November 9, 2006

In this Issue...

Detecting Early-Stage Ovarian Cancer: A Futile Attempt?
by Julie McDowell

Of all the cancers afflicting a woman’s reproductive system, ovarian cancer is the deadliest. Most cases are diagnosed too late—when the cancer has already spread to other organs. Because research has shown that ovarian cancer has a survival rate of 90% if diagnosed during stage 1, the medical community had high hopes for early detection of gene mutations associated with an increased risk for developing this cancer. However, a recent evidence report from the Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) indicates that genomic testing for ovarian cancer has failed to decrease deaths from this disease. This issue of Strategies examines this report, and what clinical laboratorians need to be aware of when testing for ovarian cancer.

Genomic testing for ovarian cancer primarily focuses on two areas: detecting genetic mutations associated with increased risk and identifying genetic changes that predict response to therapy in women diagnosed with ovarian cancer. However, genomic tests have not been shown useful in diagnosing either symptomatic or asymptomatic women, according to a new evidence report, Genomic Tests for Ovarian Cancer Detection and Management, published by AHRQ in October. In addition, a computer simulation model developed by the researchers indicates that annual screenings are unlikely to reduce deaths by more than 50%, even with the most accurate tests.

“The prospect of new strategies for the prevention of ovarian cancer morbidity and mortality based on greater understanding of the molecular biology of the disease is exciting; unfortunately, we did not find any evidence that currently available tests have had a substantial impact on improving patient outcomes,” wrote the authors in the report’s executive summary. “Our modeling work suggests that the natural history of ovarian cancer may make substantial mortality reductions difficult using a strategy based primarily on screening. Although research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.”

In the report, tests were considered to be genomic tests if they fell into one of the following four categories:

  • Tests for the presence or quality of a single gene product—for example, a radioimmunoassay for CA-125;
  • Tests for inherited or acquired mutations in genes which are associated with an increased risk for developing ovarian cancer, or which predict differential responses to therapy. Testing for polymorphisms of BRCA 1 or 2 is one example;
  • Tests for quantitative expression of either single or multiple genes that convey differential patterns of expression between normal and ovarian cancer patients that may aid in diagnosis and management, or help identify potential new single gene products for evaluation as screening and diagnostic tools; and
  • Tests for protein expression, particularly in serum, that identifies differential patterns between normal patients and patients with ovarian cancer.

The review analyzed findings from a range of tests—from those for BRCA 1 and BRCA 2 and CA-125, as well as those that identify gene expression patterns, explained Evan R. Myers, MD, MPH, one of the study’s lead authors. While the BRCA 1 and 2 tests are used to assess an increased risk, other tests are used for screening, diagnosis, and management purposes (see pgs. 14-15 of the report for a listing of current usage of genomic tests in ovarian cancer, Assays measuring CA-125 have been approved by the Food and Drug Administration (FDA) for monitoring treatment for ovarian cancer. However, Myers explained that CA-125 is useful as a diagnostic aid to ultrasound testing. For example, if a postmenopausal woman has a mass that is detected by an ultrasound, evaluating CA-125 levels can help make the diagnosis.

If it's positive, it's much more likely that she has ovarian cancer, and if it's negative, it's not as likely that she has cancer,” he explained. “In that setting, a positive test would usually lead to surgery, a negative test to follow-up in a few months.” In terms of screening guidelines, CA-125 testing is not recommended for screening purposes, but a 1994 consensus statement from the National Institutes of Health recommends annual or semiannual evaluation of these protein levels for women determined to have an increased risk for developing ovarian cancer, including women between the ages of 25–35 who are carriers of the BRCA1 mutation.

Many researchers had hoped that early screening for ovarian cancer would follow the same path as cervical cancer screening. Through routine Pap smears and testing for the virus that causes this cancer, human papilloma virus (HPV), cervical cancer can often be identified in the earliest stages. “Part of the reason that screening for cervical cancer has been so effective is that it’s a cancer that has a single cause, that people are exposed to it within a relatively narrow time frame when they are most sexually active. But most importantly, the common types of this cancer are squamous for the most part,” said Myers, who is Professor and Chief of Duke University’s Division of Clinical and Epidemiological Research, Department of Obstetrics and Gynecology in Durham, N.C. “It grows slowly, so there’s a long time where you can detect it. It also has a detectable precancerous stage.”

