In a Safety Communication directed at women and physicians, the U.S. Food and Drug Administration (FDA) alerted women “about the risks associated with the use of tests being marketed as ovarian cancer screening tests” and recommended “against using currently offered tests to screen for ovarian cancer.”1 The FDA expressed concern that women and their physicians may be misled by claims made by marketers that these tests can screen for and detect ovarian cancer and may rely on inaccurate results to make treatment decisions.
“Despite extensive research and published studies,” the FDA Safety Communication noted, “there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results.”
“I strongly agree with the [FDA],” said Sanaz Memarzadeh, MD, PhD, UCLA Professor in the Department of Obstetrics and Gynecology. “There are no effective ovarian cancer screening tests at this time, though an effective test is clearly needed.” Dr. Memarzadeh is also a gynecologic cancer surgeon and Director of the Gynecologic Oncology Discovery Laboratory, affiliated with the UCLA Jonsson Comprehensive Cancer Center.
“I think it is very important that the FDA is really providing a clear stance on this and putting out this Safety Communication, to make sure this information is communicated to everyone,” Dr. Memarzadeh added in an interview with The ASCO Post.
The concern about using inaccurate results to make treatment decisions involves both false-positive and false-negative results. Women who receive false-positive results “may undergo additional medical tests and/or unnecessary surgery and may experience complications related to both,” the FDA pointed out in its Safety Communication.
“In some cases, the surgery involves removal of the ovaries and the fallopian tubes,” Dr. Memarzadeh explained. “We know the ovaries can produce beneficial reproductive hormones throughout life in premenopausal years, and now there is evidence for that in postmenopausal years.”
False-negative results “may lead women to delay or not to seek surgery or other treatments for ovarian cancer,” according to the FDA Safety Communication. The FDA stressed it “is especially concerned about delaying effective preventive treatments for women who show no symptoms but who are still at increased risk for developing ovarian cancer.”
The consequences of false-positive and false-negative results are not hypothetical. “They are happening now,” Dr. Memarzadeh said. “It is not unusual for me to get referrals of patients who have had a CA-125 done for no good reason at all and it is elevated and the patient is very concerned.”
Recognizing the Limitations of CA-125
The two most common screening methods for ovarian cancer are transvaginal ultrasound and screening with the serum marker CA-125. “But neither alone nor together have they really panned out as good screening tests for ovarian cancer,” Dr. Memarzadeh admitted.
“The discovery of CA-125 and its association with ovarian cancer, particularly with a very specific subtype of ovarian cancer, high-grade serous ovarian cancer, was a brilliant discovery,” Dr. Memarzadeh noted. “It is a molecule of much interest, we and many other investigators are focusing on understanding it: what it does, what its normal function is, and what its function is in cancer.”
Dr. Memarzadeh continued: “But we have to recognize its limitations and that it is expressed in many other normal tissues of the body. It is expressed in the lungs and other reproductive organs. And there are benign conditions that can be associated with an increase in CA-125, such as endometriosis. Some women who have uterine fibroids may have elevated levels of CA-125. Peritonitis can cause elevation of CA-125.”
Marker for Following Diagnosed Patients
Although screening for CA-125 has never been proven to be effective for the early detection of ovarian cancer, “to some extent, it is a marker that is useful clinically for following patients in the course of disease,” Dr. Memarzadeh noted.
Through work at the Gynecologic Oncology Discovery Laboratory, “we have discovered as the cancer stem cells differentiate, the vast majority of the tumor cells have the CA-125 marker, and then you can detect the CA-125 in the serum,” she explained. Because CA-125 “is expressed in a large number of ovarian cancer cells, and then it is secreted in the blood and can be measured,” it can be a useful tool to follow patients. “It is our best marker for following patients who are diagnosed with ovarian cancer to assess the extent of the disease, although it certainly has limitations there as well.”
An effective test for ovarian cancer screening “is clearly needed,” she stated. “I am not aware of anything in the immediate pipeline as far as a test,” she said, but “in our research we are looking at it.”
In analyzing tumor samples from patients with clearly developed ovarian cancer, Dr. Memarzadeh and colleagues at the Gynecologic Oncology Discovery Laboratory found that although “the vast majority of the tumor cells express the CA-125 marker, a minor population of tumor cells that we find in all the ovarian cancers that we have tested so far do not express the CA-125 marker on the surface. This is quite a surprise to us, because CA-125 is so well associated with ovarian cancer.”
