Ovarian Cancer Study Raises Questions about Developing Markers for Early Detection
A long-awaited assessment of potential biomarkers for detecting early ovarian cancer shows that blood levels of the CA-125 protein remain the best predictor of the disease. But if there is to be any hope that screening will reduce deaths from this disease, then more accurate markers would have to be developed, researchers concluded in the March Cancer Prevention Research.
None of the 28 potential serum markers tested in the study outperformed CA-125. But for screening, the researchers noted, doctors would need a test that could detect a signal from tumors more than 6 months before diagnosis; CA-125 had its strongest signal within 6 months of diagnosis.
Although the results may seem disappointing, the findings can inform future efforts to detect the disease early, the study authors wrote. This idea was echoed by several biomarker experts who were not involved in the work but who stressed the importance of the findings.
“This is a landmark study,” said Dr. Mark H. Greene of NCI’s Division of Cancer Epidemiology and Genetics, who co-authored an accompanying editorial. “For the first time, we have a rigorous analysis of years of ovarian cancer biomarker research to determine whether these markers represent an improvement over where the field began, with CA-125.”
The results, he continued, show that a new approach is needed to find an effective screening strategy for ovarian cancer. (Preliminary results from the study were presented in 2009.)
Accelerating the Search
Dozens of potential markers for ovarian cancer have been identified over the last decade, but most could not be validated and have been abandoned. To accelerate progress, leaders of NCI’s Early Detection Research Network (EDRN) and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial developed the current validation study. Investigators were granted access to high-quality blood samples from PLCO participants, including some rare prediagnostic samples from women who developed ovarian cancer during the trial.
The study assessed how well the ovarian cancer markers performed in prediagnostic specimens in asymptomatic women compared with how the markers performed in specimens obtained at diagnosis in a different group of women. Lead investigator Dr. Daniel Cramer of Brigham and Women’s Hospital predicted that there would be different interpretations of the findings, and he stressed the importance of learning more about CA-125.
First described 30 years ago, CA-125 is widely used to assess the effectiveness of treatment in patients with ovarian cancer, but the protein is less useful for screening. Blood levels are elevated in only about half the patients with early-stage ovarian cancer, and levels can rise for reasons other than this disease. Yet, CA-125 remains the best early-detection marker for ovarian cancer.
“If CA-125 is so important, as these results tell us, then I think we need to understand this protein better,” Dr. Cramer said. For instance, some women with advanced ovarian cancer have normal CA-125 levels, and understanding this phenomenon could potentially make the protein more useful for screening, he noted.
The primary interpretation of the current study will likely be that new markers are needed and that researchers should rethink the best way to discover and develop markers. To date, most potential markers have been identified in blood collected from women at the time of diagnosis, because these are the samples that researchers have available.
But these samples often reflect late-stage disease, and they may not be useful for early detection, as the new findings suggest.
“We need to think more about how to discover these markers,” said study co-author Dr. Claire Zhu of NCI’s Division of Cancer Prevention, who was also the first author of a companion report describing a framework for evaluating panels of markers. “And while we don’t know the best approach, we hope this study will encourage discussions within the field.”
PLCO is one of several large randomized studies that have made limited samples available for biomarker research in response to proposals from investigators. “Discovery should be done in prediagnostic samples because these samples are more reflective of the biology of the disease than other samples,” said Dr. Sudhir Srivastava, who heads the EDRN.
Many researchers have said that if no single marker could detect ovarian cancer, then panels of markers might get the job done. This idea was untested until now, and, at least in this case, panels added little value to CA-125.
“The panels that were tested just didn’t perform,” said co-author Dr. Eleftherios Diamandis, a researcher at the University of Toronto who has written about cancer biomarkers. “The message of this study, unfortunately, is that we have underestimated the difficulty of finding biomarkers.”
The field has learned, however, that the best way to do this research is through rigorous validation studies that use high-quality samples like those from PLCO, he added.
With Progress, New Questions
Moving forward, perhaps the biggest unknown is the biology of ovarian cancer. Even with better strategies for developing markers, no one knows whether markers are present in the blood that could be detected early enough to help save women’s lives.
“It’s very hard to do discovery on people who are asymptomatic, where there may not be a strong signal to pick up,” said co-author Dr. David Ransohoff of the University of North Carolina at Chapel Hill. “After all these studies, we don’t really know that good markers are really there.”
Some researchers are testing the rise in blood levels of markers over time for early detection. The idea behind longitudinal studies is that each person has a natural, or baseline, level for each marker, and that one or more of these markers will start rising above the baseline level when she develops ovarian cancer.
“The hope is that longitudinal information on biomarkers will be much more valuable than a biomarker at one point in time,” said co-author Dr. Steven Skates of Massachusetts General Hospital. “The thinking is that this rise over time may be the most sensitive flag for detecting the disease as early as possible, with a marker or collection of markers.”
This approach—with CA-125 as the marker, followed by ultrasound if the blood test indicates that the woman has a high risk of ovarian cancer—is being tested in one arm of the UK Collaborative Trial of Ovarian Cancer Screening, a prospective study. “We’ll have to wait a few more years for the study’s results to see if this approach works,” Dr. Skates said.
The UK trial requires that both CA-125 and transvaginal ultrasound be positive before a woman is referred to surgery. The PLCO study, on the other hand, requires that one or the other be positive. The PLCO results are expected in the next few months.
In the meantime, the validation study provides an opportunity for the field to assess the last decade of study and how best to move forward.
“We need to know whether there are lessons to be learned about the process of biomarker discovery from these studies,” said Dr. Ransohoff. “It would also be useful to know why it has taken so long to get reliable results and how we can improve the process of discovery and validation.”
During the last decade, Dr. Ransohoff noted, some researchers made strong claims about potential markers for ovarian cancer based on preliminary data. And though the markers did not pan out, these claims were repeated by members of the media, raising false hopes about early detection.
“The new data speak for themselves, I’m afraid,” said Dr. Greene. “But this work really is a model for how these studies should be done.”
Further Reading: Ovarian Cancer Study Tests Lead Time of Potential Biomarkers