In an ongoing study to validate biomarkers for ovarian cancer, scientists collaborating with Ciphergen showed that when three newly discovered biomarkers were combined with a standard biomarker called CA 125, the test scored between .88 and .91 out of a perfect score of one, in terms of specificity and sensitivity.
“A perfect test, which could catch every single person who had early stage ovarian cancer, would have an area under the ROC curve of one,” said Rebecca Caffrey, a business development manager in the infectious disease department at Ciphergen. “Our model is between .88 and .91, which is far closer to a perfect curve than CA 125 alone, which has a score of .76.”
Caffrey said that the test is not good enough to be used to screen the general population for ovarian cancer, but that a combination of the biomarker blood test along with an ultrasound could improve early detection in women who are at high risk for ovarian cancer.
She emphasized that the three biomarkers combined with CA 125 are better for screening women at high-risk for ovarian cancer than CA 125 alone, which is the standard test that is currently used for screening women with symptoms for ovarian cancer.
The validation study was performed by Ate van der Zee of the University Hospital Groningen in the Netherlands and Ignace Vergote of the Universitaire Ziekenhuizen K.U. Leuven in Belgium. In total, it reported on 436 samples collected from 53 women with early-stage ovarian cancer, 116 women with late-stage ovarian cancer, and 98 controls.
The study is expected to continue until 1,100 samples have been analyzed.
“These results confirm our recently published findings revealing the reproducibility of the markers, when discovered using a rigorous study design,” said Gail Page, president of Ciphergen’s Diagnostics Division.
Scientists use an ROC curve to measure the sensitivity and specificity of diagnostic tests. In terms of sensitivity, results of the validation study showed that when the specificity of the ROC curve was fixed at 97 percent, the new test had a sensitivity of 74 percent — significantly higher than CA 125 alone, which has a sensitivity of 65 percent.
When the sensitivity of the ROC curve was fixed at 83 percent, the new test had a specificity of 94 percent — much higher than CA 125 alone, which had a specificity of 52 percent.
In addition to detecting the presence of ovarian cancer, the study showed that the biomarkers could also be used to track the progression of the disease. In numerous patients who gave multiple serum samples as their disease progressed, levels of the biomarkers were down before a tumor was removed, rose back to near normal levels after the tumor was removed, and dropped down again when the cancer recurred.
“The important thing is the markers are tracing the progression of the disease, which means they could be very useful for following and monitoring remission,” said Caffrey.
After the current 1,500-sample validation trial is completed, Ciphergen intends to present results to the US Food and Drug Administration, and to seek FDA approval for establishing a diagnostic test for ovarian cancer based on the biomarkers, said Caffrey.
In August, a group led by Daniel Chan, a professor and the director of the Biomarker Discovery Center at Johns Hopkins University, published a paper in the journal Cancer Research that described how they used Ciphergen’s SELDI technology to select a profile of biomarkers, then narrowed the biomarkers down to the three most promising ones. As with the current validation study, Chan’s group reported that when combined with CA125, the three new biomarkers correctly detected early stage ovarian cancer in 74 percent of women study patients who had the disease.
When CA 125 was used alone with the sample, it correctly identified cancer 65 percent of the time. The difference in sensitivity was not statistically significant, given the sample size of patients.
The purpose of the current trial is to validate Chan’s results using enough samples so that results are statistically significant.
The three protein biomarkers used in the new cancer test are called transthyretin, apolipoprotein A1 and alpha-trypsin. Even before Chan’s study, there was evidence in the literature that the three biomarkers were associated with cancer. Transthyretin and Apo A1 were reported to be decreased in patients with ovarian cancer. Alpha-trypsin was found to be associated with ovarian cancer when cleaved in one way, associated with pancreatic cancer when cleaved in another way, and associated with diabetes when cleaved in a third way.
In terms of function, Apo A1 is a major lipoprotein associated with atherosclerosis and coronary heart disease. Transthyretin is a plasma protein that transports thyroxine, a pre-cursor of a thyroid hormone, and retinol, or vitamin A. Alpha-trypsin is a cancer-related protease that chews up proteins in the environment so that cancer tumors can grow and metastasize.
In addition to ovarian cancer biomarkers, Ciphergen is also working on validating biomarkers for prostate cancer, breast cancer, Alzheimer’s disease and Chagas disease, a tropical illness caused by a blood-feeding parasite, Caffrey said.