Genetic testing for breast and ovarian cancer

INTRODUCTION — Many women feel anxious about their chance of developing breast or ovarian cancer, particularly if they have one or several close relatives with either condition. Women who have a family history of breast or ovarian cancer often wish to know if they have inherited a tendency to develop these tumors, and if so, what their lifetime risk is of developing breast or ovarian cancer.

Other women with a personal history of breast cancer, particularly if it was diagnosed at a young age, may worry that if they have inherited a tendency to develop breast and/or ovarian cancer, it may be passed on to their children.

Inherited mutations in two genes (known as BRCA1 and BRCA2) have been shown to increase the risk of both breast cancer and ovarian cancer. Genetic testing is available that may identify individuals who have inherited an altered form of one of these genes that increases the risk of breast and/or ovarian cancer. Patients who test positive can consider intensified screening or interventions to decrease the risk of cancer (medications or surgical removal of the breasts, ovaries, or both).

However, genetic testing for BRCA mutations is imperfect. Most women with a family history of breast cancer have not inherited one of these two abnormal genes, and not all women who have inherited one of these genes will develop cancer. Furthermore, the results of BRCA testing may be confusing, and do not always lead to a clear action plan. Genetic testing for BRCA mutations can create emotional turmoil and family discord, and may have an impact on future medical care and insurability. Thus, it is important for the patient, her healthcare provider, and family members to carefully consider whether to undergo such testing.

This topic review will focus on which women should consider genetic testing for the presence of BRCA mutations, issues to consider before undergoing testing, and the available options for women who are found to carry one of these mutations.

Genetic testing is not an emergency procedure. Taking time to understand the complexities, and discussing questions with health-care professionals and family members can help to clarify expectations from testing and anticipate future issues.

GENETIC TESTING GOALS — Genetic testing for breast and/or ovarian cancer analyzes the composition of the BRCA genes to look for alterations (mutations) associated with breast and/or ovarian cancer.

How do genes relate to cancer? — A person's visible characteristics (such as hair and eye color) as well as other invisible properties (including predisposition to cancer and other diseases), are determined by his or her genetic "blueprint", which is inherited from both parents as 23 pairs of chromosomes. Each chromosome is made up of a long strand of DNA. Discrete segments or sections of the DNA (called genes) contain the information that is needed to construct specific proteins that carry out the specific function of the individual cells that make up the body. There are approximately 30,000 human genes distributed among the 23 pairs of human chromosomes.

Most of the time, genes function properly and the body develops and performs normally. However, when a gene is altered (often by a mutation or change in the chemical structure of the gene), it may not provide the right signals to the body's cells to carry out their normal functions. If the affected gene is normally involved in the regulation of cell growth, a mutated gene may result in signals that allow uncontrolled cell growth. This process of uncontrolled cell growth causes tumors such as breast cancer to grow unchecked within the body.

An inherited mutation (ie, one that is passed from parent to child, and is present in all cells at the time the child is born) is called a germline mutation. In contrast, a noninherited mutation (ie, one that comes about during a person's lifetime) is called an acquired mutation. Acquired mutations can be caused by exposure to environmental agents such as radiation, chemicals (including those found in tobacco smoke), or viruses; they may also happen spontaneously. Most human cancers are thought to be caused by acquired mutations.

Most breast cancers (at least 90 percent) are not related to inherited (germline) mutations. However, for those 5 to 10 percent that are due to germline mutations, BRCA1 and BRCA2 mutations are thought to account for the majority. These genes are called tumor suppressor genes, meaning that they normally function to keep the growth of the body's cells under control. When one of these genes becomes mutated, cell growth becomes unregulated, paving the way for the development of a cancer. Most scientists believe that a cancer develops only if additional genetic mutations are acquired.

Other genes — Besides BRCA1 and BRCA2, a few other genes have been identified that are associated with breast and/or ovarian cancer, but in general, these involve rare syndromes that are related to other medical conditions and cancer types. There are also likely other, not-yet-identified, genes that are involved in inherited breast and/or ovarian cancer. This topic review will focus only on the BRCA genes.

WHO SHOULD CONSIDER GENETIC TESTING? — Genetic testing should not be done in all women with a family history of breast and/or ovarian cancer since BRCA1 and BRCA2 mutations are rare. Determining which women should consider genetic testing involves examination of an individual's personal and family history of breast cancer and/or ovarian cancer.

BRCA mutations occur in approximately 0.1 percent of individuals (1 in 1000 people). However, some ethnic groups have a higher chance of inheriting one of these mutations. For example, about 2 percent of women of Ashkenazi Jewish (Eastern European) descent carry a BRCA1 or BRCA2 mutation, and between 12 and 30 percent of breast cancers in this group are thought to be caused by mutations in the BRCA1 or BRCA2 genes. These statistics do not consider a family history of breast and/or ovarian cancer.