In addition to learning that some of the ovarian cancer cells do not express CA-125 on the surface, the discovery lab research team also learned that these are the cells “that regenerate the cancer, meaning these are the mother cells for the CA-125–positive cells,” Dr. Memarzadeh reported. “So the CA-125–negative cells make themselves, but they also make the CA-125–positive cells. And in preclinical models, we find that with this process, there is a rise in the CA-125 levels. But it is possible that if the patient only has the CA-125–negative cells, the tumor marker in the blood may be completely negative, but cancer is actually present,” Dr. Memarzadeh explained.
“We are very interested in profiling and understanding more about these cells that lack this cell-surface CA-125 antigen,” she continued. “If they don’t have the CA-125 on the cell surface, what is that they have? What is it that they secrete? This is particularly interesting because we think these are the regenerative or cancer stem cells. Could whatever they are secreting or producing potentially be used to monitor patients more accurately and perhaps be tested in the setting of an early detection test?”
Potential Clues on Early Detection
“At this point, we have analyzed patient samples and essentially found this population that doesn’t express CA-125 on the cell surface. This population contains the cancer stem cells and also contains cells that are resistant to standard therapy with carboplatin,” Dr. Memarzadeh revealed. A proposed clinical trial would target cells that don’t express CA-125 on the cells surface by adding birinapant (a synthetic small molecule with potential antineoplastic activity) alongside standard therapy. Dr. Memarzadeh said the addition of birinapant could “potentially benefit upward of 50%” of patients with this type of cancer.
She emphasized that this research is based on samples from patients who have already been diagnosed with ovarian cancer. “I think these kinds of insights may also give us some clues, potentially, into early detection of disease as well. There is a lot we still need to learn about this disease process,” Dr. Memarzadeh acknowledged.
Women at Increased Risk
Women with BRCA mutations are known to be at increased risk for developing ovarian cancer. That makes the situation “even more difficult,” Dr. Memarzadeh said, “knowing you really have no good detection test, but these women are at significantly increased risk of developing ovarian cancer.” By age 70, approximately 40% of BRCA1-mutation carriers and 18% of BRCA2-mutation carriers will have ovarian cancer, she said.
“These are clearly women who are at high risk. It would be wonderful to be able to have an effective test to screen them, but we don’t have such a marker. So these women at high risk are often undergoing surgical menopause at earlier age and having their ovaries and fallopian tubes removed because of the concern associated with developing ovarian cancer, which I will still say unfortunately is a rather deadly cancer to this day,” Dr. Memarzadeh continued.
“I generally counsel my patients who have BRCA1 that by age 40, they should consider risk-reduction surgery. For BRCA2-mutation carriers, the onset of disease is a little bit later in life, and I generally recommend risk-reduction surgery no later than age 50,” Dr. Memarzadeh said.
In addition to BRCA mutations, other factors listed by the National Cancer Institute as associated with an increased risk for ovarian cancer include a family history of ovarian cancer, hereditary nonpolyposis colorectal cancer (also known as Lynch syndrome), use of estrogen-only hormone replacement therapy, use of fertility drugs, use of talc, and obesity.2 “We know that higher [body mass index] or increased weight does increase the risk of many cancers, and those likely will include hormonally driven cancers like breast and gynecologic cancers,” Dr. Memarzadeh commented.
Removal of the Uterus
In addition to removal of the ovaries and fallopian tubes, risk-reduction surgery may also involve removal of the uterus because of “possibly increased risk of uterine cancer in these women,” Dr. Memarzadeh said. “The association between BRCA genes and uterine cancer is not as well studied, and the incidence of disease is not as high, but there are some data to suggest potentially there may be an increased risk of a subtype of uterine cancer, serous cancer, which is very similar to what we see arise from the fallopian tubes. This association with the uterine cancer is more clear among women who are BRCA1- mutation carriers,” she noted, but it is still significantly less than their risk of cancer in the ovaries and tubes.
In the academic setting where Dr. Memarzadeh practices, “the vast majority of women” at high risk for ovarian cancer do choose to have their ovaries and tubes removed. “Some women after discussion regarding the uterus, decide also to have hysterectomies, but that is more of a personal decision, taking into account the patient’s individual risk factors and history.”
Genetic Counseling and Testing
For women who have a family history of ovarian or breast cancer, but have never had genetic testing, Dr. Memarzadeh recommends that they “consider getting genetic counseling and if indicated, then genetic testing.” There is also a “higher indication for considering genetic testing” among Ashkenazi Jewish women, who “are at greater risk of being predisposed to carrying the BRCA gene,” she noted.
“I always tell women that knowledge is power. If there is a family history, having the genetic test information helps you stratify your risks. Then, like everything in medicine, there is a risk/benefit ratio—the risk of surgical menopause vs the benefit of not getting ovarian cancer.” That should be the subject, she said, of “a balanced discussion between the patient and the physician.”
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