NEW YORK (360Dx) – A decade or so after several high-profile failures, ovarian cancer researchers are again looking to multi-analyte protein assays for early detection of the disease.
In March, diagnostics firm Vermillion said during its Q4 2017 earnings call that it hopes to launch a study in Israel to explore use of its OVA1 and Overa tests in place of the established ovarian cancer marker CA125 for monitoring patients with BRCA1/2 mutations who are at high risk of developing the disease.
Last week, Steven Skates, an associate professor at Harvard Medical School and one of the developers of the ROCA (Risk of Ovarian Cancer Algorithm) test, which uses longitudinal measurements of the ovarian cancer protein marker CA125 and background risk due to age and any germline mutations combined with transvaginal ultrasound to detect ovarian cancer, told 360Dx that he and his collaborators are similarly looking at whether adding markers beyond CA125 might improve the performance of their assay.
Skates said that he and his colleagues are "evaluating multiple panels and have a variety of investigations going on at multiple stages."
Ovarian cancer was a main area of focus in the early days of proteomic test development. The disease has bleak overall survival rates but is highly curable if caught early, making it the subject of keen interest among researchers exploring biomarkers for early cancer detection.
Few of these early proteomic efforts panned out, however. Most notoriously, LabCorp pulled its proteomic ovarian cancer test OvaSure off the market in 2008 in response to concerns from the US Food and Drug Administration about the assay's development and validation. Other early proteomics players in ovarian cancer like Correlogic and and Healthlinx went out of business as they were either unable to move their tests through FDA or drive physician adoption.
Vermillion managed to win FDA clearance for OVA1 and bring it to market, but that test is intended not for monitoring or early detection of ovarian cancer but rather for assessing the likelihood that a patient presenting with an adnexal mass has ovarian cancer or benign disease and for helping decide if they should have surgery done by a gynecologic oncologist or an Ob/Gyn.
Vermillion's announcement that it is planning a study looking at the effectiveness of OVA1 and its second-generation test, Overa, for monitoring women with BRCA1/2 mutations represents a potential new application for the test.
Women with BRCA1/2 mutations are typically recommended for ovary removal, or risk-reducing salpingo oophorectomy (RRSO). However, some women decline to undergo this procedure, and in such cases regular CA125 measurements are used for monitoring in hopes of detecting cancer early if it develops.
CA125 has a poor track record as a biomarker, however, with low sensitivity for early-stage ovarian cancer a particular shortcoming. OVA1, meanwhile, has demonstrated significantly higher sensitivity (91 percent compared to 66 percent in stage I and II ovarian cancer, according to data from Vermillion), which suggests it might improve upon CA125's performance for monitoring this high-risk patient group.
"Understanding how OVA1, Overa perform in this [BRCA1/2-positive] cohort of women that is at the highest risk of developing ovarian cancer is crucial to expand the clinical utility of our tests," Valerie Palmieri, Vermillion's president and CEO, said last week on the company's Q1 2018 earnings call.
While Vermillion is taking an established multi-marker proteomic test and looking to move it towards monitoring applications, Skates and his collaborators are coming from the opposite angle — starting with monitoring and early detection efforts based around the single marker CA125 and looking to move them in the multi-marker direction.
The ROCA test, which was developed by Skates and University of New South Wales researcher Ian Jacobs and is marketed by UK-based diagnostics firm Abcodia, uses longitudinal CA125 measurements combined with transvaginal ultrasound to boost the marker's power. By repeating CA125 measurements over a series of years, the test uses patients as their own controls, the idea being that this can allow doctors to detect small but significant changes that might be missed comparing the marker against population-based cut-off scores.
The ROCA test has shown promise in some studies, including a 2013 Cancer study by MD Anderson Cancer Center researchers that found it could identify cases of ovarian cancer with 99.9 percent specificity and a positive predictive value of 40 percent in a cohort of 4,051 women followed over 11 years. A 2015 study published in the Journal of Clinical Oncology by a team led by Skates and Jacobs, who is a non-executive director at Abcodia, detected 86 percent of ovarian cancers with specificity of 99.8 percent in a cohort of 46,237 post-menopausal women age 50 years or older from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). A pair of 2017 studies, one in Clinical Cancer Research and the other in the JCO, found that the ROCA test could be useful for monitoring BRCA1/2-positive women who decline to undergo RRSO.
However, some parties, including the FDA, have argued that the test still does not have data supporting its use either for monitoring high-risk patients or the general population. In September 2016, the FDA issued a communication that recommended against using blood-based ovarian cancer screening tests, and the ROCA test specifically.
Abcodia had launched the test in a limited release in the US and UK in 2015, but suspended sales in the US and limited them in the UK in response to the FDA letter.
The UKCTOCS study has shown that the ROCA test can help shift the stage at which ovarian cancers are discovered to earlier, but whether this will improve mortality rates is not yet known. UKCTOCS researchers are currently conducting additional follow-up on patients to assess what, if any, reduction in ovarian cancer deaths resulted from using the test, and these results are expected in 2019.
In the meantime, Skates and his colleagues are looking to see whether adding markers to CA125 can boost the performance of their longitudinal approach.
"We're certainly looking at longitudinal algorithms based on panels that include CA-125 and other markers," he said, "and hopefully the extra markers will add to the sensitivity."
A study published last year in Clinical Cancer Research led by MD Anderson Cancer Center Professor Robert Bast, identified the autoantibody TP53 as elevated in ovarian cancer well before rising CA125 levels could be detected.
"TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 holds promise for earlier detection of invasive epithelial ovarian cancer," the authors wrote.
In a 2016 study in the International Journal of Gynecological Cancer, Bast and his colleagues identified a four-protein panel that distinguished between 142 stage I ovarian cancer cases and 217 healthy controls with 83.2 percent sensitivity at 98 percent specificity, and which, they wrote, could be suitable for "longitudinal algorithm development."