Enhancing Ovarian Cancer Diagnosis
Adding a Symptom Index Improves CA-125’s Sensitivity
By Deborah Levenson
Ovarian cancer causes symptoms common to other, less serious maladies and lacks a reliable screening assay. CA-125, a biomarker approved to detect residual disease, often plays a role in diagnosis as well, but it’s limited in specificity and is elevated above reference levels in only about 50%–60% of women with clinically detectable, early-stage disease. While several research teams are developing new screening and diagnostic assays based on panels that include other serum markers, a recent paper reports that using CA-125 in combination with an index of symptoms may offer a viable screening option. This issue of Strategies examines those findings.
Ovarian cancer is the second most common gynecologic cancer in the U.S., but more than 70% of women with the disease are diagnosed at its advanced stage, when cure rates are just 20%–30%. In contrast, cure rates exceed 70% for stage I and II disease, so early detection is crucial. For years, investigators and physicians thought that ovarian cancer’s symptoms developed only in later stages, but research from Seattle’s Fred Hutchinson Cancer Research Center, University of Washington , and the University of Pennsylvania has since found that many women with early-stage disease report up to three symptoms commonly associated with ovarian cancer.
Now that same research team has found that combining CA-125 with an index of symptoms including bloating, abdominal pain, and difficulty eating at least 12 times per month has a sensitivity that exceeds CA-125’s usual 50%–60%. New data show the combination approach has a sensitivity of 89.3% in both high- and low-risk women (95% CI, 80.1—95.3), 80.6% for those with early stage tumors (95% CI, 62.5—92.5), and 95.1% for later stage disease (95% CI, 83.5—99.4%). The strategy’s specificity is 83.5% for all three groups (95% CI, 79.3—87.8). However, 11.8% of the study’s high-risk women without cancer would have received false positive results from the dual strategy, according to the research. (Cancer 2008; 113: 484-489).
The results are based on data from 254 healthy women deemed at high risk for ovarian cancer because of family history and a case group of 75 women with ovarian cancer. Scheduled for surgery to remove pelvic masses at enrollment, the case group patients subsequently got ovarian cancer diagnoses. Control patients participated in a screening program for high-risk women and therefore were probably more aware of ovarian cancer’s symptoms than most women, the researchers pointed out. They used logistic regression analysis to determine the success of CA-125, the symptom index, and a dual approach at catching cancer.
Neither CA-125 nor the symptom index by itself is a good screening tool, but adding the index “definitely helped identify people whom CA-125 alone would have missed,” said researcher M. Robyn Andersen, PhD, associate member at the Fred Hutchinson Cancer Research Center. “Not everyone with ovarian cancer is CA-125 positive, nor do they all report symptoms,” she said, noting that this makes a combination strategy worth pursuing. But she cautioned, “We’re not currently recommending this strategy for women with average risk—only those at high risk for ovarian cancer who would generally be screened using CA125 anyway.”
Calling for Validation
Andersen and colleagues say their approach needs more validation, and two noted laboratorians with expertise in ovarian cancer agreed, especially if the strategy is ever expanded to women of average risk. “The strategy must be tested in much larger, multicenter populations, maybe as part of a large, ongoing study of early detection in both low-risk and high-risk women,” remarked Martin Fleisher, PhD, chairman of the Department of Clinical Laboratories and Chief of Clinical Chemistry at Memorial Sloan Kettering Cancer Center in New York.
Fleisher, who looked at the combined strategy as a possible tool for lower-risk women, wasn’t excited by it, based on the reported data. “I don’t know if [sensitivity of] 89.3% overall is good enough. This strategy is still missing lots of people. You’d like to identify 99% of cancer cases,” he said.
Also failing to muster enthusiasm, based on the strategy’s specificity, was Daniel W. Chan, PhD, professor of pathology, oncology, radiology, and urology and at the Johns Hopkins Medical Institutions in Baltimore. He likes the idea of combining CA-125 and symptoms to screen for ovarian cancer, but cautioned, “The specificity is just too low. This will generate too many false positives in the non-cancer group,” said Chan, also the director of the Center for Biomarker Discovery at Johns Hopkins.
Chan took issue with the authors’ definition of a positive symptom index as either a positive CA-125 result or having one of the mostly nonspecific symptoms, explaining that the approach will lower specificity. “There is also a lack of reported positive and negative predictive values in the targeted population,” he added. “I’m not saying the approach should be totally abandoned, but it needs some refinement and validation in a large population from multiple institutions.”
In contrast, the clinician researcher who discovered CA-125 was more upbeat about the potential for this strategy in both low- and high-risk women and praised the idea of using symptoms to identify additional women with the disease. Robert Bast, Jr., MD, vice president for translational research at M.D. Anderson Cancer Center in Houston, was concerned, however, by the 11.8% false-positive rate. “That’s quite high when you consider the patient anxiety raised by hearing that she might have ovarian cancer and by the next steps required in a patient’s workup. This strategy could generate an enormous number of ultrasounds and even many unnecessary operations if applied to all women with commonly occurring symptoms,” he explained. Calling Andersen’s data “the equivalent of a learning set,” Bast called for extensive, prospective validation of the data, particularly in women getting care in general medical practices to estimate the true specificity of the combined screen and its ability to detect women with early-stage ovarian cancer.
Other Tests and Novel Markers
Meanwhile, LabCorp recently launched a new multimarker screening test for high-risk women. OvaSure employs leptin, prolactin, osteopontin, insulin-like growth factor II, and macrophage inhibitory factor along with CA-125 to diagnose ovarian cancer at all stages. But FDA has questioned claims in the company’s promotional materials, and the Society of Gynecologic Oncologists has called for additional validation of the test.
Fleisher, Chan, and several other researchers continue to develop other multimarker screening tests for ovarian cancer. Like the laboratorians, Andersen expects such an assay to become common in the near future. But she believes her strategy, with proper validation, might improve detection in the interim. Even after better ovarian cancer assays become part of routine care, “the women’s reports of symptoms might play a role analogous to checking for lumps in breast cancer,” she postulated.