6. Is there a known association of specific types of breast cancer and BRCA gene mutations? a. Specifically inflammatory breast cancer

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1 What s Jewish about BRCA? It is estimated that about one in 40 individuals with Ashkenazi Jewish ancestry has one of these three BRCA mutations. Approximately one in 10 women with breast cancer and one in three women with ovarian cancer in Ashkenazi Jewish families have one of the BRCA1 or BRCA2 gene mutations. The following panel questions were answered by Shreshtha Madaan, MS, LCGC, Genetic Counselor specializing in hereditary cancer risk assessment from Insight Medical Genetics. Insight Medical Genetics (IMG) is a comprehensive genetic testing practice providing personalized counseling, screening and diagnostic testing for patients and referring providers in the fields of prenatal and cancer genetics for the Chicagoland area. Genetics 1. What % of the population has the CHEK2 gene that puts you at a 2-fold risk? The frequency of CHEK2 gene changes are dependent on a person s ethnicity. For someone who is not affected with cancer and does not have a striking family history, the likelihood of carrying a harmful change in the CHEK2 gene is much less than 1%. 2. Can someone inherit both a BRCA1 and BRCA2 mutation? Yes, while rare, it is possible for an individual to inherit both a BRCA1 and BRCA2 mutation. 3. Does having an autoimmune disease affect your risk for a mutation? Genetic mutations that predispose someone to cancer are almost always either inherited from a parent or obtained before a person is born, during the development of egg or sperm. If a person has an autoimmune disease, their risk for certain cancers may be increased over the general population, but their risk of carrying a mutation in a cancer predisposition gene does not increase. 4. If you are a Tay-Sachs carrier, is that indicative of BRCA? No, Tay-Sachs carrier status is not related to BRCA risk in anyway. Tay-Sachs disease and Hereditary Breast and Ovarian Cancer syndrome are two separate conditions due to mutations in different genes. 5. Is post-menopausal cancer considered hereditary? a. Ex. Grandmother s generation has 3 sisters all three were diagnosed with breast cancer after menopause. Are the granddaughters considered at risk? Any family with multiple cases of the same type of cancer should seek genetic counseling to evaluate the risk to family members. While post-menopausal breast cancer is less likely to be caused by a hereditary predisposition, certain gene changes do have later-onset cancer risks. For example, women with BRCA2 mutations are a little more likely to develop cancer closer to the average general population ages. 6. Is there a known association of specific types of breast cancer and BRCA gene mutations? a. Specifically inflammatory breast cancer Any type of breast cancer can be caused by mutations in the BRCA1 and BRCA2 genes. One factor that may be more suggestive of a hereditary predisposition is triple-negative breast cancer (TNBC), in which case the cancer

