When risk is assessed appropriately and testing is managed effectively, genetic testing for BRCA1 and BRCA2 mutations can provide patients at risk of ovarian cancer with information, options, and ultimately empowerment.
By Krishnansu S. Tewari, MD, FACOG, FACS
Ovarian cancer is the number one gynecologic cancer killer in the United States. Approximately 22,000 women will be diagnosed and nearly 16,000 women will die from the disease in 2008. Although we are continually making progress in treating patients with advanced cancers, only one in five ovarian cancer patients is likely to be cured.
At this point the most significant roadblock to progress in our treatment of ovarian cancer is the lack of effective screening tests for the general population. Currently, no test exists that allows the cancer to be detected in its earliest stages. Making matters worse, the symptoms of ovarian cancer (endorsed by the Gynecologic Cancer Foundation in 2007)—such as bloating, pelvic and abdominal pain, difficulty eating, and urinary symptoms—are often subtle, resulting in late-stage diagnoses for many women. Unfortunately, at its later stages, the disease has already spread and is very difficult to treat.
During the 1990s hard work in the laboratories paid off, with the discovery of two genes that when defective (mutated) predispose an individual to the development of certain cancers. These mutations, called BRCA1 and BRCA2, contain the blueprint for proteins that are involved in regulating the cell’s life cycle under normal (non-cancerous) conditions. When one of these genes is mutated, the risk of developing breast cancer and/or ovarian cancer is increased. The discovery of BRCA1 and BRCA2 mutations created a lot of excitement in the medical and scientific communities. Though there was still no reliable ovarian cancer screening test for the general population, much hope was derived from the idea that high-risk individuals could now be identified and benefit from increased screening and medical intervention that could potentially lead to earlier diagnosis of the disease in this population, ultimately decreasing rates of ovarian cancer.
What Are BRCA Mutations?
It is estimated that 5 to 10 percent of ovarian cancers result from mutations in the DNA that are inherited.1 BRCA1 and BRCA2 are the most common mutations associated with hereditary breast and ovarian cancer syndrome (HBOCS). Mutations in these genes can be transmitted across many generations of family members, resulting in multiple members of a family being affected by one or more cancers associated with BRCA1 or BRCA2. These mutations can be transmitted to female and male carriers and then on to their children (males and females).
A woman who inherits a BRCA1 mutation has a 20 to 60 percent risk of developing the most common form of ovarian cancer—called epithelial ovarian cancer. A woman with a BRCA2 mutation has a lower (10 to 20 percent) but not insignificant risk of developing epithelial ovarian cancer. Interestingly, although women with BRCA1 mutations who ultimately develop ovarian cancer are often diagnosed at a younger age (midforties) than those patients without a genetic predisposition, those with BRCA2 mutations who are destined to develop ovarian cancer usually are diagnosed during their sixties, similar to the average age of women with non-hereditary ovarian cancer. Patients of either gender with BRCA2 mutations may also have a higher risk of developing pancreatic, prostate, and other cancerous tumors.
So where did these BRCA mutations come from in the first place? Mutations can be either sporadic (meaning they occur spontaneously in a person’s DNA) or they may be inherited from one or both parents. Sometimes an inherited mutation can be traced back through a family history all the way to a point where the mutation may have first occurred. This is called a founder mutation. Such mutations develop in the DNA of one or more individuals of a distinct population. When the affected individuals reproduce, the mutation is passed down to the offspring and on through the generations.
For example, Ashkenazi Jews are descended from the medieval Jewish communities of the Rhineland and constitute 90 percent of the 6 million Jews living in the United States. It is estimated that one in 50 Ashkenazi Jews carries a BRCA mutation. There are three founder mutations of the BRCA genes, two affecting BRCA1 and one affecting BRCA2. Although there are many different mutations that can occur in the BRCA genes, a woman who is found to have one of the three founder mutations is likely to have descended from the medieval Jewish settlements of the Rhineland.
Genetic Testing 101
Because inherited mutations in the BRCA genes occur only in approximately one in 500 people in the general population, genetic testing for the BRCA mutations is generally advised for high-risk patients—those with two or more first- or second-degree relatives who have ovarian cancer, early-onset breast cancer (before age 50), breast cancer affecting both breasts (bilateral), or male breast cancer.
When estimating the risk of breast and/or ovarian cancer in a patient who appears to have a strong family history of the HBOCS, some doctors and genetic counselors use risk assessment models like the Myriad model (see Table 1). Genetic counselors might also draw a family pedigree—a diagram that looks like a family tree but includes notations regarding individuals in the family who have had a specific cancer. Sometimes these trees also include the age at diagnosis of the cancer and whether the family member died as a result (see the family pedigree in Table 1). Although predictive models and family pedigrees can be very useful, they have limitations. For example, when a family is small or when there is an over-representation of males in the family, the actual risk of cancer can appear to be less.1 It is important to remember that males can also pass on the mutations. For this reason an accurate family pedigree should put equal emphasis on the mother’s and the father’s side of a patient’s family tree.
