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Immune Response Marker Has Potential to Improve Ovarian Cancer Screening, Study Says

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NEW YORK – Australian researchers are taking aim at detecting advanced ovarian cancer by developing a blood test that includes interleukin-6, an immune system indicator of inflammation, along with other more established clinical markers.

The research group reported clinical results from a study published recently in Scientific Reports in which they saw increased sensitivity in testing for advanced ovarian cancer by combining IL-6 with traditional clinical risk scores and CA-125, an antigen well established for use in ovarian cancer screening. 

Magdalena Plebanski, senior author of the study and a professor at Royal Melbourne Institute of Technology (RMIT), said that she and her colleagues will need to replicate the results of the current study in a large-scale clinical trial to determine whether the findings could have a clinical impact. Nonetheless, she said, the research demonstrates that IL-6 used in combination with other markers and clinical inputs warrants further investigation, including whether the marker has potential for improving early detection of ovarian cancers.

As a result, the Australian researchers are seeking clinical collaborators interested in developing a screening test who have access to samples from women with early-stage ovarian cancers, she said.

"Our study demonstrated that by adding CA-125 to a simple immune cytokine, interleukin 6, we may be able to substitute for ultrasound and achieve better sensitivity in classifying between benign and malignant masses," Plebanski said in an interview.

In particular, the approach may have potential for use in ovarian cancer screening at the point of care, she added. A blood-based test that uses immunological markers for the detection of ovarian cancers is not available in clinics. However, such a test could enable physicians to decide whether it is necessary to refer patients for additional testing, including use of ultrasound along with other biomarkers and scores, Plebanski said.

About 94 percent of patients live longer than five years after diagnosis of early-stage ovarian cancer but only about 20 percent of all ovarian cancers are found at that early stage, according to the American Cancer Society.

In trying to diagnose the disease, clinicians use pelvic exams, transvaginal ultrasound, and CA-125 blood tests, but each method has its limitations. Checking CA-125 levels, for example, has not been found to be useful for screening, because conditions such as endometriosis and pelvic inflammatory disease often trigger high levels of the biomarker, according to the American Cancer Society.

Ephraim Tsalik, an associate professor of medicine at the Duke University School of Medicine, said there is a need for a blood-based marker for screening in women who have no signs of ovarian cancer. Notwithstanding the Scientific Reports study findings, however, IL-6 alone is not likely to have an impact on clinical decisions, he said. "I don’t doubt that IL-6 levels were higher in women with high-grade ovarian cancer as compared to those with benign lesions or healthy controls," said Tsalik, who was not involved in the ovarian cancer study. However, "once there’s a clinical suspicion, as for the women in this case, no clinician is going to stop evaluating the possibility of ovarian cancer without a biopsy."

He noted that in the study, differences were greatest between cancer and healthy ovaries, and women whose ovaries appear healthy can be screened currently through routine ultrasound and other methods.

According to Plebanski, by combining IL-6 and CA-125 with clinical risk scores, they were able to demonstrate increased sensitivity over use of ultrasound alone. "We've found that adding particular immune factors may further improve diagnosis of current advanced ovarian cancer tests," she said.

The approach may have a role as a substitute for ultrasound in specific screening settings, Plebanski said, adding that such a test could, in the future, be made available at the point of care for screening women who live in disadvantaged or distant communities and have no access to routine ultrasound testing equipment.

If the clinical utility of the approach can be further validated and obtain approval from regulators, translating the combined set of biomarkers to the clinic should be easy to accomplish because both biomarkers are already available for clinical testing, she said.

In diagnostic testing, elevated levels of IL-6 can indicate inflammation, infection, autoimmune disorders, cardiovascular diseases, and some cancers. Though CA-125 is not considered robust enough to discriminate benign from malignant masses when it is used by itself, it is currently the most important single biomarker used for epithelial ovarian cancer management.

Among tests available for ovarian cancer diagnosis, Vermillion's OVA1 proteomic test is meant to help doctors evaluate whether a patient with a pelvic mass is at high risk of having ovarian cancer and should be referred to a gynecologic oncologist for surgery. The test uses five biomarkers, including CA-125, to assess risk. In a sign of potential market acceptance, the Austin, Texas-based company last year announced preferred coverage from Blue Cross Blue Shield of Texas and Blue Cross Blue Shield of Arizona as an in-network covered test, taking overall coverage to a total of 167 million people.

