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BREAST CANCER GENE TESTING
(1999)

• Should you be tested?
• Preventive options for BRCA-positive women
• Understanding negative test results
• Unanswered questions

The American Cancer Society (ACS) estimates that about 175,000 new cases of invasive breast cancer are diagnosed each year among women in the United States, and there are more than 43,000 deaths yearly from the disease. This represents a 1-in-8 lifetime chance of developing the disease, if a woman lives to age 85. But some women’s risk is increased several-fold due to a hereditary defect in one of two genes that increase a woman’s risk for breast cancer, BRCA1 (Breast Cancer gene 1) and BRCA2 (Breast Cancer gene 2).
BRCA1 and BRCA2 were identified in 1994 as susceptibility genes for both breast and ovarian cancer. When functioning normally, BRCA1 and BRCA2 are thought to be involved in repair of damage to cellular deoxyribonucleic acid (DNA), a process that protects against tumor development. Women who have mutations in these genes, causing them to malfunction, have a 56 percent to 87 percent lifetime chance of developing breast cancer, and a 20 percent to 60 percent chance of developing ovarian cancer.
“These wide risk ranges are due to age,” says Sandhya Pruthi, M.D, a breast specialist at Mayo’s breast clinic. “About 20 percent of female BRCA1-mutation carriers will develop breast cancer by age 40, 51 percent by age 50, and 87 percent by age 70.”
BRCA1 mutations also have been linked to a higher lifetime risk of colon and prostate cancer, while BRCA2 mutations may raise lifetime risk for these and possibly other cancers.
For several years, blood tests have been available that identify abnormal BRCA1 and BRCA2 genes. The value of these test results is controversial, and whether a woman even should be tested remains a difficult decision.
Should you be tested?
With respect to breast cancer, BRCA1 and BRCA2 gene mutations are only associated with hereditary forms of the disease. About 5 percent of all breast cancers are inherited. The remaining 90 percent to 95 percent are non-hereditary and of unknown cause.
Both men and women can inherit and pass on defective BRCA genes. Families in which breast cancer is inherited typically demonstrate the following characteristics:
• Breast cancer in two or more close relatives, such as a mother and two sisters
• Early onset of breast cancer in family members, often before age 50
• History of breast cancer in more than one generation
• Cancer in both breasts in one or more family members
• Frequent occurrence of ovarian cancer
• Ashkenazi (Eastern and Central European) Jewish ancestry, with a family history of breast and/or ovarian cancer (researchers have identified two BRCA1 mutations and one BRCA2 mutation that are particularly prevalent in this group)
Breast cancer in several members of a family, especially if the disease occurs late in life, may be due merely to chance. Breast cancer is so common that random, non-inherited breast tumors may appear in more than one member of a single family. It doesn’t necessarily mean that family members have inherited an abnormal gene which predisposes them to breast cancer.