Because germline mutations are rare, and testing for them can produce indeterminate results, testing is usually offered to women who are at a high risk of having a BRCA mutation. Tools are available (such as a computer program called BRCAPRO [1]) to estimate the likelihood of a woman having a BRCA mutation based on her individual and personal history. Typically, a woman's health care provider or a genetics counselor will ask a set of questions about a woman's personal and family history and plug the answers into this risk assessment tool. The program then calculates an estimate of the chances of finding a BRCA mutation based upon a number of risk assessment tools. Guidelines from national organizations suggest that if the estimated chance of inheriting one of these mutations is greater than 10 percent (one in ten), genetic testing may be appropriate.

However, current recommendations are moving away from numerical cut-off values for determining when genetic testing should be offered. Instead, many organizations advocate using more details of an individual's and family's history as a screening tool to identify women who should be considered for BRCA testing.

Family history patterns — Doctors and patients should be aware of family history patterns that are associated with a higher risk of a BRCA mutation. These include: Multiple relatives affected with breast and/or ovarian cancer, particularly if they were diagnosed at an early age (less than 50 years old) A relative with more than one cancer, such as breast cancer involving both breasts or breast and ovarian cancer Evidence that multiple generations of a family are affected.

Women who develop breast cancer before the age of 50 are more likely to have a mutation than those who develop breast cancer at an older age. If a young woman develops breast cancer and also has a family history of breast and/or ovarian cancer, her chance of carrying a mutation increases dramatically. Family history on the father's side is as important as maternal history.

When there is a strong family history of breast and/or ovarian cancer, BRCA testing should be done on the relative who has the cancer whenever possible. If a mutation is not found, it is usually not helpful to test unaffected relatives. If a relative with breast cancer tests positive for a BRCA mutation, genetic testing should be considered for all of her at-risk adult relatives (male and female).

TESTING PROCEDURE

Pre-test counseling — Genetic testing involves taking a sample of blood and sending it to a lab for testing. However, a woman must consider a number of factors before deciding to undergo genetic testing. These include medical, emotional, practical, and financial factors that can profoundly affect a woman and her family. Women who are considering genetic testing should discuss these issues with a certified genetic counselor, if possible, to understand what is involved in the process of genetic testing. A list of certified genetics counselors and their phone numbers is available through the National Cancer Institute [2].

An example of a consent form is presented in table 1 (show table 1A-1D), and briefly discussed below.

Emotional effects for patient — Although anxiety may cause some high-risk individuals to refuse genetic testing, the available data suggest that there are no major adverse psychological effects of learning the results of BRCA testing. In fact, data from families with hereditary cancer and from individuals who underwent genetic testing in clinic settings suggest less distress in members of high-risk families who test negative for a familial mutation.

While it is normal for individuals who test positive (mutation carriers) to experience some level of distress, anxiety, or sadness, most studies suggest that these individuals do not suffer serious psychological effects or significantly increased distress levels. For many individuals, learning about positive test results can also produce feelings of relief, as risk information is clarified and a plan for managing that risk can be put into place. Women who have less significant family histories and who do not expect to receive positive results may be more vulnerable to psychological problems or high levels of distress after BRCA testing. In families that have a known BRCA mutation, it is not unusual for women who test negative to experience "survivor's guilt" for being spared a burden that other relatives have to endure.

Effects on family members — A discussion of the implications of the test results for family members is an important component of counseling. This includes identifying at-risk family members and encouraging patients to share results with their relatives.

The decision to share test results with relatives and the ramifications of that decision can cause significant emotional strain and family discord. The role of information "gatekeeper" may be overwhelming for some women, particularly as they try to attend to their own needs for emotional support. Nevertheless, studies have found that most individuals, including carriers and non-carriers, opt to share their results with at-risk relatives. For many individuals who seek testing, gaining information for family members is one of the most important benefits of testing.

