January 28, 2013

New Developments in Ovarian Cancer Detection
By Carolyn Gutierrez
For The Record
Vol. 25 No. 2 P. 22

Efforts are focusing on early diagnosis, which is key in most cancers but even more so when it comes to this type.

Although a definitive test for the early detection of ovarian cancer remains elusive, recent studies have resulted in promising new biomarkers and patient questionnaires that may enable women to be diagnosed sooner.

It’s believed that approximately 22,280 cases of ovarian cancer were diagnosed in the United States in 2012, resulting in an estimated 15,500 deaths. Considered to be relatively rare, ovarian cancer has a notoriously high fatality rate because more than 70% of patients are diagnosed during the disease’s later stages.

Unlike cancers that grow within solid tissue, ovarian cancer can spread rapidly due to the proximity of the ovaries to other organs within the peritoneal cavity. Because many ovarian cancers start out on the surface of the ovary, it’s believed that ovarian cancer, even in its earliest cellular state, can easily invade neighboring organs, such as the intestines, pancreas, and spleen. Although there has been a slight decrease in the mortality rate over the past 30 years, the overall five-year survival rate in patients with ovarian cancer is less than 45%.

Genetic Factors
About 90% of ovarian cancer cases are considered sporadic, with the remainder thought to be genetically linked. The strongest risk factor for the disease is a hereditary syndrome that studies have shown can increase a woman’s lifetime probability of ovarian cancer between 25% and 50%. Hereditary ovarian cancer syndrome may be present if the patient has had a relatively young (under 50) first- or second-degree family member with ovarian cancer (on both the mother’s and father’s side of the family) or has had multiple family members from the past two to four generations who had ovarian or related cancers.

The most common hereditary syndrome is the breast ovarian cancer syndrome in which there is a mutation of the tumor suppressor genes BRCA1 and BRCA2. Although considered rare in the general population, BRCA mutations have been found in approximately 2% of women of Ashkenazi Jewish descent.

Although not all women who carry the BRCA mutations will necessarily develop ovarian cancer, researchers estimate that 35% to 45% of women with the BRCA1 mutation are at risk, while those with the BRCA2 mutation have a 15% to 25% lifetime risk. However, studies have shown that one-half of the women with BRCA1 mutations did not have a family history of ovarian cancer.

CA 125
Women who are found to have BRCA mutations may be screened via cancer antigen-125 (CA 125), a widely used but extremely limited blood serum-based tumor marker test.

A protein manufactured on the surface of cells, CA 125 is released into the bloodstream. Women with advanced ovarian cancer tend to have high levels of the protein, and use of the CA 125 test can be helpful in monitoring treatment. Used alone, the CA 125 test is not considered to be an effective tool for early screening because it returns a true positive result for only approximately 50% of stage 1 ovarian cancer patients. False-positives are possible with the CA 125 test, as many other conditions, such as pelvic inflammatory disease, endometriosis, cirrosis, and pancreatic cancer, are associated with elevated levels of CA 125.

Overall, studies have shown that the CA 125 test has not significantly reduced ovarian cancer mortality rates. Because early detection is paramount to successfully treating the disease, researchers are evaluating other biomarkers that may act as effective diagnostic tools.

Biomedicine Breakthrough
In 2010, a team of scientists at the Georgia Institute of Technology detected ovarian cancer from a single drop of blood serum with almost 100% accuracy through metabolic profiling using a mass spectrometer and computer algorithms. The spectrometer sorted and analyzed thousands of metabolites—the hormones and by-products of chemical reactions—found in the blood chemistry of 44 women with ovarian cancer and 50 healthy women. A computer model was then created to distinguish and classify the metabolic differences among the cancerous serum and healthy control samples.

According to study coauthor John McDonald, PhD, chief research scientist at the Ovarian Cancer Institute and a professor of biology at the Georgia Institute of Technology, “The metabolite study was an effort to bring in analytical chemists who specialize in mass spectrometry approaches to look for patterns that could potentially be diagnostic [for ovarian cancer].” 

