Genetic research - in particular, the massive Human Genome Project - has dramatically changed our thinking about disease. It has not only improved our understanding of classic inherited maladies, such as Huntington's disease, but also altered the way we evaluate our risk of cancer, heart disease, diabetes, and other common conditions. Genetic tests are now available for a number of specific gene mutations that raise cancer risk.

Of these genetic tests, the one most widely used detects mutations in genes known as BRCA1 and BRCA2, which are associated with breast and ovarian cancer. (BRCA stands for BReast CAncer.) After an introduction in research and specialty clinics, BRCA1 and BRCA2 testing is now widely available.

But even for this test, scientists have only partial information on what results mean and how women can best use them to protect their health. The medical, emotional, and social questions raised by BRCA1 and BRCA2 testing are relevant to all cancer susceptibility tests. If you are considering such a step, the key to an informed decision is learning as much as possible about how testing is done and the implications of the results.

What does it mean to have a breast cancer gene?

BRCA 1 and BRCA2 are tumor-suppressor genes. Everyone has two copies of each gene, and when working properly, they produce proteins that keep cell growth in check. But mutations can render these genes inactive, increasing your risk for developing breast, ovarian, and certain other cancers. Every child born to someone with a BRCA mutation has a 50% chance of inheriting that mutation. "Having the breast-cancer gene" usually means having a BRCA1 or BRCA2 mutation.
Women with certain BRCA mutations will have a lifetime risk for breast cancer three to seven times that of the general population. BRCA1 mutations have also been linked to an increased risk for ovarian cancer - in particular, with early-onset ovarian cancer - and a possible increase in colon cancer and in men, prostate cancer. BRCA2 mutations increase the risk for ovarian cancer (although not an early-onset form), early-onset prostate cancer, male breast cancer, melanoma, and cancers of the pancreas, gallbladder, and stomach.

According to one study, if a woman develops ovarian cancer at any age or breast cancer before age 50 - and has a family history of breast or ovarian cancer - she has a 40% chance of a BRCA1 or BRCA2 mutation.

Who should be tested?

You are most likely to be a candidate for genetic testing if your family history suggests a heightened risk for harmful mutations. A key indicator is having three or more first-degree (mother, sister, daughter) or second-degree (grandmother, aunt, niece, half-sister) relatives on one side of the family who developed breast or ovarian cancer. There is also some suspicion if:
You have a family member with a BRCA1 or BRCA2 mutation.
Breast cancer has occurred before age 45 in your family.

You have close relatives with ovarian and/or breast cancer.
A member of your family has bilateral breast cancer or multiple cancers.
One of your close male relatives has breast cancer.

You are of Ashkenazi Jewish ancestry (1 in 40 may have BRCA1 or BRCA2 mutations).
Making an informed choice

Genetic testing is complex and changing rapidly. Although a primary care doctor may be able to provide informed counseling, it's generally better to consult a specialist when considering such a test. Programs specializing in cancer genetics usually have several health professionals available, including a geneticist or genetic counselor, a medical oncologist, and a gynecological oncologist.

Before undergoing a test for the BRCA gene (or any other sort of genetic test), you should be adequately prepared and know what to expect. You may want to include a family member or other support people in your counseling sessions.
• Gather family information. In the initial screening process, a genetic counselor will usually request medical information on three generations of your family, including the types of cancer (primary site) that any of them have developed and the age of onset.

You will need information on both your father's and your mother's sides of the family, since an altered BRCA gene is as likely to be inherited from either one. Gather information on all types of cancer because breast cancer can occur as part of a familial cancer syndrome not obviously related to BRCA.

• Talk before you test. A specialist should thoroughly discuss the benefits and risks of genetic testing, addressing both medical and non-medical issues. This discussion should include the cost and complexity of the testing; the possible outcomes; what is known and not known about the value of early detection and prevention strategies for mutation carriers; the possible psychological and social impact; how testing may affect other family members; who will have access to test results; and alternatives to the test.