For most women though, the most important question in deciding whether to be tested remains: “What can be done if a defective gene is found?”
Preventive options for BRCA-positive women
Identification of a BRCA mutation means that a woman is known to be at high risk for breast and ovarian cancer. She and her physician then must decide on a preventive strategy.
One option for BRCA mutation carriers is risk avoidance, which involves engaging in behaviors that are believed to reduce cancer risk, such as limiting alcohol consumption and increasing regular exercise.
Other preventive options include frequent screening tests (surveillance), chemoprevention, or prophylactic (preventive) surgery.
For years, deciding which option was best for an individual woman was made more difficult by a lack of data regarding the effectiveness of each option. Recent studies, however, have provided more solid data, and women now can consider each alternative knowing how effective it is likely to be.
Increased screening
A non-invasive preventive option following a positive genetic test is to increase breast cancer screening. This includes monthly breast self-examinations (BSE), regular breast exams by a health care provider and more mammograms. The ACS reports that the breast cancer mortality rate has been decreasing during the past few years, a trend attributed to increased screening — leading to detection of cancers at an earlier stage — combined with more effective treatments.
Chemoprevention
A second option for women with mutations in BRCA genes is “chemoprevention,” the use of drugs to prevent the development of disease. Tamoxifen is currently the treatment most commonly used to reduce breast cancer risk in high-risk women.
The Breast Cancer Prevention Trial (BCPT), sponsored by the National Institutes of Health (NIH), reported in 1998 that tamoxifen reduces the risk of breast cancer by 45 percent in women at high risk for the disease. The BRCA mutation status of the study participants is still being assessed.
Tamoxifen may cause serious side effects, including an increased risk of endometrial cancer, deep vein thrombosis and pulmonary embolism. In addition, a study published in the July 30, 1999, issue of the journal Science suggested that after 2 to 5 years of use, tamoxifen may lose its effectiveness against breast cancer and may even begin to promote the disease
Despite these complications, tamoxifen has clearly been proven beneficial in reducing the incidence of disease in women at high risk for breast cancer. It is not known yet how long the risk-reduction remains after women stop taking tamoxifen. Research on this drug is ongoing. A new drug, raloxifene, currently is being compared with tamoxifen in one of the largest breast cancer prevention trials ever — the Study of Tamoxifen and Raloxifene (STAR).
Prophylactic surgery
A third preventive option for BRCA mutation carriers is prophylactic surgery. A study of women with a family history of breast cancer, published in the January 14, 1999, issue of the New England Journal of Medicine, reported that prophylactic mastectomy reduced the risk for breast cancer by 90 percent, and reduced breast cancer mortality by 80 percent. These data may help some high-risk women make an informed decision about this preventive option. However, prophylactic mastectomy cannot guarantee prevention, since some breast tissue may remain after surgery
While prophylactic oophorectomy (removing both ovaries) has so far been intended to reduce ovarian cancer risk, it also may benefit BRCA mutation carriers. A study published in the September 1, 1999, Journal of the National Cancer Institute reported that prophylactic oophorectomy reduces the risk of breast cancer in women under age 50 who carry BRCA1 mutations, presumably due to the decrease in ovarian hormone exposure.
This surgery may cause serious side effects. Premenopausal women who undergo oophorectomy experience immediate menopause, which is associated with long-term complications such as early osteoporosis, menopausal symptoms, heart disease and premature mortality. Hormone replacement therapy (HRT) may improve overall health, but this treatment may increase the risk of breast cancer.
Understanding negative test results
If a BRCA mutation is not found during genetic testing, questions may remain about a woman’s risk for breast and ovarian cancer.
Two possible scenarios include:
• Negative test results, a family history of breast cancer, and no known relative with a BRCA mutation — In this case, a woman may be at high risk of hereditary breast cancer from an unidentified gene mutation, and little assessment of her own risk can be made. Testing for BRCA gene mutations is, for this reason, most informative if a mutation has previously been identified in an affected family member.
• Negative test results, a family history of breast cancer, and at least one relative known to have a BRCA mutation — In this case, the absence of a BRCA mutation means that a woman has not inherited her family’s increased risk. This does not mean, however, that her risk of breast cancer is zero, but only that of the general population.
Unanswered questions
Much remains to be learned about BRCA mutations. There are over 200 mutations so far identified on the BRCA1 and BRCA2 genes, and not all of these mutations carry the same risk of cancer. The level of risk associated with each BRCA mutation isn’t known.
So, having a defective BRCA gene doesn’t mean you will get breast cancer. Test results can’t determine exactly how high your risk is, at what age you may develop cancer, how aggressively the disease might progress, or how your risk of death from breast cancer compares to other women.
The BRCA1 and BRCA2 genes are the subject of intensive research. With increased understanding, it may one day even be possible to use gene therapy to replace defective BRCA genes with functional copies.
In the meantime, women at high risk for hereditary breast cancer still face many difficult decisions.