Other than the Australian research team, investigators at Uppsala University and the University of Gothenburg's Sahlgrenska Academy in Sweden are also targeting screening and detection of ovarian cancers and are developing a multiplexed test that uses plasma protein biomarkers. Further, the University of Pittsburgh is developing a combined protein assay that measures MIF, OPN, and IL-8 autoantibodies alongside CA-125 to improve the ability to detect early-stage cancer.

Plebanski said she and her colleagues initiated the Australian study because they wanted to improve on existing methodologies and determine whether it is possible to use a blood test to "spare women having to travel thousands of miles in rural Australia to find an ultrasound machine."

With fellow investigators Nirmala Chandralega Kampan at Monash University, Orla McNally at the University of Melbourne, and Michael Quinn at the Hudson Institute of Medical Research, Plebanski kicked off the training phase of the study at the Royal Women's Hospital in Melbourne in 2016.

They recruited 80 women undergoing ovarian removal surgery but excluded 15 patients who had significant concomitant heart, liver, or vascular disease; were taking immunosuppressive drugs; or had concomitant active cancer such as breast cancer, colorectal cancer, or ovarian cancer other than the high-grade type.

Of the remaining 66 women, 33 had newly diagnosed high-grade serous ovarian carcinoma; 12 women had benign ovarian masses; and 21 women in a control group were undergoing risk reduction surgery because of a known genetic mutation or had a family history of ovarian or breast cancers, or both.

In the training cohort, the group evaluated four ovarian cancer tests, including CA-125 and clinical risk scores, along with a panel of 28 immune soluble biomarkers. They also analyzed six promising immune biomarkers alone and in combination with conventional tests, and it emerged that IL-6 was the main driver of variability.

In the training cohort, the combination of IL-6 with current tests improved the overall predictive probability, Plebanski said.

To evaluate the results, the group used a two-step approach to triage women with a suspicious ovarian mass. The first step consisted of identifying patients with IL-6 levels greater than 3.75 pg/ml and the second step included measurements of CA-125 or a risk score. Using the two-step approach, the misclassification percentage of ovarian cancer in patients was reduced to between 3.03 percent and 4.54 percent from between 9.09 and 10.6 percent using CA-125 or a risk score alone.

Further, in the training phase, CA-125 alone showed an area under the curve value of .96 when used to distinguish patients with malignant masses from those with benign masses, while CA-125 along with IL-6 showed an area under the curve value of .99 when used for the same purpose. CA-125 alone showed an area under the curve value of .75 when used to distinguish samples from patients with benign masses on ovaries from samples taken from healthy patients, while CA-125 with IL-6 showed an area under the curve value of .99.

The group implemented a validation phase of the study that consisted of using clinical samples obtained through the Ovarian Cancer Tissue Banking program at the Hudson Institute, Australia. The investigators included 50 women undergoing surgery for a suspected ovarian mass. They also obtained blood from 10 women with histologically confirmed endometriosis and recruited 19 healthy volunteers at the Royal Women's Hospital and Monash University.

Because interleukin-6 is a commonly recognized inflammatory cytokine, its levels can be elevated in conditions other than advanced ovarian cancer, and that necessitated testing the findings obtained during the training cohort in patients with cofounding conditions. In the validation phase of the study, the investigators, therefore, eliminated the inclusion and exclusion criteria that were used in the training phase. 

Seven out of 25 patients with high-grade serous ovarian carcinoma and five out 25 women with benign ovarian masses had complex medical co-morbidities, such as major cardiovascular diseases, complicated or uncontrolled medical conditions, or active autoimmune diseases, or they were taking immune suppressing medications.

In the presence of confounding factors, serum measurements reflected similar diagnostic sensitivity improvements following the addition of IL-6, Plebanski said.

Plebanski added that as an immunologist witnessing the development of treatments that harness the immune system to fight cancer, she is keen to explore how researchers can similarly leverage the immune system for diagnostics.