No screening biomarker appears to work better than CA 125 alone in detecting ovarian cancer, according to an analysis of prediagnostic specimens from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
During a teleconference from the annual meeting of the American Association for Cancer Research, Dr. Daniel W. Cramer reported on a collaboration between the National Cancer Institute's Early Detection Research Network (EDRN) and the Specialized Programs of Research Excellence (SPORE) to compare the best screening markers for ovarian cancer, first in case-control specimens that were drawn at the time of diagnosis (phase II specimens from 160 cases), then in blood that was drawn months or years prior to diagnosis (phase III specimens from 119 cases) among women enrolled in the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer) screening trial.
Funded by the NCI, the PLCO trial enrolled more than 150,000 men and women aged 55–74 years to be studied by various screening arms, including one to test CA 125 (cancer antigen 125) and pelvic ultrasound for ovarian cancer, between 1992 and 2001.
“The first question we wished to answer was how much we can infer about a test's performance in prediagnostic specimens based upon their performance at the time of diagnosis,” said Dr. Cramer, professor of obstetrics and gynecology at the Brigham and Women's Hospital and Harvard Medical School, both in Boston. “The second question we wished to answer was whether a panel of markers can add value over a single marker alone, with the current standard being CA 125.”
More than 24 different markers and 4 panels of markers were studied. Dr. Cramer reported that the top-performing marker was CA 125, followed by human epididymis protein 4 (HE4) and CA 72–4.
“Moving from the phase II specimens to the phase III specimens, there was a predictable loss in the performance soonest for markers that might be identified as acute phase reactants,” he said. “But we also found that even the standard markers like CA 125 seemed to lose their value as you got more remote from diagnosis.”
At best, marker panels and algorithms tested in the study added “marginal improvement” over CA 125 alone.
Although the PLCO concluded that general population screening with combined CA 125 and transvaginal ultrasound cannot be recommended, a larger trial in the United Kingdom recently concluded that screening was “feasible” (Lancet Oncol. 2009;10:327–40). In that trial, measurement of CA 125 followed by transvaginal ultrasound as a second-line test was able to achieve a sensitivity of 89.5%, a specificity of 99.8%, a positive predictive value of 35%, and a ratio of surgeries to detected cases of 2.3.
“The differences between the two trials were due to the use of CA 125 before referral for ultrasound and improvement in sensitivity and specificity with serial CA 125 testing,” Dr. Cramer explained.
Although general population screening for ovarian cancer cannot be recommended now, he said, “I think the foundations for moving it forward can be clearer.” This can be accomplished, he proposed, by conducting blood tests followed by ultrasound for positives, not imaging as a primary modality; by using serial CA 125 rather than a static cutoff, and by investigating whether serial markers or the addition of epidemiologic variables can further improve performance.
“I think the NCI should form a stakeholder panel to explore the feasibility of starting a screening trial of ovarian cancer, or at least a demonstration project,” he concluded.
The study was sponsored by the NCI's EDRN and SPORE. Dr. Cramer reported that he had no conflicts to disclose.