Education and counseling should not be aimed at persuading you to be tested. Indeed, one study found that after counseling, women were almost three times less likely to want a genetic test. If you decide not to be tested, or wish to delay your decision, you can still ask your clinician to screen you for cancer as thoroughly as someone with a known mutation. If you are considering the test primarily for the future benefit of your daughters or other relatives, you can ask to have DNA samples prepared and stored for possible testing at a later date.

• All tests are not alike. Several hundred mutations in BRCA1 and BRCA2 have been reported. Some are found in all ethnic groups; others seem restricted to one ethnic group or even one family. If breast and ovarian cancer in your family is associated with a particular mutation, a single-mutation test is available. In many cases, however, the test will involve more than one mutation. For example, one standard test checks for the three harmful mutations most commonly found in Ashkenazi Jewish women. A comprehensive analysis covers all known mutations in the genes. Depending on the number of mutations tested and how quickly the results are made available, laboratory fees can range from a few hundred to thousands of dollars.

Many insurance companies cover BRCA1 or BRCA2 testing for women with specific risk factors. But some exclude payment for women who already have breast cancer, even when that information is needed to interpret test results in other family members. In any case, you may wish to pay out-of-pocket rather than through your health insurer (see box, "Issues of Discrimination and Privacy").

Making Sense of the Results

Genetic test results create strong feelings, whatever the outcome. When they learn of a mutation, most people are more distressed than they expected. But not all studies on the subject agree; one showed no increase in depression scores with positive tests and no decrease in depression scores when the results were negative. Many women find that the resolution of uncertainty is a positive thing.

Because you are likely to have questions and may want emotional support, most practitioners require that you receive the results in person. The implications for yourself and other family members will be explained, and you may be given written materials to help you understand the information. The program should provide for follow-up counseling with a genetic counselor, a family counselor, an oncologist, or a surgeon who can help you make decisions about cancer detection or prevention.

A positive test. This means a cancer-susceptibility mutation was found. Ask how it alters your risk of breast, ovarian, and other cancers. A positive test does not mean you will definitely develop cancer and it does not tell you at what age cancer could occur or how serious it might be.

A negative test. If you are found negative for a mutation already identified in affected relatives, your risk for breast and ovarian cancer is probably no higher than average. If you lack information on affected family members, however, a negative result is not so reassuring. It could mean that you did not inherit the BRCA1 or BRCA2 susceptibility gene, or it could mean that another gene is contributing to your family's cancers.

An inconclusive test. You may not get a clear answer. For example, if the test finds an unfamiliar variation in BRCA1 or BRCA2, specialists will not know whether it is harmless unless there are comparable test results on cancer patients in your family. In one study of 213 women, more than one in eight had variations in BRCA1 or BRCA2 that could not be characterized.

The likelihood of an uncertain result is greater if you are a member of an ethnic group that was not represented in the early BRCA family studies. A study of African American women from high-risk families found that African American and Caucasian women had different risk-conferring mutations and the African Americans carried many genetic variants of unknown significance.

As further evidence accumulates, the meaning of your test may change. Testing one or more family members with cancer may help clarify the results.

Implications for the Future

Despite these uncertainties, BRCA testing can help a breast-cancer patient make treatment decisions in light of her estimated risk of developing ovarian cancer or cancer in her other breast - both of which are more likely among those with certain mutations.

Women who do not have cancer but learn that they have harmful mutations are commonly counseled about risk-reduction strategies. In the past, there was often little or no information on whether these strategies helped, but now, some evidence is beginning to become available.

• Reducing ovarian cancer risk. If you have a cancer-susceptibility mutation or a family history that suggests an elevated risk, you may be screened more closely than women who do not have these risk factors. For ovarian cancer, tests that have not proved useful for general screening are considered reasonable for women at higher risk. An example is regular pelvic ultrasound and blood testing for CA-125 (a protein sometimes detected in early-stage ovarian cancer).
In addition, a 1998 New England Journal of Medicine study reported that using oral contraceptives might lower the risk for ovarian cancer. Among 207 women who were BRCA1 or BRCA2 mutation carriers, taking the pill for up to three years lowered risk by 20%; six years of pill use lowered the risk by 60%.

