OVARIAN CANCER Current Serum Markers and Their Clinical Applications BY ALICIA ALGECIRAS-SCHIMNICH, PhD, DABCC

Clinical Laboratory News, March 2013
Excerpts by: Leticia M. Acosta, M.S.

The American Cancer Society estimates that 22,280 new cases and 15,500 deaths from ovarian cancer occurred in the U.S. in 2012. The disease is the leading cause of death from gynecological cancers, as well as the fifth-leading cause of cancer deaths in women. Unlike breast cancer in which great strides have been made in detecting early–stage disease and saving lives, many women die of ovarian cancer because the early stages have no obvious symptoms and no screening tests have proven to be effective. 

Today, only a limited number of tumor markers for ovarian cancer have been cleared by the U.S. Food and Drug Ad-ministration (FDA). Tumor marker applications range from screening and monitoring therapy response or recurrence to selecting treatment and predicting prognosis.

Origin and Classification

Approximately 88% of ovarian cancer cases present in women 45 years of age and older, with a median age of diagnosis of 63 years. Most cases are diagnosed in later stages of the disease, which explains the poor survival rate. If diagnosed at stage 1, the 5-year survival rate is about 93%; however, only 15% of all cases are detected at this stage, Most women, 63%, are diagnosed at stage 3 or higher. The 5-year survival rate is only 27%. 
Ovarian cancer is often thought of as a single disease; however, it is composed of several related, but distinct, tumor categories. Oncologists define three main types of tumors based on the type of cells that the tumor originates from: epithelium, germ cell, or stroma. The vast majority, 90%, of ovarian malignancies originate from epithelial cells. Epithelial ovarian tumors are further subdivided into five histological subtypes: serous, mucinous, endometrioid, clear cell, and transitional, and of these, epithelial serous carcinomas represent the majority of all primary ovarian carcinomas. Ovarian germ cell tumors develop from the cells that produce the ova or eggs, whereas ovarian stromal tumors are a rare class of malignancies that develop from connective tissue cells which hold the ovary together and produce the female hormones estrogen and progesterone. These tumors combined account for as few as 5-10% of all ovarian cancers. This complexity makes it challenging to identify and characterize effective biomarkers for ovarian cancer.

CA125: A WIDELY USED MARKER

CA 125, also known as mucin 16 (MUC16), is a cell-surface, glycoprotein antigen normally expressed in tissues de-rived from coelomic epithelia, such as ovary, fallopian tube, peritoneum, pleura, pericardium, colon, kidney, and stomach. It is FDA cleared as an aid in detecting residual or recurrent epithelial ovarian carcinoma in patients who have undergone first-line therapy. It is also indicated as an aid in monitoring response to therapy.

About 89% of women with advanced ovarian cancer have elevated levels of CA125. However, the biomarker’s sensitivity is poor in early stages of the disease, with an average of just 50% for stage 1. The sensitivity increases to about 90% for stage 11 or greater. CA125 also lacks specificity, as patients with nongynecological cancers, including breast, colon, endometrial, and pancreatic, also have elevated levels of this analyte. Levels are higher in benign conditions, such as endometriosis, uterine fibroids, heart failure, liver and renal disease. 

Due to its lack of sensitivity and specificity in a single determination, CA125 is not recommended for screening asymptomatic women. Furthermore, screening resulted in unnecessary surgeries due to false-positive test results. These findings support the position of various professional entities that ovarian cancer screening has little effect on reducing mortality rates while at the same time increasing the risk of harm at the same time increasing the risk of harm in patients with low risk of ovarian cancer. In contrast to its poor utility as a screening biomarker, studies show that CA125 is useful as an aid in assessing the risk of a malignant versus benign tumor in women who present with an adnexal mass. Identifying women at higher risk of malignancy not only enables clinicians to triage patients who will benefit from more specialized care, but it also decreases morbidity and mortality and increases overall survival in the patients referred for surgical intervention.

HE4: THE NEWEST SERUM MARKER

Human epididymis protein 4 (HE4) was first identified in the epithelium of the distal epididymis and originally thought as protease inhibitor involved in sperm maturation. It is overexpressed in 93% of serous, 100% of endometrioid, and 50% of clear cell tumors, but not in mucinous ovarian carcinomas. It has higher sensitivity than CA125, 72.9% vs. 43.3%, respectively, at a specificity of 95%. Researchers also found HE4 to be elevated in more than half of the ovarian cancer patients who did not have elevated CA125 levels. Today clinicians use CA125 and HE4 in combination as an aid in assessing the likelihood of finding malignancy during surgery in women presenting with a pelvic mass.

The Risk of Ovarian Malignancy Algorithm(ROMA) takes into consideration the concentration of two analytes and the patient’s menopausal status to generate a score on a scale of 0-10, which translates to a high or low likelihood of finding a malignancy based on cutoffs. Women with ROMA scores above the cutoff have an increased risk of ovarian cancer, and should be referred to a gynecological oncologist prior to surgery.

OVA 1: A MULTI-ANALYTE ASSAY FOR RISK STRATIFICATION

The OVA 1 test from Vermillion, Inc. measures the serum levels of five analytes—CA125, transthyretin (prealbumin), apoliprotein A1, beta2 microglobulin, and transferrin-using two different immunoassay platforms, The Roche Elecsys for CA125 and the Siemens BN11 for the four other analytes. A high probability of malignancy is defined as a score of >5.0 in premenopausal women and >4.4 in postmenopausal women. Clinicians should never use the OVA1 test as a screening test for women without an adnexal mass. The test has several limitations that laboratory professionals should make clinicians aware of.

Laboratory professionals should strongly dis-courage clinicians from using current biomarkers as screening tools because they lack specificity and sensitivity and their misuse might lead to unnecessary treatments for women and increased burden to the healthcare system. Researchers continue to investigate new biomarkers for screening, diagnosing, and monitoring the disease. Before these biomarkers can be introduced to clinical practice, properly designed clinical trials are need-ed to determine if they will become useful clinical tools. That day cannot come soon enough for the thousands of women who die each year from this silent disease and their families.

Letty Acosta