Biomarkers Not Sufficiently Accurate for Early Intervention in Ovarian Cancer

Roxanne Nelson

December 30, 2009

December 30, 2009 — Ovarian cancer is often a lethal disease, and one reason for this dismal prognosis is that it is usually not diagnosed until it has reached an advanced stage. Early detection could help reduce the associated mortality rate, but currently there are no specific and sensitive screening methods. Potential ovarian cancer biomarkers include cancer antigen CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 proteins. Researchers now report that serum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before a clinical diagnosis is made.

However, these biomarkers only become substantially elevated in the last year before diagnosis, according to findings published in the January 6, 2010, issue of the Journal of the National Cancer Institute.

However, although these markers are not accurate enough to prompt early intervention in existing screening protocols, the study authors explain, modest but statistically significant increases in risk associated with CA125, HE4, and mesothelin were identified. This finding is consistent with many of the established epidemiologic risk factors for ovarian cancer.

"I still think biomarkers may play a role in a cost-effective screening program, although none of these seem accurate enough either alone or together to justify their use in average-risk women," lead author Garnet Anderson, PhD, told Medscape Oncology.

"I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted," said Dr. Anderson, who is with the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

One problem, cites Dr. Anderson, may lie in the approach used in identifying candidate biomarkers. "Most of the discovery work done so far has been conducted in women with advanced-stage disease and compared them to healthy women," she explained. "If discovery work were done in samples like the ones we used here, representing specimens collected months to years prior to the advanced stage diagnosis, we might have a better chance of finding earlier signals of aggressive disease."

Another opportunity for improving screening and early diagnosis lies in imaging, she adds. "Currently the most common and only affordable imaging option that could be considered for routine screening is transvaginal ultrasound, but it performs poorly in terms of accurately determining those women [who] have ovarian cancer from those who do not," said Dr. Anderson. "A substantial improvement in this area would be very exciting."

Detectable Levels Reached Shortly Before Diagnosis

In this study, Dr. Anderson and colleagues analyzed prediagnostic serum samples and patient data from the Carotene and Retinol Efficacy Trial, a randomized chemoprevention trial that evaluated the effects of beta-carotene and retinol on the incidence of lung cancer among individuals at high risk for the disease.

The serum samples were obtained 0 to 18 years before a diagnosis of ovarian cancer was made in 34 patients (15 with advanced-stage serous carcinoma) and during a comparable interval before the reference date from 70 matched control subjects. Immunoassays were conducted to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in the samples.

Results showed that concentrations of CA125, HE4, and mesothelin became slightly elevated in patients with ovarian cancer vs the control subjects approximately 3 years before their diagnosis. However, these biomarkers only reached detectable elevations within the final year before diagnosis. Thus, the discriminatory power of the markers was limited, the study authors note, because accuracy only increased shortly before diagnosis.

Not the Last Word

In an accompanying editorial, Patricia Hartge, ScD, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, Bethesda, Maryland, notes that it has been "surprisingly difficult" to create a successful screening program for asymptomatic women with ovarian cancer.

However, the authors of this study have taken a "valuable step toward the successful design of such a screening program by demonstrating one reason why screening regimens that are based on markers, or panels of markers, can fail," writes Dr. Hartge.

She points out that these results are "not the last word in serum markers or in combinations of markers." Instead, serum markers are likely to form a key element in any screening regimen, with the lead time and other parameters being taken into account.

not the last word in serum markers or in combinations of markers.

However, for right now, there are no proven biomarkers, panel of biomarkers, or overall screening program that works well, explained Dr. Hartge. "The current report, with its sobering implications, brings us closer to understanding the crucial elements in designing any effective early detection program for ovarian cancer."

The National Cancer Institute funded the study. Dr. Anderson has disclosed no relevant financial relationships. Coauthor Lieling Wu is currently employed by Baxter Healthcare, Inc, and holds stock in this company but is not involved in projects related to ovarian cancer.

J Natl Cancer Inst. 2010;102:1-3, 26-38.

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