 Heredity and Breast Cancer—the BRCA Gene Breast Cancer Genetic Counseling Prophylactic Mastectomy for BRCA Gene Carriers Who Should be Tested for the BRCA Gene Mutations? Genetic Risk Factors for Breast Cancer Heredity and Breast Cancer—the BRCA GeneWhat do we know about heredity and breast cancer?Breast cancer is a common disease. Each year, approximately 200,000 women in the United States are diagnosed with breast cancer, and one in nine American women will develop breast cancer in her lifetime. But hereditary breast cancer — caused by a mutant gene passed from parents to their children — is rare. Estimates of the incidence of hereditary breast cancer range from between 5 to 10 percent to as many as 27 percent of all breast cancers.In 1994, the first gene associated with breast cancer — BRCA1 (for BReast CAncer1) was identified on chromosome 17. A year later, a second gene associated with breast cancer — BRCA2 — was discovered on chromosome 13. When individuals carry a mutated form of either BRCA1 or BRCA2, they have an increased risk of developing breast or ovarian cancer at some point in their lives. Children of parents with a BRCA1 or BRCA2 mutation have a 50 percent chance of inheriting the gene mutation. What do we know about hereditary breast cancer in Ashkenazi Jews?In 1995 and 1996, studies of DNA samples revealed that Ashkenazi (Eastern European) Jews are 10 times more likely to have mutations in BRCA1 and BRCA 2 genes than the general population. Approximately 2.65 percent of the Ashkenazi Jewish population has a mutation in these genes, while only 0.2 percent of the general population carries these mutations.Further research showed that three specific mutations in these genes accounted for 90 percent of the BRCA1 and BRCA2 variants within this ethnic group. This contrasts with hundreds of unique mutations of these two genes within the general population. However, despite the relatively high prevalence of these genetic mutations in Ashkenazi Jews, only seven percent of breast cancers in Ashkenazi women are caused by alterations in BRCA1 and BRCA2. What other genes may cause hereditary breast cancer?Not all hereditary breast cancers are caused by BRCA1 and BRCA2. In fact, researchers now believe that at least half of hereditary breast cancers are not linked to these genes. Scientists also now think that these remaining cases of hereditary breast cancer are not caused by another single, unidentified gene, but rather by many genes, each accounting for a small fraction of breast cancers. In our Breast Cancer Questions researchers discuss a recent advance in understanding hereditary breast cancer, and the challenges that remain.Is there a test for hereditary breast cancer?Hereditary breast cancer is suspected when there is a strong family history of breast cancer: occurrences of the disease in at least three first or second-degree relatives (sisters, mothers, aunts). Currently the only tests available are DNA tests to determine whether an individual in such a high-risk family has a genetic mutation in the BRCA1 or BRCA2 genes.When someone with a family history of breast cancer has been tested and found to have an altered BRCA1 or BRCA2 gene, the family is said to have a "known mutation." Positive test results only provide information about the risk of developing breast cancer. The test cannot tell a person whether or when cancer might develop. Many, but not all, women and some men who inherit an altered gene will develop breast cancer. Both men and women who inherit an altered gene, whether or not they develop cancer themselves, can pass the alteration on to their sons and daughters. But even if the test is negative, the individual may still have a predisposition to hereditary breast cancer. Currently available technique can't identify all cancer-predisposing mutations in the BRCA1 and BRCA2 genes. Or, an individual may have inherited a mutation caused by other genes. And, because most cases of breast cancer are not hereditary, individuals may develop breast cancer whether or not a genetic mutation is present. How do I decide whether to be tested?Given the limitations of testing for hereditary breast cancer, should an individual at high risk get tested? Genetic counselors can help individuals and families make decisions regarding testing. (For a description of what genetic counselors do, see Frequently Asked Questions About Genetics.)For those who do test positive for the BRCA1 or BRCA2 gene, surveillance (mammography and clinical breast exams) can help detect the disease at an early stage. A woman who tests positive can also consider taking the drug tamoxifen, which has been found to reduce the risk of developing breast cancer by almost 50 percent in women at high risk. Clinical trials are now under way to determine whether another drug, raloxifene, is also effective in preventing breast cancer. Credit for Article BRCA Gene ScreeningThe theory of genetic risks factors for certain cancers has been described since the time of ancient Rome. In 1866, Paul Broca, a