Once risk has been determined and an individual has been identified as a candidate for genetic testing, the next step is to perform the test. The first test should preferably be on a relative of the candidate who is affected by breast and/or ovarian cancer. This way if a BRCA mutation is found on the affected relative, the high-risk patient’s DNA can be screened for the specific mutation that person carries. If such a relative is unavailable for genetic testing, the high-risk patient will need to have genetic testing performed on the entire BRCA1 and BRCA2 genes. When evaluating a patient with Ashkenazi heritage on both sides of the family, it becomes especially important to screen for all three founder mutations.
It is very important that the high-risk patient be counseled that genetic testing (of her affected relative and/or of her own DNA) will only help determine whether she carries a BRCA mutation. If the genetic-testing results are negative for mutations in BRCA1 and BRCA2, while this is certainly reassuring, it does not mean that the individual is completely without risk of developing ovarian cancer. In this situation the risk of developing ovarian cancer through a spontaneous or sporadic mutation in a BRCA gene or an as-yet-undescribed cancer-predisposing gene is the same as that of general population (approximately one in 60).
Fear of Testing
Despite the seemingly obvious benefits of genetic testing, many high-risk patients are nevertheless hesitant to go through the process. Although many health insurance carriers cover BRCA testing, many patients—and oncologists—have voiced concerns about genetic discrimination by employers or insurance companies. To date, however, there have been no documented cases of genetic discrimination based on BRCA status. Furthermore, there are protections afforded by the Health Insurance Portability and Accountability Act (HIPAA) of 1996. Because the law defines a preexisting condition as one for which medical advice, diagnosis, care, or treatment was recommended or received during the six-month period prior to an individual’s enrollment date, HIPAA protects individuals who undergo genetic counseling and testing so that they cannot be dropped by a carrier or charged premiums if they are found to carry a genetic mutation that increases their risk of a specific disease.
Patients are also often reluctant to undergo genetic testing because they are afraid of a positive test result. Appropriate and timely referrals to genetic counselors before any genetic testing is performed, however, can help an individual’s outlook and ability to psychologically deal with an unwanted result. The most important thing prospective patients must understand is that a positive result is not a death sentence. Although the risk is higher for those who carry the mutation, not everyone found to have a BRCA mutation will develop ovarian cancer. Moreover, although the higher risk of ovarian cancer cannot be removed completely among patients with a BRCA mutation, there are several measures that can be taken to significantly reduce the risk and preventive steps that can often catch the disease early.
Managing Risk: Screening and Prevention
For women who have tested positive for the BRCA1 or BRCA2 mutation, the good news is that the knowledge gained through testing can create a real sense of empowerment. Now, instead of wondering about risk and living in fear, taking a proactive role in screening and preventive measures can provide a sense of control and might actually alleviate stress. Screening and preventive steps recommended for high-risk women include intensified screening, chemoprevention, and prophylactic (precautionary) surgery.
Methods that have been considered for ovarian cancer screening include pelvic exams, ultrasound studies, and measurement of CA-125 in the blood. The CA-125 blood test is not specific for ovarian cancer and can be abnormally elevated for a variety of non-cancer conditions, including infections and injuries.
Though intensified screening for women in the general population has not been found to be cost-effective nor medically successful, among women found to carry a BRCA mutation, intensified surveillance is recommended. The National Comprehensive Cancer Network guideline recommends transvaginal ultrasound together with CA-125 screening every six months starting at age 35 years or five to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family. Performing the ultrasound through the vagina allows the ultrasonographer to better assess the ovaries. Both screening tests (ultrasound and CA-125) are best measured on days 1 through 10 of the menstrual cycle in high-risk patients who have not yet entered menopause.
There is evidence that this intensified screening may actually lead to early diagnosis of ovarian cancer in this high-risk population. In a study of 62 women with BRCA mutations who had ultrasounds on the ovaries as well as measurement of CA-125 twice a year, after an average of 17 months, 22 of the 62 women had at least one suspicious test that required further testing. Ten of these 22 women were eventually taken for exploratory surgery, and five were found to have ovarian cancer or ovarian-related cancer that was in the early stages (Stages I and II). The other 12 patients were not operated on because their CA-125, which had been elevated, returned to normal levels. Two of these patients, however, eventually chose to have their ovaries removed as a precaution, known as a prophylactic bilateral salpingoophorectomy (BSO); ovarian cancer was found on the ovaries at the time of their removal.