2 tumor itself is lacking estrogen receptor, progesterone receptor, and the Her2Neu marker. However, an inflammatory breast cancer is no more likely to be caused by BRCA mutations than a non-inflammatory cancer. 7. How does endometrial/uterine cancer compare in terms of heredity risks? BRCA1/2 mutations are not known to increase the risk of endometrial and/or uterine cancer. There are certain other cancer predisposition syndromes that do increase the risk of those cancers. One of the most striking increases in risk of endometrial or uterine cancer is linked to Lynch Syndrome, caused by mutations in different genes. Risk Assessment and Genetic Testing 1. Should I have genetic testing? Before taking a genetic test to learn if you are at high risk for cancer risk, it is recommended that you speak with an expert who specializes in cancer genetics such as a genetic counselor or medical geneticist. This is the best way to make sure that you receive the most up-to-date information in order to make informed medical decisions. They will evaluate your family medical history and assure the proper test is ordered and results are interpreted correctly. A genetics expert will also be able to determine the best person in your family to have testing. Find a genetic counselor near you here. 2. What is the current thought for screening for BRCA2 when someone has a positive family history of pancreatic cancer? At this time, there is no standard-of-care pancreatic cancer screening. Many studies are underway to evaluate different screening methodologies for early detection of pancreatic cancer. If you are diagnosed with a BRCA2 mutation and have a family history of cancer, a personalized plan for screening should be developed with your physician. This may involve ultrasounds or other forms of imagine of the upper GI tract. 3. Is BRCA testing expensive? Do most insurance companies pay for the test? The cost of genetic testing ranges from several hundred to several thousand dollars. Costs can vary but most insurance companies will cover the cost of genetic testing in individuals who have either a personal history or family history of cancer and who meet certain guidelines. If you choose to have genetic testing at the time of your appointment, a genetic counselor can ensure that you are informed about any potential out-of-pocket costs. The cost of genetic testing is separate from other fees related to the appointment. 4. Are BRCA test results ever wrong? BRCA testing performed by reputable labs is very accurate, and incorrect test results are very rare. However, interpretation of the test results can be complex and depends on which test was ordered. For this reason it is important to speak with a qualified genetics expert before and after BRCA testing to assure that the proper test was ordered and results were interpreted correctly. If you are concerned that your test results may be incorrect, speak with your genetic counselor about second opinion genetic testing. 5. If I test negative am I still at risk for breast cancer? Yes, even if a test is negative there is still a risk for developing breast cancer. There are MANY factors that contribute to developing cancer. In fact, only about 5-10% of women with breast cancer have tested positive for a BRCA mutation. Cancer is caused by a combination of genetic and environmental factors. Gene mutations only explain a subset of all cancers. You may still be at increased risk depending upon the cause of the cancer in your family and personal risk factors.

3 6. What age should young girls, with a father who died at 55 from breast cancer and was positive for a BRCA mutation, be tested? Since management recommendations begin at the age of 25, a woman with a positive BRCA family history should consider speaking with a genetic counselor around that age to determine whether she would like to proceed with genetic testing. 7. Should I be re-tested for other possible genes if I have a strong family history of breast cancer and was negative for BRCA1 and BRCA2? You should meet with a genetic counselor to determine if additional genetic testing will be appropriate for you. A counselor will be able to talk to you about your family history and let you know if additional testing is necessary. 8. If an individual has parents who both have BRCA mutations could that individual have 2 mutations? Does that impact overall risk for breast/ovarian cancer? Yes it is possible for an individual to inherit BRCA mutations from both parents. If both parents carry a BRCA2 gene mutation, there is a 25% risk with each pregnancy of having a child with Fanconi anemia, which is an inherited disorder, associated with physical abnormalities, an increased risk of blood cancers, and other serious problems. Fanconi anemia is inherited in an autosomal recessive pattern, meaning that if a child inherits two copies of the BRCA2 gene with a mutation (one from each parent) they will be born with the disease. More information about Fanconi Anemia can be found here. If an individual inherits both a BRCA1 and BRCA2 mutation they are generally expected to have the same breast and ovarian cancer risks as a single BRCA1 mutation. However, depending on family history, there may also be higher risks of pancreatic cancer, and melanoma. 9. Would you recommend testing for the daughter of a woman who died from inflammatory breast cancer at 40 years of age? a. What age should testing be completed? In order to recommend testing, a complete family history needs to be collected (including the unaffected individuals in the family as well). If you are considering testing, seek a genetic counseling visit where you can discuss all of the options available to you. Testing is generally recommended between the ages of 18 and 25, as breast surveillance for BRCA mutation carriers would begin by age 25 in most families. 10. Can you please speak about PALB2 mutations and recommendations related to additional genetic testing? a. Should I get expanded testing if I have a family history and negative BRCA testing? PALB2 mutations are currently linked to an increased risk of breast cancer. There are no definitive studies at this time relating PALB2 to ovarian cancer. If your family has undergone negative BRCA testing and is considering more testing, talk with a genetic counselor about whether PALB2 testing is appropriate for your family. Some families may benefit from larger panels that can explore many more genes relating to breast cancer, including PALB What should I do if my insurance company won t pay for the cancer screening tests ordered by my doctor? There are resources that can help you with appealing these decisions. A genetic counselor can also help work with you to provide the appropriate letters of medical necessity to justifying the cost of testing. The Patient