French physician, reported ten cases of breast cancer spanning four generations of his wife’s family. Recently it has been shown that genetic predisposition accounts for five to ten percent of ovarian and breast cancers. Mary-Claire King and associates, in 1990, localized the first major susceptibility gene for breast and ovarian cancer on chromosome 17 and have referred to it as BRCA1 (BR=Breast and CA=Cancer). Since that time BRCA2, which predisposes its carriers predominately to breast cancer, has also been isolated. BRCA is thought to be a tumor suppressor gene that codes for a protein that regulates transcription of genes involved in cellular proliferation. To date, over 100 mutations on BRCA1 which are associated with truncation of the protein have been discovered. Missense mutations, which are aberrations in the DNA that do not appear to confer any changes to the protein, have also been described, but, the clinical relevance of these changes is unclear. The “two hit” model for genetic predisposition assumes that a carrier is born with a mutation in one of the two BRCA genes, but that the normal BRCA gene imparts its protective effects until such time that the normal gene undergoes a mutation for what ever reason (e.g. environmental factor). At that point, the tumor suppressor protein is no longer encoded properly and a cancer develops. Seven percent of breast cancers and ten percent of ovarian cancers are related to susceptibility genes, mainly BRCA1 and BRCA2. Obviously not all susceptibility genes have yet been identified. It is suspected that as many as 1,000,000 (about 0.5% – 0.6%) United States women are carriers of the altered BRCA1 or BRCA2 gene. Ashkenazi Jewish women are at particularly high risk with over 1% carrying the gene. Women that carry the mutation have an 82% risk of breast cancer and a 44% risk for ovarian cancer (BRCA1) by the age of 70. Interestingly, these women are often afflicted at a younger age with a 59% risk of breast cancer before the age of fifty, and often these patients will be afflicted with cancer before the age of 40. The American Society of Clinical Oncology recommends that cancer predisposition testing be offered only when: 1) the person has a strong family history of cancer or very early onset of the disease; 2) the test can adequately be interpreted; and 3) the results will influence medical management. However, “strong family history” was not defined. Early studies that tested first generation relatives of cancer patients afflicted before the age of forty showed that approximately 53% had a deleterious mutation in BRCA1. If the relative was diagnosed with cancer between the age of 40 and 60, the mutation rate dropped to 16%. Therefore, determination of who should be tested should be based both on the number of relatives that were affected, and equally as important, the age at which they were affected. Management of patients that carry the aberration of the BRCA gene is still evolving. Medical modifications, at a minimum, should include increased screening for breast and ovarian cancer, and discussions of prophylactic surgery. Lifestyle modifications should include refraining form alcohol, weight loss in the overweight patient, possible use of oral contraceptives, and cessation of smoking—all of which have been shown to have a deleterious effect on breast cancer. The use of antioxidants in this group of patients may also prove to be of benefit. Counseling for genetic testing, as per the American Society of Clinical Oncology, should involve the following eleven points:
Credit for Article Breast Cancer Genetic Counseling
What is a BRCA gene?A functioning BRCA gene prevents tumor growth by limiting cell division. Every cell in the body has two copies of each gene. Individuals predisposed to breast cancer are born with a mutation in one of their two copies of a BRCA gene. For breast cancer to occur, both BRCA copies must be mutated. Once a second BRCA mutation is acquired, the cell divides uncontrollably, resulting in a tumor. Individuals beginning life with one mutated BRCA gene are pre-disposed to breast cancer development because their cells have only one safety belt (1 normal BRCA gene) to prevent mass cell division. Non-breast cancer predisposed individuals have two safety belts (2 normal BRCA genes) at birth and, thus, have a lower risk of developing a breast tumor.How were the BRCA genes found?The localization of BRCA1 and BRCA2 within the human genome enabled the creation of the breast cancer predisposition genetic tests. The BRCA genes were decisively identified as loci for breast cancer development upon mutation through genetic research involving 237 large, breast cancer-affected families. The BRCA1 and BRCA2 genes were pinpointed to chromosome 17 and chromosome 13 in 1994 and 1995 respectively.Why are Ashkenazi Jewish women especially at risk?Ashkenazi Jewish women display a particularly high prevalence of breast cancer. The localization of BRCA1 and BRCA2 has enabled the realization that three mutations may be the