New ovarian cancer screening trials show promising results
By Andy Koopmans
Researchers have been working to develop a reliable and safe screening tool for ovarian cancer for years, and a recent study published in the journal Cancer indicates that the science may be close.
The study, led by Drs. Robert Bast and Karen Lu at The University of Texas MD Anderson Cancer Center, looked at rising values of the protein and ovarian cancer biomarker CA-125 in 4,000 women over 11 years. Women were given yearly blood tests and those with sudden increases in CA-125 were given an ultrasound. Of these, 103 women had ultrasound and 10 women underwent exploratory surgery. Four were found to have early stage ovarian cancer, five had ovarian tumors that were benign or of low malignant potential and one was found to have endometrial cancer.
The Bast-Lu study is among a number of projects that aim to improve upon the results of the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial conducted by the National Cancer Institute, which ended in 2006. That study screened post-menopausal women at average risk using both CA-125 and annual ultrasounds. The study concluded that this protocol was sending too many women to surgery for the number of cancers found.
Dr. Nicole Urban, an ovarian cancer researcher in the Translational Outcomes Research Program of the Public Health Sciences Division at Fred Hutchinson Cancer Research Center, said that the Bast-Lu study, together with a similar study in Britain that has been tracking more than 200,000 post-menopausal women for more than a decade, the UK Collaborative Trial of Ovarian Cancer Screening, promise to shed new light on the use of CA-125 and ultrasound screening on reducing death from ovarian cancer. In the U.K. study, 50,000 participants have been receiving the same protocol as the Bast-Lu study, 50,000 have been receiving yearly ultrasounds and 100,000 have been receiving no screening as part of a comparison, or control, group. “Reports from the Bast-Lu study and the U.K. study reassure us that the two-step protocol is safe—the two steps being biomarker measurement followed by ultrasound screening only for women with increases in CA-125 —but what nobody knows yet is whether it decreases mortality. If it does, that’s going to be very important.” Urban said.
Urban’s guess is that the U.K. study will show a reduction in mortality, but perhaps not as much as 30 percent, which, she said, is an arbitrary “gold standard” for success and wide adoption of a screening protocol because studies in mammography have shown a 30 percent reduction in mortality from breast cancer.
“It will be very interesting to see what the U.K. trial shows. I expect that the imaging protocol will send too many women to surgery and that the CA-125 two-step protocol will not: using CA125 to select the women for imaging is likely to be safe in the sense that it won’t send too many women to surgery. It is much more difficult to predict efficacy, but I’m hoping the U.K. trial will show at least a 10 percent reduction in mortality for the two-step protocol.”
Anticipating that the CA-125 screening protocol will need to be improved to be widely adopted, Urban is currently conducting her own randomized trial of 1,200 high-risk women in Washington, California and Pennsylvania using the CA-125 biomarker in combination with a novel marker her group discovered called HE4.
Urban said that her preliminary results are consistent with the Bast-Lu study, but their cohorts are different. While the Bast-Lu study involves post-menopausal women at average risk of ovarian cancer, Urban’s involves pre- and post-menopausal women at high or elevated risk. This includes women who carry the BRCA mutation, those with a strong family history of the disease and those with three out of six lifestyle risk factors, such as never having taken oral contraceptives. Urban’s study is still in phase 1, which looks at safety. “We need to make sure that the protocol is not sending too many women to surgery, and it’s not,” she said. In comparison, the aforementioned NCI-sponsored PLCO study sent nearly 15 women to surgery to find one cancer. “That’s too many. That’s a lot of unnecessary surgery occurring because ultrasound tends to detect benign pelvic masses,” she said.
Urban indicated that the Bast-Lu and U.K. trials have resulted in significantly fewer false-positive results, requiring only two to three surgeries for every case found.
Urban’s trial combining CA-125, HE4 and ultrasound in high-risk women has had similar results. “In my trial, we have sent three women to surgery and two of them were found to have cancer. So, that’s also a very good ratio. I am hoping that HE4 will prove to be a good addition to the screening protocol,” she said.
Urban and colleagues discovered the HE4 biomarker 15 years ago and already it has been approved by the Food and Drug Administration for monitoring ovarian cancer recurrence.
Together with CA-125 it also is used in an FDA-approved test called ROMA, short for “Risk of Ovarian Malignancy Algorithm,” to help determine the likelihood of malignancy among women with a pelvic mass.
Urban ultimately hopes to expand her HE4/CA-125/ultrasound trial by opening it up to high-risk women nationwide via the Southwest Oncology Group, a national research collective whose data analysis core is housed at Fred Hutch. Regarding the Bast-Lu study, she said, “I’m very happy that they reported encouraging results. I’m crossing my fingers that the U.K. trial will also do well. Positive results will allow us to move toward even more improvements in ovarian cancer early detection and screening.”