With the exception of lung cancer, many of the cancers arising from these squamous cells tend to grow relatively slowly. But cancers that arise from gland-forming cells, called adenocarcinomas, tend to be more aggressive and metastasize to lymph nodes or other organs more quickly, explained Myers. Most ovarian cancers are adenocarcinomas that arise from the surface of the ovary,” he added. “Ovarian cancers are more likely to spread quickly, compared to cervical cancers, both because of the cell type and because the ovaries are already in contact with the organs that ovarian cancer typically spreads to, so it's physically easier for the cancers to spread.”

Because of the way the ovarian cancer cells behave, there’s simply not much time for detection prior to when the cancer has already reached the advanced stages. Even if there were a very sensitive test, it’s unlikely that ovarian cancer deaths would decrease by more than 50%, unless screening was done more than once a year. However, this might not be practical, since its hard enough encouraging women to get annual exams, much less a test every six months, said Myers.

How should clinical laboratory directors approach these findings? Myers hopes that lab directors will cast a skeptical eye on tests—both screening and diagnostic—for ovarian cancer. “Clinical lab directors should be very wary about claims concerning screening tests for ovarian cancer,” he explained. “For diagnostic tests, the jury is still out, we just didn’t find very much that has been shown to be better than CA-125. It does have a role in helping make the diagnosis of ovarian cancer, especially in postmenopausal women. One of the things that we recommend is directly comparing any new test to CA-125.”

More Evidence Reports on the Way

The new report represents the first in a series of systematic reviews that will be conducted through a partnership between AHRQ and a CDC pilot program called the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). The findings from the report will be forwarded to the EGAPP Working Group, who will develop conclusions and recommendations based on the evidence.

Over the next year, the EGAPP Working Group is expected to publish recommendations based on four evidence reviews currently in process. An evidence report on testing adults with depression for cytochrome (CY) P450 polymorphisms is scheduled to be released by AHRQ in the next two months. This report will evaluate published studies on whether testing for these polymorphisms in adults taking selective serotonin reuptake inhibitors for depression improves outcomes, as well as the analytic and clinical validity of tests that identify key CYP450 polymorphisms.

CDC established the pilot program in April 2005, explained Linda Bradley, PhD, EGAPP Project Director in the agency’s National Office of Public Health Genomics. “It’s a pilot project to implement and evaluate a process for systematic review of genomic applications that are transitioning from research to practice,” she added. Experts from Department of Health and Human Services agencies, including AHRQ, the National Genome Research Institute, FDA, Centers for Medicare & Medicaid Services, and the Health Resources Services Administration were involved in planning EGAPP, and many are still involved. “The goal was to put together an independent non-federal working group, which is currently composed of 13 multidisciplinary experts. EGAPP has members with a lot of experience doing evidence-based reviews, including current and former members of the U.S. Preventive Services Task Force, as well as members from the public health, clinical laboratory, genomics, ethics, and epidemiology sectors.”

Like the report on ovarian cancer testing, some of the other EGAPP reports will be done by AHRQ evidence-based practice centers, which are considered to have a gold standard approach to evidence reviews. Other reviews will likely be done through an independent contractor. “For tests that have broad public applications and a large volume of literature, it will be necessary to use a format like AHRQ’s, because they have the knowledge and ability to do these kinds of really large and complex in-depth reviews,” said Bradley. “But other topics that have a very small literature volume might be tackled in a different way using a more targeted or rapid turnaround process, especially if there’s important information that we want to get it into practice appropriately or potential harm that needs to be looked at before a test goes into practice.”

For more information:

The entire “Genomic Tests for Ovarian Cancer Detection and Management” report can be found online

Additional information on EGAPP can be found on CDC’s Website,

The NIH Consensus Statement is available online at the National Cancer Institutes’ Web page on Genetics of Breast and Ovarian Cancer,

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