Costs and insurance coverage — Because the BRCA genes are large and include hundreds of different mutations, testing is expensive. Commercial charges by Myriad Genetics Laboratories® (which are subject to change) are as follows: Full BRCA1/2 testing, which includes testing for five large rearrangements in BRCA1 and for very high risk families, rearrangement testing in BRCA1 and BRCA2 — $3120 Once a mutation is identified in an affected individual, analysis for the specific mutation in relatives costs $385 Analysis of the three specific mutations most commonly seen in Ashkenazi Jewish individuals is $460

A list of testing laboratories is available through the Gene Tests website, at www.genetests.org (click on "Laboratory Directory"). However, full sequencing is provided in the United States by only one commercial laboratory, Myriad Genetic Laboratories®. Genetic testing for BRCA1 and BRCA2 is very expensive, but in the United States, most health insurance companies will cover 80 percent or more of the costs. In many instances, a letter of medical necessity is required from a physician or genetic counselor to demonstrate the potential impact of a positive test result on future care (eg, whether a positive result will be used to intensify screening efforts or recommend surgery). Many people are concerned about the possibility of health insurance discrimination if they have a positive result from a genetic test. This phenomenon has been difficult to document. Two types of insurance may be affected for patients who test positive: the person's health insurance and their life insurance.

The 1996 Health Insurance Portability and Accountability Act (HIPAA) contains provisions to protect individuals with group insurance from having their individual health insurance premiums raised or canceled because of a preexisting condition, including a genetic test result. Some state laws also provide protection. However, there are loopholes that do not cover people with individual (private) insurance and those applying for life insurance. Several websites are available that provide additional information on this subject [3,4]. The effect of a positive genetic test on the ability to obtain life insurance is less clear. Presently there are no federal laws addressing this issue.

Options for treatment if a mutation is identified — Before a genetic test is done, it is important that the woman understand her options for treatment (see "Options after testing positive" below).

Post-test counseling — It is a good idea to schedule an in-person meeting with a genetics counselor or physician to receive the genetic testing results. During this meeting, test results will be explained. This is an excellent time to bring up any questions related to the testing technique or reliability of results.

During the post-test counseling session, patients should review the possible implications of test results on family members. Patients are encouraged to share their results with family members.

INTERPRETING THE RESULTS — Interpretation of test results is not always clear cut. A negative test does not mean that a woman will never develop cancer; nor does a positive test mean that she will definitely develop cancer.

The easiest tests to interpret are those done after a mutation has already been identified in one or more close relatives who have breast and/or ovarian cancer. A positive result occurs when an individual tests positive for the same mutation as their relatives. A negative result occurs when an individual tests negative for a mutation that has already been identified in their family.

If an affected high-risk individual is the first to be tested in a specific family, results may be less clear. There are a number of possible results: A mutation could be present in BRCA1 or BRCA2 but was not detected by available methods A mutation in another risk-conferring gene that is rare and/or not yet identified could be present The individual being tested could have developed a sporadic (noninherited) rather than hereditary cancer. Another possibility is that a BRCA1 or BRCA2 alteration may be identified that is considered to be a "variant of uncertain significance." This means that it could possibly be a newly identified deleterious mutation or it could simply be a normal change in the gene. Such changes appear to be more common in certain ethnic groups, such as African-Americans. Further research will clarify the significance of many of these changes.

OPTIONS AFTER TESTING POSITIVE — Usually, women who test positive for a BRCA mutation are referred to specialists who can review their options. Several alternatives are available for women who are at increased risk for breast and ovarian cancer: increased surveillance (screening) for breast and ovarian cancer, preventive surgery, and/or the use of medications to reduce the risk of cancer (called chemoprevention). Cancer risk might best be decreased through a combination of some or all of these methods (show table 2). Women considering genetic testing should discuss the table with their healthcare provider.

Intensified breast cancer screening — Women who have inherited BRCA1 or BRCA2 mutations are recommended to increase the level and frequency of screening strategies as follows: Monthly breast self-examination (BSE) beginning at age 18; women should be specifically instructed on how to perform BSE) Clinical breast examination two to four times annually beginning at age 25 Annual mammography beginning at age 25; in some women, mammography may be recommended every 6 months Annual breast MRI to take place approximately 6 months after the annual mammogram. Magnetic resonance imaging (MRI) uses a strong magnet rather than x-rays or radiation to create a detailed image of a part of the body. Breast MRI appears to be more sensitive than screening mammogram for detecting early breast cancers in high-risk women, and several experts groups (including the National Comprehensive Cancer Network and the American Cancer Society) now recommend annual breast MRI for these women.

However, there are insufficient data to recommend breast MRI instead of screening mammography in any group of women. One reason is that MRI does not appear to be as sensitive for diagnosing conditions such as ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer.

Despite these recommendations by several expert groups, studies do not definitively prove that intensive screening improves cancer outcomes in women who inherit BRCA mutations. A major problem is that many of the screening tests are not sensitive enough to pick up early cancers at a time when they are most likely to be cured.

