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4,000-plus Patient Study Suggests ROCA Test Specific Enough for Use as Ovarian Cancer Screening Dx

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A longitudinal study of the Risk of Ovarian Cancer Algorithm has found that the algorithm in combination with transvaginal ultrasound offers suitable specificity and positive predictive value for it to be used as an ovarian cancer screening test in post-menopausal women.

Detailed in a paper published this week in the journal Cancer, the study followed 4,051 women over 11 years and found that the ROCA test was able to identify cases of ovarian cancer with 99.9 percent specificity and a positive predictive value of 40 percent.

Given the relative rareness of ovarian cancer – around one in 2,500 in the post-menopausal population – and the fact that a definitive diagnosis requires surgery and removal of the ovaries, such high specificity and PPV are "absolutely crucial" requirements for any screening test for the disease, Karen Lu, a researcher at MD Anderson Cancer Center and first author on the paper, told ProteoMonitor.

Developed in the mid-1990s by Steven Skates, a researcher at Massachusetts General Hospital, and University of Manchester researcher Ian Jacobs – both co-authors on the Cancer paper – the ROCA test uses longitudinal measurements of the ovarian cancer protein marker CA125 combined with transvaginal ultrasound to enable early detection of the disease.

Identified in the early 1980s as a potential ovarian cancer marker, CA125 has to date not proven suitable as an early detection screening tool due to a lack of specificity and the difficulty of establishing universal cutoff values given the natural variation of the protein's expression levels in the normal population.

The ROCA test, however, uses repeated CA125 measurements over a series of years, allowing patients to serve as their own controls. Women are given an initial CA125 measurement based upon which they are assigned different levels of follow-up. In the case of a low-risk score, patients are instructed to come back for an additional CA125 measurement in a year; in the case of an intermediate-risk score, they are instructed to come back for an additional measurement in three months; and, in the case of a high-risk score, they are given a transvaginal ultrasound and referred to a gynecological oncologist.

Of the 4,051 women followed in the Cancer study, 5.8 percent of women were referred each year to the three-month follow-up CA125 test and 0.9 percent each year were referred to ultrasound and examination by a gynecological oncologist. In total over the 11 years, 10 women underwent surgery based on the test. Four of these women had invasive ovarian cancers; two had ovarian tumors of low malignant potential; one had endometrial cancer; and three had benign ovarian tumors.

The study, Lu said, was not sufficiently powered to provide sensitivity data, but, she noted, the ongoing UK Collaborative Trial of Ovarian Cancer Screening, of which Manchester's Jacobs is the principal investigator, will allow for determination of the ROCA test's sensitivity as well as collection of survival data.

"Oftentimes when we have an early kind of excitement [from a trial] that is preliminary, we then have to say, 'Ok, let's start planning for the definitive trial,'" Lu said. "But in this case, the definitive trial is actually ongoing." In fact, she noted, the UKCTOCS researchers have completed the CA125 screening portion of the work and "are now just waiting for the survival analysis."

Launched in 2001, the UKCTOCS is following 200,000 women age 50 and over who have been randomized to either a screening arm – half of which will receive ROCA testing and half of which will receive ultrasound – or a standard of care arm. Results from the trial are expected by 2015, Lu said.

Ovarian cancer had been a significant focus of proteomics research, especially on the commercial side of the field, with a number of protein biomarker firms including Correlogic, Healthlinx, Vermillion, and Fujirebio having developed tests for the disease.

While Correlogic shut down in 2011 after selling its remaining assets to Vermillion in bankruptcy proceedings (PM 12/2/2011), and Healthlinx went into bankruptcy in May, Fujirebio and Vermillion have managed to bring US Food and Drug Administration-approved ovarian cancer diagnostics to market, offering, respectively, their ROMA and OVA1 tests.

Both of these tests, however, are approved specifically for aiding treatment of patients presenting with a pelvic mass, helping to determine whether they should be referred to a gynecological oncologist for surgery. As such, Lu said, they don't overlap with the ROCA test, which is intended as a general ovarian cancer screening tool in asymptomatic post-menopausal women.

UK biomarker firm Abcodia owns the rights to the ROCA test, which it has licensed from Skates and Jacobs. The company declined to comment on any commercialization plans. Abcodia has also licensed from Jacobs the 500,000 serum samples he collected for the UKCTOCS trial, which it plans to use in biomarker development and validation collaborations in a number of diseases.

Lu said that she and her colleagues at MD Anderson are also investigating other protein markers to see if they might increase either the sensitivity or the breadth of the test. As she noted, CA125 is elevated in around 80 percent of ovarian cancers, "but there are some less common subtypes" that the protein is not useful in detecting.

"So one reason to add markers would be to increase the number of ovarian cancer subtypes that are covered," she said. "We would also love to have an additional marker that could pick up [ovarian cancer] even earlier."

She declined to say which markers the researchers were investigating. In the Cancer paper the authors cited the proteins HE4, CA72.4, and MMP7 as markers that are "being studied alone and in combination to evaluate whether they potentially increase sensitivity without decreasing specificity."

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