Can a simple blood test detect early signs of ovarian cancer? This question has been asked repeatedly over the last decade, and an answer may finally come this summer.

In a closely watched study, five research groups are validating their most promising ovarian cancer markers using high-quality blood samples from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, including some prediagnostic samples from women who developed ovarian cancer during the trial.

The validation study, coordinated by NCI's Early Detection Research Network (EDRN), could show whether panels of markers can detect ovarian cancer in blood collected 6 months or more before cancer was discovered. If markers do predict ovarian cancer, the question then becomes: How long before a clinical diagnosis are the markers informative?

Earlier is always better, and for this disease in particular. Ovarian cancer has been called a "silent killer" because the vast majority of cases go undetected until the later stages, when women have few treatment options. The hope now is that a blood test for early detection is within reach.

"Everybody has a real sense of urgency now," said Dr. Daniel Cramer of Brigham and Women's Hospital, who leads one group. "We've been saying for years that we'll get a marker for ovarian cancer, but it hasn't happened yet. This is the first good test to see if we can come up with a panel of markers for ovarian cancer from PLCO samples."

The PLCO is one of several large, randomized studies that have been making limited samples available for biomarker research based on proposals from investigators. These studies have rare prediagnostic samples that were collected before anyone knew that a person had a particular cancer. Such samples are considered "more pure" and may more accurately reflect the biology of ovarian cancer than other specimens.

The vast majority of prediagnostic blood samples for ovarian cancer are collected from women just prior to surgery for a suspected ovarian tumor. But impending surgery and anesthesia, for example, might alter at least some potential markers in women with the cancer but perhaps not in a comparison group.

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The PLCO biorepository has serial blood samples from 150,000 people collected at 10 sites across the country, making it a veritable gold mine for biomarker research. Because samples were collected and stored before a diagnosis was known, the researchers minimized the chances of inadvertently introducing a bias or systematic difference between the cancer and comparison groups.

Similarly, in the validation study, great care was taken to eliminate factors that, in the end, could mislead investigators.

"If the biomarkers do not detect ovarian cancer in these samples, it will be because of the biology of ovarian cancer and not because of how the study was designed or implemented," said Dr. Christine D. Berg of NCI's Division of Cancer Prevention and the leader of PLCO.

The validation study is being managed by Dr. Christos Patriotis of NCI's Cancer Biomarkers Research Group with Dr. Sudhir Srivastava, who heads the EDRN program.

The study could yield a variety of markers, including some that improve the sensitivity of the protein CA-125 test. This marker is routinely evaluated when diagnosing ovarian cancer, but it cannot be used alone because only some women with ovarian cancer develop elevated levels, and levels can be elevated for reasons other than cancer.

"Many potential biomarkers have been proposed to be added to CA-125 for the early detection of ovarian cancer, and the PLCO samples will help us select the most promising of those markers," said Dr. Robert Bast, Jr., of the University of Texas M.D. Anderson Cancer Center, who discovered CA-125 and is an investigator in the study.

Beyond early detection and diagnosis, markers are needed to assess risk and guide difficult clinical decisions. For instance, some women with genetic risk factors for breast and ovarian cancers have their ovaries and fallopian tubes removed as preventive measures after childbearing years.

The validation study could yield markers that identify women without the risk genes who nonetheless have a high risk of the disease within 5 to 10 years. Other markers could identify women who have a family history of ovarian cancer but are at such low risk that they could safely avoid preventive surgeries, at least in the short term.

Before any of these markers can be used in the clinic, they would need to be tested prospectively, and the challenges of early detection are substantial.

"It may be helpful to think about what we're trying to do," said Dr. Nicole Urban of Fred Hutchinson Cancer Research Center, another lead investigator. "With a screening program, a woman comes in and you get a blood sample and try to predict if she's going to be diagnosed with cancer. You're trying to find cancer that would kill the woman, but you're trying to find it early enough that you can cure it. And this is tough."

Dr. Urban is nonetheless optimistic that screening for ovarian cancer using markers will ultimately succeed. She predicts that serial blood samples from randomized trials may be required to discover the markers and track their changes over time.

"There is no single marker that will be sensitive enough to distinguish all the ovarian cancer patients from healthy women," said Dr. Gil Mor of Yale University, who leads the fourth group. His team has developed panels with two types of markers - proteins produced by ovarian tumors and proteins produced by the body in response to very early changes associated with ovarian cancer.

All of the groups have taken essentially similar strategies, noted Dr. Anna Lokshin at the University of Pittsburgh Cancer Institute, the principal investigator for the fifth study group. "We are all now waiting for the results." The data are being analyzed, and answers could come within months.

"A lot of people around the country are holding their breath to see the results," said Dr. David Ransohoff, a cancer epidemiologist at the University of North Carolina at Chapel Hill, who consulted on the project.

"These are some of the best groups in the country; they are investigating an important question; and the specimens are among the best available to answer it," he continued. "If the results are positive in these samples, it will be enormously good news for the field."

—Edward R. Winstead