The Georgia Tech study is unique in that McDonald’s research team is not looking at the actions of a single protein such as CA 125 but rather the patterns of 20,000 metabolic characteristics that are recognizable only by computer analysis. “It’s very difficult to analyze that kind of data unless you have a sophisticated computer algorithm, so we brought in an expert on pattern recognition algorithms, which is the same thing they use to do facial pattern recognition,” McDonald says.

The study demonstrates the potential of emerging biomedical technologies to identify significant biomarkers in the blood or other bodily fluids for early disease detection. “The initial run was very successful, and we were able to discriminate cancer patients’ serum from normal with high accuracy,” McDonald notes.

Despite the study’s compelling results, it could be many years until the mass spectrometry test appears in a clinical setting. McDonald says each metabolite must be identified for patent approval and funding, a time-consuming process. “The basic scientific discovery is there, and now it’s a question of getting it into practical terms,” McDonald says.

Cell Stiffness Study
Another Georgia Tech biomarker study indicated that the stiffness of an ovarian cancer cell could be measured to predict its metastatic potential. Scientists have long known that cancer cells appear to be less stiff than healthy cells. The “softness” of metastatic cells is an adaptive characteristic; it gives the cells higher motility to more easily invade blood vessels or lymph systems when spreading throughout the body.

At Georgia Tech, scientists used atomic force microscopy to measure the stiffness of healthy and metastatic ovarian cancer cells. The investigators found that the degree of stiffness seemed to be correlated to the cell’s metastatic potential. These parameters could be another useful biomarker in evaluating metastatic cells in ovarian and other forms of cancer.

As with the spectrometry study, more research is needed before a cell stiffness biomarker can be utilized in a clinical setting.

At McDonald’s Georgia Tech lab, the emphasis is on an integrated approach to cancer study. By combining advanced technologies from diverse fields such as engineering, computational sciences, and molecular biology, researchers can perhaps further refine developing methodologies to detect cancer.

“I think at this point the approach with the most potential to get into clinical practice the quickest is the metabolic profile, and we’re really putting a lot of effort into that,” McDonald says.

Two-Minute Questionnaire
A recent study completed at Seattle’s Fred Hutchinson Cancer Research Center demonstrated that a deceptively simple three-question survey may be a key tool in early detection of ovarian cancer.

As part of a series of ovarian cancer symptom studies performed in collaboration with Barbara Goff, MD, director of gynecologic oncology at the University of Washington School of Medicine, researchers evaluated the effectiveness of several symptom-screening surveys.

The survey that proved to be the most beneficial featured a mere three questions and asked patients whether they had experienced one or more of the following symptoms associated with a risk of ovarian cancer: abdominal and/or pelvic pain, feeling full quickly and/or unable to eat normally, and abdominal bloating and/or increased abdomen size.

Perhaps the most important question in the survey asked women about the frequency and duration of their symptoms. Ovarian cancer specialists consider the frequency and duration of symptoms to be critical indications that further screening may be in order.

Twelve thousand women ranging in age from 40 to 87, more than one-half of them postmenopausal, participated in the study, which was conducted at a Seattle women’s health clinic. About one-half of the participants were visiting the clinic for a health concern or follow-up, and the other one-half was composed of patients receiving mammograms or other routine health exams.

Investigators found a positive symptom score for 5% of the survey participants, who were then advised to receive ovarian cancer testing. Of the 60 women who received additional testing, one was immediately diagnosed with ovarian cancer. During a 12-month follow-up period, none of the 95% of participants with a negative symptom score developed ovarian cancer.

The researchers concluded that with its ease of use and minimal false-positives, a symptom-screening survey might be a viable early detection tool for ovarian cancer in the primary care setting. It’s also believed that a symptom survey might be useful in conjunction with other tests such as the CA 125.