4 Advocate Foundation provides services to help patients work with their insurance companies to get the care they need. 12. Should someone be tested if there is only prostate cancer in the family? At this time, a family history of only prostate cancer is not highly suggestive of mutations in BRCA1/2. However, some family histories are considered uninformative, in that they perhaps don t have many women in the family and mutations may be masked. Talk to a genetic counselor if you feel that you have a very strong family history of prostate cancer, as there might be research studies that your family can enroll in. 13. Where can you undergo testing and how much does it cost? Typically most people undergo hereditary cancer testing through a genetic counselor. A genetic counselor would perform a thorough risk assessment and order appropriate testing for you based on your personal and family history. The cost of testing varies by test, and by insurance company. Out-of-pocket costs for BRCA1/2 testing, if only analyzing the common Ashkenazi Jewish mutations, tends to be less than $500 for most people. Breast Cancer/Surgery 1. Can you explain triple negative breast cancer? A diagnosis of triple negative breast cancer means that the three most common types of receptors known to fuel most breast cancer growth estrogen, progesterone, and the HER-2/neu gene are not present in the cancer tumor. This means that the breast cancer cells have tested negative for hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR). Since the tumor cells lack the necessary receptors, common treatments like hormone therapy and drugs that target estrogen, progesterone, and HER-2 are ineffective and therefore chemotherapy is usually recommended. Triple negative breast cancer occurs in about 10-20% of diagnosed breast cancers and is more likely to affect younger people, African Americans, Hispanics, and/or those with a BRCA1 gene mutation. Triple negative breast cancer can be more aggressive and difficult to treat. Also, the cancer is more likely to spread and recur. The stage of breast cancer and the grade of the tumor will influence prognosis. 2. As a woman with a BRCA mutation, what kind of doctor should I be meeting with about a surveillance plan for breast and ovarian since a breast surgeon will mainly address breast only. You should seek a meeting with a gynecologic oncologist, one who can help you start screening for ovarian cancer risk or help make a plan for removing your ovaries. You should also establish care with a breast specialist or breast oncologist for your clinical breast exams. A dermatologist can screen you for melanoma annually. If you have a family history of pancreatic cancer, a gastroenterologist specializing in hereditary cancer risk may help you determine if any pancreatic screening is appropriate for you. 3. Does a bilateral mastectomy eliminate my risk for breast cancer? Bilateral mastectomy is the most effective way to lower the risk for breast cancer, decreasing the risk by about 95%, but it doesn't lower the risk to zero. Even the most experienced breast surgeon cannot remove all breast tissue because the tissue of the breast extends right up to the skin. Because the skin must be saved a small amount of breast tissue always remains after a mastectomy, therefore posing a small risk of developing breast cancer after surgery. 3. Is nipple-sparing mastectomy safe? Nipple-sparing mastectomy is a type of skin-sparing procedure that allows a woman to retain her own areola and nipple. During the surgery the breast tissue is removed from underneath the nipple and areola and the entire nipple areola complex remains. A sample of the patient s tissue beneath the nipple is tested during surgery, and if cancer cells are found, the entire nipple-areolar complex is removed. Unfortunately during nipple

5 sparing mastectomy the nipple loses most, if not all of its normal sensation and can change and flatten with time. Complications from nipple-sparing mastectomy include nipple necrosis, which can lead to partial or complete loss of the nipple after surgery. There have been very few reported cases of cancer developing in a nipple after mastectomy. A recent study has shown that the amount of tissue left behind in nipple-sparing mastectomy is extremely small. More long-term studies are needed to calculate the actual risk. 5. How do I decide what type of reconstruction I should have? Choosing a method of reconstruction is very personal. Each procedure has advantages and disadvantages. Not all surgeons perform all procedures, and often, surgeons recommend only the techniques they perform. The most important actions a woman considering reconstruction can take is to learn about her options, decide which is best for her, then consult with and choose a surgeon who is experienced and expert in the technique she prefers.

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