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 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
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
"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
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
"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,"
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."