cause of one-third of breast cancer cases in Ashkenazi Jewish women under the age of forty. High rates of particular genetic mutations among withdrawn populations such as the Ashkenazi Jews can be explained by the founder effect. The founder effect is predominant among culturally or geographically isolated groups and is apparent when single mutations are linked to genetic transmission in the majority of occurrences.Why was the breast cancer predisposition gene test created?As stated by Gauthier-Villars, Gad, Caux, et al., “it must be remembered that the main purpose for breast cancer predisposition testing is to provide women at high risk with better supportive care. Today, a major challenge for clinical research is to identify the modalities for prevention that will allow reduction of the morbidity and the mortality linked to a high predisposition to breast cancer” (Gauthier-Villars, Gad, Caux, et al., 1171).Why undergo genetic counseling and BRCA testing?According to Lerman, Seay, Balshem, and Audrain, healthy female relatives of individuals with ovarian or breast cancer tend to exaggerate their risk of incurring either form of cancer and, thus, accurate risk assessment is essential to quality genetic counseling for breast cancer. Breast cancer genetic counseling serves the goal of helping women to analyze their own and their relatives' risk of developing breast cancer.In BRCA screening, genetic counselors offer services in compiling family histories, personalizing epidemiology, and, more recently, conducting genetic testing to empower healthy women of families stricken by breast cancer to alter their lifestyles and healthcare to ensure avoidance or early detection of breast cancer. In addition, breast cancer victims and healthy members of a single family can enable accurate screening of female family members by obtaining a sequence of their BRCA genes. Detection of a familial BRCA mutation in individuals outside of the Ashkenazi Jewish population requires time-consuming genetic analysis of a large number of affected and unaffected family members in order to identify the specific BRCA mutation for a particular family. Who can be tested for BRCA mutations?The BRCA tests are currently offered only to individuals with at least a 20% likelihood of carrying a well-defined mutation in BRCA1 or BRCA2. In order for predisposition testing to occur, the familial mutation must already be well characterized by sequencing the BRCA genes of affected and unaffected family members. A first-degree relative of a carrier of a BRCA1 or BRCA2 mutation, whether mother, daughter, or sister, generally faces a 50% risk of combating breast cancer in the course of her lifetime.Numerous medical and genetics organizations have released suggestions to guide the process of testing for the presence of a mutation in the BRCA loci, including the American Society of Clinical Oncology (ASCO), the American Society of Human Genetics (ASHG), the National Society of Genetic Counselors (NSGC), the task force of the Cancer Genetics Studies Consortium (CGSC) of National Human Genome Research Institute, the task force of the National Institutes of Health — Department of Energy, and the French National Institute of Health and Medical Research. These organizations agree that testing for a BRCA1 or BRCA2 mutation, as with any well-defined genetic mutation, requires the informed consent of the individual to be tested after extensive counseling as to the epidemiology of the mutation of interest, the family history of the individual, and the potential impact of test results, including mental, physical, and insurance discrimination effects. In addition, children should not be tested for BRCA mutations. The advisory organizations disagree, however, on the appropriate professionals to conduct predisposition screening and on notification of family members of genetic test results without the consent of the tested individual. The ASHG and other groups believe that only genetic counselors or geneticists should conduct testing and that relatives have the right to genetic test results if the course of the familial disease may be improved or avoided by more rigorous screening and monitoring. The ASCO, in contrast, demands that clinical oncologists also be allowed to perform BRCA tests and that the tested individual’s permission be obtained prior to release of any results. The groups agree that relevant professionals from a variety of fields should be consulted, including psychologists, radiologists, surgeons, geneticists, and oncologists. What can the test tell me?Testing positive or negative for a BRCA mutation is simply a risk assessment, not a certainty of experiencing or avoiding, respectively, breast cancer. Individuals with a BRCA mutation have an 80% risk of developing breast cancer by age 80. Therefore, 20% of BRCA mutation carriers never develop breast cancer. A first-degree relative of a carrier who tests negative for the mutation has the same breast cancer risk as women of the general population, namely 11%, down from