, OvPlex™ delivers

92% specificity and 94% sensitivity

OvPlex™ is likely to reduce the false negative rate of CA125 by up to 19% and the

false positive rate by up to 42%.

Summary

Displays better diagnostic performance than CA125 alone, both for the detection of

early and late stage ovarian cancer. At a threshold of 0.45, OvPlex™ displays, 94%

sensitivity and 94% specificity

May improve the detection of ovarian cancer. At equivalent specificity with CA125,

OvPlex™ delivers 97% sensitivity

May reduce the false negative rate of CA125 by up to 19% and the false positive

rate by up to 42%

Traditional CA125 values are also provided for reference.

THANK YOU