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Genetic Tests Further Complicate Ovarian Cancer Controversies

Genetic Tests Further Complicate Ovarian Cancer Controversies

Oncologists still have no screening test that reliably can detect ovarian cancer in its early stages, and recent genetic advances, while shedding new light on the disease, have further complicated the issue.

"The recent identification of many of the genes responsible for inherited ovarian cancer risk has added further complexity and controversy to screening efforts," said Beth Y. Karlan, md, director of the division of gynecological oncology, Cedars-Sinai Medical Center, Los Angeles, and associate professor of obstetrics and gynecology, UCLA School of Medicine.

Evidence suggests the BRCA1 and BRCA2 genes account for only about 5% to 10% of all breast and ovarian cancers, but probably cause most cases of familial breast-ovary cancer syndrome and site-specific ovary cancer syndrome, she told the American Cancer Society's National Conference on Cancer Prevention and Early Detection, sponsored, in part, by the Centers for Disease Control and Prevention.

MLH1 and MSH2, both DNA mismatch repair genes, appear responsible for many cases of the familial cancer syndrome or Lynch syndrome II, including ovarian, endometrial, and nonpolyposis colon cancers, she said. However, she added, "the clinical usefulness of these new genetic tests is still uncertain."

BRCA1 Testing Most Controversial

The most notable controversy surrounds BRCA1 testing, she said. Women with BRCA1 mutations have an estimated risk of 48% for ovarian cancer and 87% for breast cancer by age 70. The list of BRCA1 mutations is both long and growing. Recently, investigators have found that about 1% of Ashkenazi Jewish women (Eastern European descent) carry a specific mutation, known as 185delAG. As a result of such findings, requests from asymptomatic women for BRCA1 screening have soared.

However, Dr. Karlan said, "The number of scientific uncertainties that exist due to the heterogeneity of the BRCA1 phenotype and differences in disease penetrance make medical recommendations based on these findings difficult."

Effectively screening asymptomatic women could markedly reduce the toll from ovarian cancer. Projections put its 1996 death toll in the United States at 14,800 and the number of new cases at 24,700.

"With symptoms rarely present in early disease, the majority of ovarian cancer patients first seek medical attention only after the tumor is already metastatic," Dr. Karlan noted. "Stage for stage, however, ovarian cancer has approximately the same prognosis as breast cancer. Finding an effective means of early detection for asymptomatic women would likely shift the stage distribution of ovarian cancer to favor earlier stage disease and thereby improve the survival and quality of life for these women."

Little Change Since 1994 Consensus Conference

Dr. Karlan said little had changed, however, to clarify the usefulness of screening asymptomatic women since the National Institutes of Health's 1994 Consensus Conference on Ovarian Cancer. Its report concluded that scientific data did not support the general use of the best studied and most commonly used screening tests, transvaginal sonography and the CA 125 serum tumor marker. It further warned that the test might increase rather than decrease morbidity and mortality by increasing the number of unnecessary bilateral oophorectomies among screened women.

Transvaginal sonography can show changes in the structure of the ovaries, but the specificity of these changes have proved a problem. To improve transvaginal sonography's accuracy in ovarian cancer screening, a number of teams have coupled it with color Doppler imaging. "Unfortunately, in the screening setting, color Doppler has not been able to reliably detect tumor-associated neoangiogenesis," Dr. Karlan said.

CA 125, an antigen shed by the majority of epithelial ovarian cancers, has not proved successful in screening asymptomatic women for early tumors, she added, in part because of "the large number of benign conditions that are associated with CA 125 elevation, as well as the fact that CA 125 is only elevated in 23% to 50% of patients with stage I ovarian cancers."

Nonetheless, the consensus panel did urge that high-risk women undergo annual pelvic and rectovaginal examinations and transvaginal sonography and CA 125 screenings.

Dr. Karlan also noted that transvaginal sonography and CA 125 are currently being evaluated in high-risk women as part of the National Cancer Institute's PLCO (prostate, lung, colon, and ovary) cancer screening trial. Study investigators plan to ultimately enroll a total of 74,000 women over age 60 for ovarian cancer screening.

"While some investigators have debated the cost effectiveness of the currently available screening modalities, we must first determine the effectiveness of these tests in diagnosing early ovarian cancer and in reducing disease-specific mortality," she said.

Dr. Karlan also cited significant barriers to developing effective screening tests. The location of the ovaries within the peritoneal cavity greatly limits access for direct examination. Furthermore, and because the cancer frequently has reached an advanced stage before detection, researchers have had difficulty in identifying early genetic alterations and other factors that lead to the transformation of ovarian cells.

Nonetheless, investigators have turned to a number of novel approaches to explore the physical and molecular characteristics of ovarian tumors, she said. The Human Genome Project and other molecular genetics findings are providing insights into carcinogenesis that could have important implications for the malignancy.

"Ovarian cancer is a serious disease of increasing magnitude," she concluded. "A clinically applicable marker for early disease detection is urgently needed to reduce disease mortality."

 
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