the 50% estimated likelihood.What is my risk if I am a BRCA carrier?Mutations in either BRCA1 or BRCA2 account for about two-thirds of all familial breast cancer occurrences, with BRCA1 variation causing 28% and BRCA2 responsible for 37%. Women who carry either BRCA mutation have a roughly eight in ten likelihood of developing breast cancer by the age of seventy. Mutation of the BRCA1 gene and, to a lesser extent, BRCA2, also predisposes women to ovarian cancer. BRCA1 has been associated with 80% of familial ovarian and breast cancers with 15% occurring with BRCA2 mutation, thus accounting for 95% of all familial concurrent ovarian and breast cancers.The resultant breast cancer forms of BRCA1 and BRCA2 mutations can be distinguished on the basis of prevalence of medullary tumors and tubule formation. Both BRCA1 and BRCA2-related breast tumors commonly invade the duct system and “…exhibit poor histologic grade,” BRCA1 is linked to medullary tumors and extremely rapid division of cells while BRCA2 tumors feature “…a low rate of tubule formation rather than a high mitotic index” (Gauthier-Villars, Gad, Caux, et al., 1175). Studies of familial breast cancer have yielded mixed results on the prognosis of BRCA1- and BRCA2-linked breast cancers relative to non-familial breast cancers. What can I do if I am a BRCA mutation carrier?Women with a high risk of breast cancer development can enhance their likelihood of avoiding breast cancer by engaging in one or more of the following treatment options: rigorous cancer surveillance, prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention via Tamoxifen treatment.Experts and patients alike have reached consensus that increased surveillance is essential for high-risk women. BRCA carriers 25 years of age and older should be seen twice yearly by a specialist and obtain a mammogram annually. In contrast to more invasive alternatives, heightened breast examination avoids tissue removal and harmful side effects for individuals who never incur breast cancer. Unfortunately breast cancer develops in 80% of BRCA mutation carriers and the value of surveillance depends on the patient’s long-term cooperation. Probably the greatest debate for BRCA mutation carriers is whether or not to undergo a prophylactic mastectomy in order to reduce risk of breast cancer development, the effects of radiation and chemotherapy if diagnosed, and the mental stress of impending development of breast cancer. Prophylactic mastectomy, as a major appearance-altering surgery, poses negative effects, such as significant mental stress, including feelings of lost femininity and beauty, as well as the possibility of complications in surgery. The tissue loss inherent in prophylactic mastectomy is irreversible. In addition, prophylactic mastectomies reduce but do not remove the likelihood of breast cancer. High-risk women are, however, 90% less likely to experience breast cancer following removal of both breasts. Prophylactic oophorectomy, or removal of the ovaries, is an additional choice for women with a high risk of breast cancer because exposure to ovary-derived estrogen enhances risk of breast cancer. If conducted before age 40, this procedure reduces breast cancer risk by 50% in comparison with natural menopause for both BRCA1 carriers and women in the general population. Oophorectomy allows high-risk patients to maintain breast tissue but forces early menopause. Unfortunately, post-oophorectomy hormone replacement therapies may enhance a woman’s risk of uterine cancer or breast tumor development. Subjecting BRCA carriers to prophylactic chemotherapy and radiotherapy has yielded conflicting results and carries uncertain side effects, especially for young women. Treatment of high-risk women with Tamoxifen, an agent that interferes with estrogen, has, in some studies, been shown to lower the risk of breast cancer occurrence in high-risk patients in the course of treatment but post-treatment preventative value is still unclear. In addition, although participants do not sacrifice tissue, those over the age of fifty suffer increased risk of uterine cancer, blood clots, and cataracts with Tamoxifen treatment. The details of BRCA testing?Finding an altered portion of the BRCA1 or BRCA2 gene can take several weeks and BRCA testing may be expensive and/or not covered by health insurance. In addition, tested individuals should consider not informing their insurance companies in order to avoid rate hikes with finding of a mutation (insurance discrimination).Credit for Article The Center for Restorative Breast Surgery was established to serve as a dedicated resource for women seeking the most advanced methods of breast reconstruction utilizing the body’s own tissue. Founded by Frank J. DellaCroce, M.D., FACS and Scott K. Sullivan, M.D., FACS, the Center for Restorative Breast Surgery specializes exclusively in state-of-the-art breast surgery techniques (DIEP, SIEA and GAP flap procedures) that allow for breast reconstruction without sacrifice of important functional muscles. |
