Advancements in Ovarian Cancer Biomarkers

Ovarian cancer is the sixth most common cancer in women and causes approximately 152,000 deaths every year worldwide. Unfortunately, it is often not found until the later stages, and the overall five-year survival rate is around 40 percent. This percentage increases when ovarian cancer is discovered in stages I or II.

Earlier detection is constantly at the forefront of ovarian cancer research, and biomarkers can be helpful in detection.

In 1965, scientists introduced the first serum biomarker for epithelial ovarian cancer, which was a significant milestone. However, biomarkers in ovarian cancer have not progressed as much as those in some other cancers, and early identification remains a significant challenge.

"Accurate biomarkers for screening or detection of the most common epithelial type of ovarian cancer are lacking," said Steven Vasilev, M.D., a board-certified integrative gynecologic oncologist and medical director of this field at Providence Saint John's Health Center, and a professor at Saint John's Cancer Institute in Santa Monica, California.

"This is unfortunate because 75 percent of all ovarian cancers are diagnosed in late stages, when cure is possible in less than half the cases," he added.

"Biomarkers can help determine the next course of action," said Guillermo De Angulo, M.D., a board-certified pediatric oncologist at Nicklaus Children's Hospital and KIDZ Medical Services in Miami.

For example, germ cell tumors form from reproductive cells and mainly occur in the testicles or ovaries.

"Certain ovarian tumors in the pediatric world are of the germ cell variety and produce alpha-fetoprotein [AFP] or human chorionic gonadotropin [hCG] biomarkers," De Angulo said. "So if you take the ovarian tumor out and these biomarkers drop to zero, then you know that patient is free of disease. However, if the biomarker does not drop or increases, then chemotherapy will be needed."

Only a few tumors in ovarian cancer produce biomarkers.

"A biomarker will not be useful if you have a tumor that does not express that biomarker," De Angulo added.

Vasilev explained that if a doctor discovers an ovarian mass through imaging studies, such as ultrasound, then biomarkers can help differentiate whether the mass may be malignant.

Examples of these types of biomarkers are:

• CA-125 (cancer antigen 125): This is a substance produced by some ovarian cancer cells. High levels of CA-125 in your blood could be a sign of ovarian cancer, but other conditions, such as endometriosis, can also cause increased levels.
• CEA (carcinoembryonic antigen): These antigens are produced by some types of cancer. A CEA blood test can sometimes help diagnose and manage ovarian cancer.
• CA 19-9 (cancer antigen 19-9): This is a protein that has heightened levels in some women with ovarian cancer. However, clinicians cannot use this test alone to diagnose ovarian cancer.

"These markers are more helpful after menopause, as they can be highly inaccurate in premenopausal women," Vasilev said.

"Newer, multifactorial biomarkers, such as OVA-1 combined with the reflex test Overa for indeterminate results, are helpful to decipher if a gynecologic oncologist should be involved in the surgery if cancer-staging biopsies become necessary," he added.

Only a limited number of tumor markers for ovarian cancer are cleared by the U.S. Food and Drug Administration (FDA). OVA-1 and Overa are FDA-cleared blood tests for ovarian cancer that help determine cancer risk in women presenting with an adnexal mass, a growth in the pelvic region.

"These tests are not FDA-approved for deciding whether or not to proceed with surgery," Vasilev explained. "Rather, they are only meant to help guide which surgeon should be involved due to the level of cancer risk."

Screening for ovarian cancer remains complicated.

"Currently, the U.S. Preventive Services Task Force does not recommend screening using biomarkers or ultrasound in asymptomatic women without known high-risk hereditary cancer syndrome," Vasilev said. "The reason is that current markers are very inaccurate, and the risks are significant. These risks include death from unnecessary diagnostic surgery when the biomarker is falsely elevated in the absence of cancer."

Detecting ovarian cancer in its early stages could significantly improve outcomes for women. Unfortunately, researchers have yet to find accurate screening methods for early disease due to the complexity of ovarian cancer.

"The future lies in molecular analysis of circulating cell-free DNA found in the blood from tumor cells in the body that die and release their DNA," Vasilev said. "This is called a ctDNA 'liquid biopsy' and is currently being incorporated into the management of advanced cancer cases."

However, Vasilev explained that the accuracy of liquid biopsies for screening is not yet established, and the biopsies can lead to false positives—meaning the test can be positive, but there is no cancer present in the body.

"Research in this area is rapidly progressing," he said. "In the future, liquid biopsies may help with screening, early detection, monitoring for recurrence, earlier detection of recurrence and, based on the actual molecular defects found in the DNA, may help guide therapy, as well."