At first glance, ovarian cancer symptoms appear unremarkable and may very well signal other conditions. Yet, in older women, frequent and recurring abdominal symptoms are less than ordinary. Although it is particularly lethal in younger women, ovarian cancer is predominantly considered to be an aging disease, with an average patient age of 60.

M. Robyn Andersen, PhD, lead author of the study and a member of the Fred Hutchinson Cancer Research Center’s public health sciences division, says, “When women get to be age 50, when they go through menopause, those symptoms, in healthy women, decrease. It’s generally a period of relatively fewer lower abdominal symptoms because they are no longer menstruating. The symptoms associated with menstruation should go away with age, and if they come back a year or two after menopause, that’s the time to talk to a doctor.”

To raise awareness and challenge the idea that the disease is “silent,” ovarian cancer survivor groups have been distributing literature detailing the Seattle study’s list of symptoms. “If women bring these symptoms to the attention of their doctor—particularly if they say, ‘This is frequent. This is new to me. I’m concerned about ovarian cancer’—their doctors are very likely to screen them,” Andersen says.

Women with a high risk and unresolved abdominal symptoms lasting for several weeks may be candidates for the CA 125 blood test and/or a transvaginal ultrasound. For women with an average risk, ovarian cancer specialists emphasize that these tests are not recommended because they frequently deliver false-positives in screening trials.

Even more troubling, in a component of the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that looked at multimodal screening with CA 125 and ultrasound, it was found that 15% of the women who had surgery following a false-positive result experienced complications. “If we could best identify who is at the highest risk before they go to ultrasound, that would be the goal so as to reduce unnecessary surgeries for women,” Andersen says.

Until more definitive screening tests come to the forefront, abdominal surgery following a positive ultrasound is often the imperfect next step. Unfortunately, researchers note that by the time ovarian cancer is spotted on an ultrasound, the malignancy has oftentimes already metastasized.

If the cancer is relatively small—even if it is found at later stages—surgeons may be able to completely remove it, leading to a good prognosis. Despite the risks of complications, surgery combined with chemotherapy remains the standard treatment.

Prevention Measures
Because late-stage ovarian cancer continues to have a bleak outlook, with only marginal improvements in US survival rates over the past 30 years, early detection remains the Holy Grail.

“For a diagnostic test to be meaningful, it has to be able to be done in a reasonable fashion within the population,” says Robert Wenham, MD, a gynecologic oncologist at the center for women’s oncology at Moffitt Cancer Center in Tampa, Florida. “So you have to be able to screen in a manner and in a frequency which would impact the disease without terribly impacting the patient.”

As with other forms of cancer, prevention may be possible in some women. Studies have shown that interventions such as birth control pills may decrease the risk for ovarian cancer. “If taken between five to 10 years, birth control pills can decrease a woman’s risk of ovarian cancer by 50% to 70%,” Wenham says. “That’s no small feat right there.”

The United Kingdom’s National Cancer Intelligence Network recently reported a 20% drop in ovarian cancer deaths in England over the past 10 years, particularly in women aged 40 to 69. The protective effects of birth control pills and their widespread use are thought to be partially responsible for the gains.

In the United States, tubal ligations have been shown to reduce the risk of ovarian cancer by 50%. In women with inherited BRCA mutations and a strong family history of breast and ovarian cancers, removal of the ovaries and fallopian tubes may lower their risk for ovarian cancer by 95%.

“I think there is a lot of opportunity to prevent [ovarian cancer]. I think the more we understand how these cancers evolve, the more we’re going to be able to intervene,” says Wenham, adding that “the screening side of things is going to be a little more problematic. We still don’t know if it’s going to be possible to detect early ovarian cancer in which it would be meaningful for a patient. We can detect it earlier, but it’s unclear whether we can detect it early enough.”

— Carolyn Gutierrez is a freelance writer in New York City.