Photo by Todd McNaught
A team of Seattle researchers, including investigators in the Public Health Sciences Division, has identified a protein that could improve diagnosis of ovarian cancer, a disease that often goes undetected until it is advanced and difficult to cure.
Researchers found that the protein, known as HE4, was more effective at distinguishing true cancers from benign ovarian disease than the only other commercially available test, which detects the presence of a protein called CA125. HE4 was initially characterized as a potential early-detection marker by PHS researchers in collaboration with Dr. Leroy Hood, director of the Institute for Systems Biology, and Dr. Michel Schummer, who worked with Hood while both were at the University of Washington.
The study, led by Dr. Ingegerd Hellstrom and colleagues at the Pacific Northwest Research Institute, was published in the July 1 issue of Cancer Research. Drs. Nicole Urban and Martin McIntosh of PHS co-authored the paper. Urban is principal investigator of the Pacific Ovarian Cancer Research Consortium, a multi-institutional grant from the National Cancer Institute that funded the study. McIntosh is project leader for the early-detection portion of that proposal.
Urban said that if the HE4 biomarker performs well in larger studies, HE4 could become a cancer-screening test that reduces the number of needless surgeries performed as a result of false-positive diagnoses.
"Right now, there are two ways to screen women for ovarian cancer, by CA125 test or by pelvic ultrasound, both of which also detect conditions that are not true cancers," she said. "Depending on the clinical follow-up a woman receives, that can lead to a large number of unnecessary surgeries.
"We found that HE4 works as well as CA125 in detecting cancer cases but performed better in the sense that it did not identify cancer falsely in serum samples from women with benign ovarian disease."
HE4 is a protein that is secreted by ovarian-cancer cells into the bloodstream. The biomarker test, which has been licensed by Fujirebio Diagnostics Inc., the company that markets the CA125, test is based on an antibody that specifically recognizes HE4.
Ovarian cancer will strike about 25,000 women in the United States this year and will cause more than 14,000 deaths. Because the disease typically causes ambiguous symptoms, only one quarter of all ovarian-cancer cases are detected when the disease is still confined to the ovary, a time when cure is possible and treatment can lead to five-year survival rates of up to 95 percent. For that reason, scientists are eager to develop a reliable test for early diagnosis.
The HE4 test successfully identified cancer in 30 of 37 blood-serum samples from women known to have the disease, while the CA125 test identified 29 cases. When used together, both biomarkers detected 33 of the 37 cancer cases. However, the number of women with benign ovarian disease with elevated HE4 is far fewer than with CA125.
"There are lots of new markers for ovarian cancer, but HE4 is the first one that even comes close to matching the performance of CA125, which may be the best serum-cancer marker ever identified," McIntosh said. "HE4 may play a role in screening when used with CA125, or may even replace it as the top candidate."
Still, to detect all ovarian-cancer cases, Urban said further research is needed.
"Both biomarkers miss some cancers, even when used together," she said. "What we hope to do now is identify additional biomarkers that when used in conjunction with CA125 and HE4 will detect all ovarian cancers."
Urban said that Fred Hutchinson researchers will use serum from women whose cancers are undetectable by both the CA125 or HE4 tests to identify new biomarkers unique to those cancers.
The researchers also plan to conduct a much larger analysis of the HE4 biomarker and other candidate markers using serum samples from hundreds of women. Dr. Garnet Anderson and colleagues of the Women's Health Initiative, a large national study whose clinical coordinating center is housed in the PHS Division, will evaluate some of the samples. Among the samples to be tested are those that were collected from women a year or more before they were diagnosed with cancer, which will help scientists to evaluate how early in the disease process the HE4 test can detect ovarian cancer.
"To be valuable, a marker should elevate very early in the disease process," McIntosh said. "CA125 levels have been shown to begin elevating nearly 18 months before symptoms begin. We do yet know how HE4 will perform in this regard."