By Dana Hinesly

 If the concept of a blood test for ovarian cancer rings a bell, it could be because the topic is in the news with increasing regularity. It seems any advancement in the science related to screening and testing for this lethal disease is widely trumpeted by print and broadcast media. And lately, considerable progress is being made, specifically in the area of proteomics—the science of proteins, their structure and function, and the role they may play in disclosing the existence of diseases.

A recent announcement came from Ciphergen Diagnostics, a division of Ciphergen Biosystems Inc (Fremont, Calif). In April, Ciphergen announced a material transfer agreement with the National Cancer Institute’s Clinical Proteomics Reference Laboratory (CPRL).1

“The CPRL is setting up a variety of proteomic technologies, including our ProteinChip™ System, and integrating them into a platform more suited to clinical reference laboratory testing than to research,” says Eric Fung, MD, PhD, vice president of Medical Affairs, Ciphergen Diagnostics. The patented ProteinChip System allows the detection of multiple diagnostic markers using surface enhanced laser desorption ionization (SELDI) technology. “That means having the reproducibility, throughput, ease-of-use, and automation that those in a clinical reference laboratory are accustomed to.”

Ciphergen’s involvement in the CPRL is just one of the company’s several high-profile projects, including work with the University of Texas MD Anderson Cancer Center and a collaboration with researchers at Johns Hopkins in a multisite, 500-patient study. The latter effort led to the discovery of three biomarkers with the potential to detect ovarian cancer in stage I and stage II.

“The test involves known biomarkers versus pattern recognition only,” says Carol Berry, MBA, senior director, marketing, Ciphergen Diagnostics. “We’re using our ProteinChip Technology to discover novel biomarkers, identifiy the biomarkers, and tie them back to the biology of the disease before we move into assay development.”

Popular Science
Just last summer, the H. Lee Moffitt Cancer Center and Research Institute (Tampa, Fla) published the results of a 3-year study that examined lysophosphatidic acids and related lysophospholipids and specific subspecies of those substances.

“Using a relatively small set of samples, we were able to determine that the results are promising and warrant further evaluation,” says Rebecca Sutphen, MD, director of clinical genetics at Moffitt. “Further studies should evaluate the potential inclusion of these lysophospholipids in a panel of substances for a blood test for ovarian cancer,” she says.

In the study, lysophospholipids levels in women with ovarian cancer were elevated when compared to levels in healthy women.2 The study included hundreds of women from Bayfront Medical Center (St Petersburg, Fla), Morton Plant Hospital (Clearwater, Fla), Tampa General Hospital, and Bay Area Oncology (both in Tampa).3 This cooperative approach meant that the study was much more representative of cases occurring around the state, says Sutphen, principal author of the study.

Since the announcement, the work at Moffitt continues. Additional testing will validate their findings on lysophospholipids and will include the evaluation of proteomic biomarkers in an additional set of 250 ovarian cancer samples and 250 control cases.

“In these tests, we’ll use a very sophisticated proteomics technology that allows us to not only look for patterns of protein in the blood, but to specifically identify the proteins that are contributing to the ability of the test to differentiate between cases and control,” Sutphen says.

Correlogic Industries Inc (Bethesda, Md) is focusing on protein-pattern recognition. The company’s OvaCheck test screens blood, enlisting proteomics and innovative technology to recognize protein patterns present in women with ovarian cancer.

 Peter Levine

Since its introduction in early 2002, OvaCheck has met with notable governmental roadblocks. Currently in discussions with the Food and Drug Administration to determine the test’s appropriate regulatory path, Correlogic is moving ahead with validation tests.4 This work has incorporated more than 1,000 individual patient samples collected through a number of different mechanisms to ensure even geographic distribution and reduce any possible sample bias, says Peter Levine, president and CEO, Correlogic.

“The focus of Correlogic’s effort from the beginning has always been to bring a test to market that is intended for women at increased risk for ovarian cancer,” says Levine.

An Uphill Battle
Currently, there are no screening tests for ovarian cancer that have been proven to reduce the risk of dying from the disease.5 Despite considerable advances in treatment, the mortality rate for ovarian cancer has not significantly changed in 20 years. While ovarian cancer accounts for only 3% of all woman-specific cancers, it ranks fourth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system.6

When looking at the statistics, the intense media reactions should come as no surprise—but the excitement must be kept in perspective. Regardless of the approach applied by a lab, scientists stress the importance of informing the public about the actual nature of their research.

“Unfortunately, some of the media releases have made people believe that we’re close to having a blood test for ovarian cancer, and I don’t think that’s a very fair assessment,” says Sutphen. “None of these studies have been based on sufficient numbers of samples to get to that point.”

Though the advances hold promise, a lot of work is left to be done. The current wave of tests are not intended for use in screening in the general population, but researchers feel they will likely have a place as part of a panel of assessment options available.

“Proteomics has the opportunity to radically improve health care by incorporating sophisticated multivariate analysis into clinical laboratory testing,” says Gail Page, president, Ciphergen Diagnostics. “We believe that by working closely with thought leaders in the clinical, laboratory, proteomics, and bioinformatics fields; executing properly designed scientific studies; and taking a careful, measured approach, we will be able to bring novel, high-value tests to the clinical arena within the next year.”

The hope is that these tests could provide another resource for physicians treating women with increased risk for ovarian cancer.