Thus far only one study has assessed the value of removing the ovaries (prophylactic oophorectomy) of women who have an elevated cancer risk because of inherited mutations. According to the study, the procedure reduces the risk for ovarian cancer by more than half, but women sometimes still develop a closely related cancer on the peritoneal wall.
Last year, researchers reported that women with BRCA1 or BRCA2 mutations rarely develop ovarian cancer before age 40 (although their average age of onset, at 54, is eight years younger than of women without mutations). Given this finding, younger BRCA mutation carriers might decide to delay surgery until after having children.

• Reducing breast cancer risk. A woman with a BRCA1 or BRCA2 mutation may be advised to continue monthly breast self-examinations, have a clinical breast exam more than once a year, and have regular mammograms (but perhaps start at an earlier age than usual). But no studies have demonstrated that enhanced screening improves breast cancer diagnosis and survival in women with BRCA1 or BRCA2 mutations.

Among high-risk women (not necessarily those with a BRCA1 or BRCA2 mutation), prophylactic mastectomy can reduce the risk for breast cancer up to 90%. Taking tamoxifen reduces the risk by about half for women in general, but it has not been tested specifically in BRCA mutation carriers.

Although its main purpose is to prevent ovarian cancer, prophylactic oophorectomy reduces the risk for breast cancer as well, most dramatically when surgery is performed before age 40.
For Further Information

• FORCE - Facing Our Risk of Cancer Empowered

(954) 255-8732,

Information for women at increased risk of breast and ovarian cancer due to family history or to known genetic mutations.

• CancerNet: A Service of the National Cancer Institute
(800) 4-CANCER (422-6237)

A call-in cancer genetics information service with directories of specialists and other resources.
• National Society of Genetic Counselors
(610) 872-7608,

Professional organization for genetic counselors with a directory of members specializing in cancer.


Concern about discrimination in employment or insurance has prevented many people from pursuing genetic testing. Before you decide, ask about your state's laws on genetic discrimination (more than 30 states offer some protection) and find out what measures you can take to keep your test results private.

Myriad Genetic Laboratories - currently the only commercial provider of BRCA1 and BRCA2 tests - has negotiated contracts with some insurers that authorize payment but explicitly deny insurers the test results. But even taking such a test could suggest that you are at high risk, as would any protective measure you might take afterwards. As a result, even when their insurers cover BRCA1 and BRCA2 testing, some women prefer to pay for it out-of-pocket in order to keep their results private.

Genetic counselors themselves recognize the importance of these concerns. In a recent survey, 85% said they would be tested if they were at high risk - but fully two-thirds would not seek insurance coverage, and one in four would use an alias.

The Coalition for Genetic Fairness, a group of medical and civil rights organizations, seeks a strong federal law against all discrimination based on predictive genetic information, including family history. The coalition is especially concerned about employment discrimination (since most people obtain insurance through their jobs) and about the disclosure of genetic information without an individual's consent.


Raising the Question. You or your primary physician become concerned that your personal and family history raises your risk for certain cancers. You are referred to a genetic counselor or specialty clinic.
Risk Assessment. Your medical and family history is evaluated. This may involve contacting key family members and gathering medical records.

Education and Counseling. The benefits, risks, and limitations of genetic testing are explained and thoroughly discussed.

Physical Exam. A pre-test physical may be advised to detect existing cancer.

An Informed Decision. You take your time making a decision and may revisit your genetic counselor for further discussion. If you decide to be tested, the clinician will review your decision with you and obtain your written informed consent. If you decide not to be tested, the genetic counselor will discuss appropriate screening and prevention strategies in light of your estimated risk.

Testing. Blood is drawn and sent to the appropriate laboratory. Results may take several weeks.
Post-test Counseling. Results are disclosed in person and their significance is explained. Psychological support is provided.

Further Discussion. With input from specialists, you make decisions about preventive measures and cancer screening. You can decide which family members should be informed of test results, including those at risk of a mutation or those whose results might clarify an uncertain result.

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