Ovarian cancer screening

High risk women — Women who have inherited a BRCA mutation have an increased risk of developing ovarian cancer and may benefit from tests to detect it at an early stage. However, unlike screening for breast cancer, screening tests for ovarian cancer are not very accurate in detecting disease. These tests have suboptimal sensitivity (ability to detect early ovarian cancer) and specificity (ability to differentiate ovarian cancer from other conditions that cause abnormal test results).

Nevertheless, periodic surveillance is often recommended for women with a BRCA mutation who do not undergo prophylactic (preventive) surgery to remove the ovaries (see below). Screening for these women involves a combination of pelvic examination, vaginal ultrasound, and measurement of blood levels of CA 125 (a tumor marker used to determine the effectiveness of treatment in women with ovarian cancer that may also be useful in detecting ovarian cancer in women with no history of this cancer). The optimal frequency for screening has not been determined, although most centers recommend considering ovarian cancer screening every 6 to 12 months beginning between ages 25 and 35.

Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not have a BRCA mutation should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.

Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.

Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.

Prophylactic (preventive) surgery — As an alternative to undergoing frequent screening, some high-risk women consider prophylactic surgery to reduce their risk of developing a cancer. Prospective studies of women who undergo surgical removal of both breasts (termed a prophylactic bilateral mastectomy) show at least 90 percent reduction in the risk of breast cancer for high-risk women, including those with BRCA mutations [6,7].

Surgical removal of the ovaries and fallopian tubes (termed a prophylactic bilateral salpingo-oophorectomy, or BSO) has been shown to be protective against ovarian cancer (approximately 85 to 95 percent reduction) and breast cancer (approximately 40 to 50 percent reduction for premenopausal women) in carriers of BRCA mutations [8,9]. The benefits of BSO are greatest in women undergoing the procedure before menopause, particularly before age 40, after childbearing has been completed. Due to the lack of effective tests for ovarian cancer screening (see "Ovarian cancer screening" above), it is recommended that BRCA1 and BRCA2 carriers undergo prophylactic BSO by age 35, or once childbearing is completed.

Despite these benefits, only a small minority of women who are mutation carriers pursue prophylactic surgery, particularly mastectomy. However, studies of women who have undergone prophylactic mastectomy have found that the large majority reported satisfaction [15]. Prophylactic BSO is generally more accepted, perhaps because of the limited effectiveness of screening for ovarian cancer and because it reduces risk of both ovarian and breast cancer.

Prophylactic surgery may have psychological benefits by reducing a woman's concern that she'll develop cancer, but there are also risks that her quality of life may be negatively affected by surgery. It is important to discuss the medical, psychological, and emotional impact of prophylactic surgery before considering such surgery.

Medications to reduce the risk of cancer — The drugs tamoxifen and raloxifene may prevent the development of breast cancer (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Oral contraceptives have also been studied for use in preventing breast cancer.

Tamoxifen — Studies evaluating the benefit of tamoxifen in BRCA mutation carriers are limited. Early reports suggest that at least in women who have breast cancer and a BRCA mutation, tamoxifen can reduce the risk of getting a second breast cancer in the opposite breast by about 40 to 50 percent [10]. However, whether this improves survival, and whether tamoxifen is beneficial for mutation carriers who do not have breast cancer are unknown.

There are risks of taking tamoxifen. It increases the risk of the following, particularly in patients over the age of 50 (see "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"): Cancer of the lining of the uterus (endometrial cancer and sarcoma) Stroke Blood clots within deep veins, usually in the legs (deep vein thrombosis) Blood clots in the lungs (pulmonary embolism)

Raloxifene, in contrast to tamoxifen, is not associated with many of the most serious side effects seen with tamoxifen. However, it has not been studied yet in women with BRCA mutations, and its benefits in this group are unknown.

Oral contraceptives — Use of oral contraceptives (birth control pills) is associated with a decreased risk of ovarian cancer in the general population. The situation in women with inherited BRCA mutation is less clear. At least one study suggests that oral contraceptives decrease ovarian cancer risk in BRCA mutation carriers [11], but other studies have not confirmed this finding. In addition, there is concern that oral contraceptives may increase the risk of breast cancer, particularly in BRCA1 mutation carriers. More information about oral contraceptives is available in a separate topic review. (See "Patient information: Hormonal methods of birth control").

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

(www.nci.nih.gov/)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The National Comprehensive Cancer Network (NCCN)

Includes physician guidelines for hereditary breast and/or ovarian cancer
(www.nccn.org)
The American Cancer Society

Includes a guide to the causes of breast cancer with a discussion of BRCA genes
(www.cancer.org)
The Susan G. Komen Breast Cancer Foundation

(www.komen.org)
National Ovarian Cancer Coalition

(www.ovarian.org/)
Facing Our Risk of Cancer Empowered (FORCE)

(www.facingourrisk.com)


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