How effective is CA 125 and other biomarkers to screen for ovarian cancer?

Originally published in MedPage Today

by Michael Smith, MedPage Today North American Correspondent

Rising blood levels of several biomarkers show the presence of ovarian cancer — just not early enough.

That’s the conclusion of a retrospective longitudinal case-control study of levels of half a dozen proteins linked to the disease, according to Garnet Anderson, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

In the study, three of the six markers started to rise slightly three years before diagnosis, they reported in the Jan. 6 issue of the Journal of the National Cancer Institute.

But the “likely lead time” is probably a year or less, Anderson and colleagues wrote.

“One cannot expect these markers to routinely detect cancer more than a year earlier than it would be diagnosed clinically,” the researchers noted, adding it’s not known whether a one-year lead time is enough to lower the risk of death from the disease.

The report has “sobering implications,” according to Patricia Hartge, ScD, of the National Cancer Institute in Bethesda, Md.

Writing in an editorial comment in the journal, Hartge said many women would already have an advanced malignancy by the time such markers raised a red flag.

That doesn’t rule out the use of biomarkers, she said, adding that the study gives valuable information on what’s needed to develop a successful screening program.

She noted that “daunting arithmetic” faces those trying to prevent premature death from ovarian cancer. U.S. incidence is 13 cases per 100,000 woman-years — “proverbial needles in the haystack.”

The study looked at pre-diagnostic serum samples (contributed over periods of up to 18 years) from 34 women who were later diagnosed with ovarian cancer and 70 matched controls. The women were taking part in the Carotene and Retinol Efficacy Trial (CARET), which studied the effects of beta-carotene and retinol on the incidence of lung cancer.

In the serum samples, the researchers looked at levels of CA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 — all of which have been shown to be elevated in ovarian cancer.

They found that smoothed mean concentrations of CA125, HE4, and mesothelin began to rise in cancer patients (compared with controls) about three years before diagnosis but reached detectable elevations only within the final year.

On the other hand, compared with controls, the concentrations of B7-H4, DcR3, and spondin-2 did not rise, although they have been seen to be elevated in ovarian tumors.

The areas under the receiver operating characteristic curves for the first three biomarkers ranged from 0.56 to 0.75, indicating a limited discriminatory power, the researchers said.

But accuracy increased over time, they said. For instance, the area under the curve for CA125 was 0.57 at four or more years before diagnosis, but rose to 0.68 between four and two years from diagnosis, and to 0.74 less than two years from diagnosis.

The “markers are not accurate enough to prompt early intervention in existing screening protocols,” Anderson and colleagues wrote, although multivariate regression analyses did find statistically significant increases in risk associated with all three.

Research now “should focus on identifying markers that extend lead time rather than those that simply add sensitivity near the time of clinical diagnosis,” the researchers argued.

They cautioned that their sample size was small, all the women were heavy smokers, and few samples were collected in the two or three years just before diagnosis.

Also, because the samples were contributed at different times, the interpretation of biomarker levels “must be interpreted with caution,” they wrote.

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