Although intensified surveillance may allow cancers to be diagnosed in the early stages, it would obviously be even better to prevent them altogether. Some factors that have been associated with a reduced risk of ovarian cancer include starting menstruation late, having children, tying off the fallopian tubes, using birth control pills, and early menopause. These factors may also be protective to women with BRCA mutations.
Recent studies have looked at the way birth control use in particular affects ovarian cancer risk for BRCA mutation carriers. One study reviewed birth control pill usage in 207 BRCA mutation carriers who had ovarian cancer and compared the findings with 161 of these patients’ sisters who did not have ovarian cancer. The researchers found that the occurrence of ovarian cancer was decreased by 50 percent among birth control pill users.<<a href=”#_edn3″ name=”_ednref3″>3 In another study that involved 3,000 patients with BRCA mutations, birth control pills were associated with a decreased incidence of ovarian cancer in both BRCA1 and BRCA2 carriers.
An important point needs to be made here: Although the data concerning birth control pills are well accepted, women with BRCA mutations considering this method of cancer prevention need to be very carefully counseled. Some studies have shown that there is a slightly increased risk of early breast cancer among BRCA mutation carriers who use birth control pills; and because women with BRCA mutations are already at higher risk of developing breast cancer, this may not be an acceptable method of ovarian cancer prevention for many of these patients.
Prophylactic bilateral salpingoophorectomy is perhaps the most effective way to reduce the risk of ovarian cancer in women from the general population as well as those who carry BRCA mutations. Unlike a prophylactic mastectomy, which many women with BRCA mutations will consider, a prophylactic BSO affects body image less because the ovaries are internal organs. Prophylactic BSO can often be accomplished on an outpatient basis, using minimally invasive surgical techniques such as laparoscopy.
Occasionally, the ovaries that are removed when a patient undergoes a prophylactic BSO are found to contain an early cancer. In a study of more than 500 women with BRCA mutations, 259 had undergone precautionary removal of what had been thought to be healthy ovaries before surgery. Six of these women were found to have Stage I ovarian cancer at the time of the procedure. Among the patients in the study with BRCA mutations who did not undergo prophylactic BSO, 58 women (nearly 20 percent) ultimately developed ovarian cancer. In the group that had prophylactic BSO, two patients were eventually diagnosed with a condition that is very similar to ovarian cancer, known as primary peritoneal carcinoma. Primary peritoneal carcinoma arises along the inner surfaces of the abdomen and the pelvis, and, like ovarian cancer, requires surgery and chemotherapy. Although we do not know for certain that BRCA mutations are the cause of some primary peritoneal carcinomas, it is understood that prophylactic BSO does not prevent 100 percent of ovarian-like cancers from developing, but the reduction in risk is probably greater than 95 percent.
Because many fallopian tube cancers have been found to be associated with BRCA mutations, current recommendations for women who are planning to have their ovaries removed prophylactically suggest that strong consideration be given to removing as much of the fallopian tubes as possible at the time of surgery. Because many patients with BRCA mutations are at such high risk of developing breast cancer, the oncologist may also advise patients to undergo hysterectomy at the time of removal of the ovaries and the fallopian tubes. This is because many women with breast cancer will go on to receive hormonal therapy in the form of the anti-estrogen drug tamoxifen [Nolvadex®]. Tamoxifen can cause irregular uterine bleeding and can double the risk of developing endometrial cancer (cancer along the inner lining of the uterus).
A hysterectomy combined with removal of the ovaries and the fallopian tubes can also be performed laparoscopically, but the surgeon will remove the uterus through the vagina so as not to have to break it up to fit it through the small holes in the abdominal wall where the laparoscopy equipment has been placed. Keeping the uterus intact prevents unintentional spillage of an unknown cancer that may already exist in the uterus and enables the pathologist to better examine all aspects of the specimens. In fact, in such cases the pathologist will usually make many more cuts of the ovaries and, in particular, the fallopian tubes to look for hidden cancers.
Despite the benefits, undergoing prophylactic BSO (with or without hysterectomy) presents a very difficult choice for many women because the procedure will mean an end to their ability to bear children and will also cause them to go into premature menopause. Current recommendations advise women with BRCA mutations to consider prophylactic BSO once their childbearing has been completed or at age 35. This age was selected because the average age that hereditary ovarian cancers occur among women with BRCA1 mutations is during the midforties.
Women with an increased risk of ovarian cancer can be identified through genetic testing for mutations in the BRCA1 and BRCA2 genes. Although a positive result from genetic testing may cause understandable emotional anguish, it is important for women to understand that this knowledge may also empower them in such a way that they can defeat this disease through a combination of intensified screening, chemoprevention, and/or prophylactic surgery.
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 Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. New England Journal of Medicine. 2002;346(21):1616-22.