“It’s another tool for the physician to look at in addition to a whole myriad of other things: the woman’s age, her overall health and symptoms, sonograms,” says Levine. “A doctor does his own pattern recognition—they look at all these things together, and then they make a decision.”

Promise for the Future
The good news is, every announcement is a step forward in the fight against ovarian cancer.

“Most experts in the field have come to the conclusion that it is going to require multiple biomarkers to achieve the high levels of sensitivity and specificity necessary to avoid false positives and false negatives,” Sutphen says. “Fortunately there are a lot of people working on it, and all of this data together is very valuable.”

Moreover, the research holds promise for treatments for other diseases.

“In the next 2 to 3 years, as we accumulate more experience and more samples, we are very interested in evaluating staging and the efficacy of treatment,” says Levine. “There are a lot of other things that can be done with the same general technology in the same disease area.”

Dana Hinesly is a contributing writer for Clinical Lab Products.

1. Accessed 6/13/05.
2.   Accessed 6/13/05.
3.   Accessed 6/13/05.
4. [removed][/removed] The Lancet. Accessed 6/13/05.
5. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002;52(1):23–47.
6. [removed][/removed].   Accessed 6/13/05.

In the Headlines
In the latest news out of the desert southwest, researchers at the Nevada Cancer Institute collaborated with Yale University and George Washington University in a study investigating the possibility that a blood test can be used to help indicate the existence of ovarian cancer in its earliest stages.

 Patricia Bray-Ward, PhD

“Historically, the best results these studies ever got to was about 70% sensitivity, with much poorer sensitivity in early-stage cancer,” says Patricia Bray-Ward, PhD, of the Nevada Cancer Institute (Las Vegas), the state’s official cancer research facility. “This test is different because it has much higher sensitivity and specificity.”

This research is not the first to explore ways to detect ovarian cancer while it is still treatable, but Bray-Ward says it sets itself apart because, “We are actually looking at known proteins.”

 The Nevada Cancer Institute’s test identifies four proteins— leptin, prolactin, osteopontin, and insulin-like growth factor-II —whose presence could indicate stage I or stage II ovarian cancer.1 Conducted as a blind study with more than 200 women, it correctly diagnosed 95% of the women with the disease and also identified 95% of those who were healthy.2

“There’s still a lot of work that needs to be done,” says Bray-Ward. However, she is confident that these initial levels of sensitivity and specificity increase the likelihood the science will hold up to additional validation. The next step for the team is to explore the performance of the test in a larger population group. “We’ve done a comparison of ovarian cancer patients with cancer-free women, but we have not yet done an extensive comparison using women with other kinds of cancer to find out how the test is going to perform in the real world.”

1.   Accessed 6/13/05.
2.   Accessed 6/13/05.

Risk Factors
Knowledge is power. Arming themselves with the facts about their chances of getting a disease is one way women can take a proactive approach to their health care. When it comes to ovarian cancer, the good news is that it is rare when compared to other cancers. According to the American Cancer Society, a woman’s average lifetime risk for ovarian cancer is only about 2%, and her lifetime chance of dying from the disease is 1%.

However, even with such a low average risk, some women are more likely to be diagnosed with the disease than others. As research progresses, the list is likely to change, but the following are some of what are believed to be specific risk factors:

Age. The older the woman, the greater her risk. Ovarian cancer is found primarily in post-menopausal women, typically those more than 50 years of age. Roughly half of those cases are in women older than 65.
Personal History. Studies indicate that components of a woman’s personal history can increase risk, including obesity in early adulthood, infertility—whether infertility drugs are administered or not—and childbearing status.

Family History. Women with blood relatives diagnosed with ovarian cancer have a higher risk of getting the disease themselves, particularly if the relative was a mother, sister, or daughter. For more extended relatives—cousins, aunts, and grandmothers, for example—the risk is slightly less, but still above average.

Previous Cancer. In studies, women who have had breast or colon cancer have been found to have an increased risk for ovarian cancer.

Estrogen Replacement Therapy or Hormone Replacement Therapy. Studies about the impact these two postmenopausal treatments have on ovarian cancer are inconsistent, but some indicate that long-term use can have adverse side effects, including increased risk for the disease.

Talcum Powder. Regular use of talc in the genital area could increase the risk of ovarian cancer. The link was believed to have been the asbestos present in talc products, but the risk continued after the removal of asbestos more than 20 years ago, indicating other factors may be involved.

Common Symptoms of Ovarian Cancer
Though it is the seventh most common cancer among women, ovarian cancer deaths rank fourth, making it more fatal than any other cancer of the female reproductive system. This high mortality rate is due in part to the fact that ovarian cancer is rarely discovered in the early, more treatable stages.

 Without an accurate screening test, it is up to women to watch for symptoms, including:
•    generic discomfort, pain, pressure, or bloating in the abdomen or pelvis;
•    unexplained vaginal bleeding;
•    pain in the back or legs;
•    stomach upset, such as nausea, indigestion, or gas;
•    unusual weight loss or gain, or a sudden loss of appetite;
•    bowel upset, including diarrhea or constipation
•    frequent urination; and
•    abnormal fatigue or shortness of breath.

A woman who experiences any of these symptoms should visit and communicate honestly with a physician who can evaluate their significance and take into account her overall physical condition, personal health, and family history.