Watching Women's Health

Screening for ovarian cancer — focus on genetic risks

Most women have just over a 1% lifetime risk of developing cancer of the ovary. However, in some families, there are multiple cases of ovarian and/or breast cancer, and risks are much greater. What do we know about inherited susceptibility to ovarian cancer?

The biggest breakthrough has been the discovery of harmful mutations in the BRCA 1 and BRCA 2 genes. BRCA 1 and 2 are tumor suppressor genes located on chromosome 17 that prevent uncontrolled cell growth. With certain mutations, BRCA genes are less effective in regulating cell growth, and ovarian, breast and other cancers are more likely to occur.

A BRCA mutation can be detected through a blood test. There are well-accepted recommendations about which family cancer histories should trigger genetic counseling and possible BRCA testing. Genetic counseling is helpful, so an accurate family medical tree is constructed and appropriate candidates for BRCA testing are identified. Before getting the blood test, it is important that women fully understand the implications of both positive and negative BRCA results, and also of declining to do the test.

When possible, it makes sense first to test a family member who has been diagnosed with breast or ovarian cancer. If a BRCA mutation is found, other family members can undergo limited testing for that specific mutation.

Both females and males can inherit BRCA mutations. Men with BRCA mutations have an increased risk of breast cancer, as well as pancreatic, early-onset prostate, and possibly, testicular cancer.

Women with BRCA mutations have an increased lifetime risk of ovarian cancer ranging from 20-50%. Risks for developing breast cancer are even higher, in the 60-80% range.

If a harmful BRCA mutation is found, most physicians recommend prophylactic removal of the ovaries after childbearing is complete, in most cases by age 40. (Along with removal of the ovaries, additional steps would be taken to reduce breast cancer risk.)

Prior to completion of childbearing, BRCA positive women should be aware of ovarian cancer symptoms and have regular vaginal ultrasounds and CA-125 testing — though imperfect, these tests are the best we have for screening high risk women. We also recommend younger women use oral contraceptives when feasible. Oral contraceptives can reduce ovarian cancer risk by 50%, though the exact benefit in BRCA positive women is not known.

What if BRCA testing is negative? That means cases of ovarian and/or breast cancer in a particular family are not due to a BRCA mutation, but may be associated with other mutations that have not yet been identified. With high risk family histories, the same risk reducing strategy is appropriate.

Improving ovarian cancer screening in the future, for both high and average risk women, will almost certainly involve more accurate serum markers and better ultrasound discrimination between normal and abnormal ovarian structure.

Does recognizing symptoms lead to early diagnosis of ovarian cancer?

I wrote earlier about the difficulties of diagnosing early ovarian cancer by routinely screening asymptomatic women at average risk for this disease. But what if physicians did a better job of screening women with symptoms linked to ovarian cancer? Could we make the diagnosis at an earlier, more treatable stage?

A recently published study looked at these questions. 

813 women with ovarian cancer (including 212 diagnosed in an early stage) and 1313 otherwise similar women were interviewed about symptoms they experienced before their date of diagnosis (or comparable date for the control group).

Symptoms included early satiety, bloating, abdominal or pelvic pain and urinary changes. A woman was considered symptomatic if she had new onset of any of these symptoms in the year before diagnosis, with symptoms occurring daily for at least a week.

Women who had been diagnosed with ovarian cancer were 10 times more likely than women in the control group to report having had at least one of these symptoms. However, most women reported having symptoms for a relatively short time before diagnosis, regardless of whether their cancer was found in an early or late stage.

(One limitation of the study is that it relied on accurate recollection of symptoms. And, women with a cancer diagnosis may recall symptoms differently than the control group.)

Like other current screening approaches for ovarian cancer, the authors' symptom index had a low positive predictive value. Using their approach, 100 symptomatic women would have to be evaluated to identify one woman with early ovarian cancer.

The other 99 women would undergo ultrasounds, blood work and in some cases, unnecessary surgery, looking for a disease they did not have. At the same time, women who had early ovarian cancer but no symptoms, would not be recognized.

The editorial accompanying the article concludes

Importantly, these findings remind us that wide recognition of symptoms alone will not incrementally improve the overall survival from ovarian cancer. Rather, they highlight the urgent need to develop better molecular markers and improved imaging modalities for ovarian cancer screening. The recognition of specific symptoms associated with ovarian cancer has value. However, to truly affect the cure of ovarian cancer, we need better diagnostic tools for asymptomatic women.

Next, I'll look at what we know about inherited susceptibility to ovarian cancer.

Screening for ovarian cancer —still a work in progress

With good reason, ovarian cancer is the most feared gynecologic malignancy. Hardly a clinic day goes by without one of my patients asking if we've figured out how to screen for cancer of the ovary.

Most often discovered after it has spread from the ovary, ovarian cancer is the leading cause of death from gyn cancers and the fifth-leading cause of cancer deaths in women. Yet, an effective screening test for ovarian cancer, comparable to a pap smear or a mammogram, remains an elusive goal.

Why is it so hard to screen for cancer of the ovary?

The foremost reason (fortunately) is that ovarian cancer is not among the most common cancers — it affects 1.4% of US women. It is easier to develop effective screening tests for more common conditions, especially if we are trying to screen everyone potentially at risk.

Secondly, the ovaries are relatively small organs that are deep in the pelvis. Only with surgery can the ovaries be visualized directly. And, as part of their normal function prior to menopause, they change size and create cysts that come and go. A normal ovary can at times feel concerning on pelvic exam and look concerning on ultrasound, especially in the second half of the menstrual cycle. Even postmenopausal women can have cysts on their ovaries that are completely innocent.

During my residency in the 1980's, there was great hope that regular pelvic ultrasounds and blood tests for a serum marker, CA-125, would prove to be effective screening tests. Unfortunately, these tests did not pan out. 

Compared to control groups, women regularly screened with ultrasounds and CA-125 blood tests had more surgery for benign conditions that didn't actually threaten their health. And they did not have a reduced risk of dying from ovarian cancer. The ovarian cancers that were found in the screened group were often in advanced stages. The goal of finding ovarian cancer early was not met.

There have been ongoing efforts to identify women with ovarian cancer based on family history, genetic testing and a constellation of symptoms involving the pelvic organs. There have also been attempts to create more accurate ultrasound criteria for early diagnosis.

In future posts, I will discuss recent studies involving these approaches. But be forewarned — diagnosing ovarian cancer early enough to save lives remains a formidable challenge.