BRCA1 and BRCA2. BRCA1 and BRCA2 Clinician Guide KNOWING WHAT TO LOOK FOR KNOWING WHERE TO LOOK AND KNOWING WHAT IT MEANS

Transcription

1 BRCA1 and BRCA2 BRCA1 and BRCA2 Clinician Guide KNOWING WHAT TO LOOK FOR KNOWING WHERE TO LOOK AND KNOWING WHAT IT MEANS

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3 BRCA1 and BRCA2 Breast cancer is the most common cancer in women, diagnosed in ~12% of American women. While the majority of breast cancer occurs in women with no family history of breast cancer, approximately 5-10% of all cases of breast cancer are associated with a mutation in a single, highly penetrant cancer predisposition gene. Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast and ovarian cancer (HBOC). Women who carry a disease-causing mutation in one of these genes have a significantly higher risk of developing breast and/or ovarian cancer. There are also other types of cancer associated with a BRCA1 or BRCA2 mutation, including fallopian tube, primary peritoneal, and endometrial (serous) cancer in women, breast and prostate cancer in men as well as pancreatic cancer in both men and women. Mutations in BRCA1/2 are thought to account for approximately 15% of male breast cancers. 1 Prevalence of BRCA1 and BRCA2 Mutations Mutations in BRCA1 and BRCA2 are found in all ethnic and racial backgrounds. Mutations occur in approximately 1 in 400 to 1 in 800 individuals in the general population in the United States, but are seen more frequently in individuals of Ashkenazi Jewish descent. 2,3,4 Approximately 1 in 40 individuals of Ashkenazi Jewish ancestry carry one of three diseasecausing founder mutations in BRCA1/2: c.68_69 delag (also known as 185delAG or 187delAG), c.5266 dupc (also known as 5382insC or 5385insC) in BRCA1, and c.5946 delt (also known as 6174delT) in BRCA2. Genetics of BRCA1 and BRCA2 Mutations in both BRCA1 and BRCA2 are inherited in an autosomal dominant manner. Therefore, an individual carrying a disease-causing mutation in BRCA1 or BRCA2 has a 50% chance of transmitting the mutation to a child, either male or female. Almost all individuals with a mutation in BRCA1 or BRCA2 inherit it from a parent. Therefore, the siblings of an individual with a mutation have a 50% chance of carrying the same familial mutation. Extended family members are also at increased risk to test positive for the familial BRCA1 or BRCA2 mutation. The exact risk depends on the relationship to the patient. CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2 1

4 CLINICAL INDICATIONS FOR BRCA1/2 GENETIC TESTING The following individuals have an increased risk for hereditary breast and ovarian cancer and are appropriate candidates for BRCA1/2 testing: 1. An individual diagnosed with breast cancer, with one or more of the following: Diagnosed age 45 Two primary breast cancers with the first diagnosed age 50 Diagnosed age 50 with 1 close* relative with breast cancer at any age or limited family history Diagnosed age 60 with triple negative disease Diagnosed at any age with 1 close* relative with breast cancer diagnosed age 50 Diagnosed at any age and 2 close* relatives with breast cancer at any age Diagnosed at any age with 1 close* relative with epithelial ovarian, fallopian tube or primary peritoneal cancer Diagnosed at any age and 2 close* relatives with pancreatic cancer or aggressive prostate cancer at any age Diagnosed at any age with a close* male relative with breast cancer diagnosed at any age Diagnosed at any age and of Ashkenazi Jewish ancestry, OR 2. Any woman diagnosed with epithelial ovarian, fallopian tube or primary peritoneal cancer at any age, OR 3. Male with breast cancer at any age, OR 4. An individual with a personal history of pancreatic cancer or aggressive prostate cancer and 2 close* relatives with breast and/or ovarian, fallopian tube or primary peritoneal cancer and/or pancreatic or aggressive prostate cancer, OR 5. An unaffected individual with a close* relative meeting the above criteria In some cases, limited family history may not allow for evaluation of these criteria. Limited family history is typically defined as <2 first- or second-degree female relatives living beyond 45 years on the same side of the family. *Close blood relatives include first, second and third-degree relatives on the same side of the family. 2

5 Genetic Test Results and What They Mean There are three possible outcomes of genetic testing: positive, negative and variant of unknown significance (VUS). Positive Result A positive result indicates that a disease-causing mutation was identified in that individual and the risk for cancer is increased. Knowledge of a positive result provides valuable information to the patient, physician and family members. Knowledge of a patient s genotype can assist in making management and treatment decisions. Furthermore, testing of the patient s family members can allow for accurate predictions of cancer risks. Negative Result A negative result means that a disease-causing mutation was not identified in the individual tested. A negative result can have different interpretations based on the following scenarios: True Negative: An individual who tests negative for a known familial mutation is not a carrier of a known cancer-predisposing mutation that has been identified in another family member. The risk for cancer in this individual is generally not expected to be greater than the general population risk. While general population screening is usually indicated, clinical assessment of the complete family history of cancer and personal risk factors is important to determine appropriate management. Uninformative Negative: If testing was performed on an individual with a cancer diagnosis, this means that we do not have an explanation for why this individual developed cancer. Genetic counseling is recommended, as additional testing may be considered based on the individual s medical and family history. If testing was performed on an individual without a personal history of cancer and based only on family history, the risk for cancer may remain increased as the exact cause of the cancer in the family remains unknown. Testing of an affected family member may help clarify this individual s cancer risks. Variant of Unknown Significance (VUS) A variant of unknown significance (VUS) indicates that the pathogenicity of the variant cannot be clearly established. To further clarify the clinical CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2 3

6 significance of this variant, testing of family members may be helpful. If a relative with a related cancer is found to have the same variant, it may provide evidence that the variant may be disease-causing. The greater the number of affected family members who carry the VUS, the greater is the likelihood that the VUS is pathogenic. With consistent linkage of the VUS with family members with related cancers, in addition to other evidence, the variant found may be reclassified as a family-specific mutation and predictive genetic testing can be offered to extended family members. Conversely, a VUS could be determined to be benign through this and other research. GeneDx will review a patient s detailed family history to determine if family members are eligible for complementary targeted variant testing through our Variant Testing Program. BRCA1/2-Associated Cancer Risks and Pathology Mutations in BRCA1 and BRCA2 increase the lifetime risk for breast and ovarian cancer significantly over the general population risk. In general, the risk of breast and ovarian cancer is slightly higher for BRCA1 mutation carriers than BRCA2 mutation carriers and usually the cancers occur earlier for BRCA1 mutation carriers in comparison to BRCA2 mutation carriers. Women with BRCA1 mutations have between 57-87% lifetime risk to develop breast cancer and women with BRCA2 mutations have a 41-84% lifetime risk to develop breast cancer. 3,5,6,7 The lifetime risk to develop ovarian cancer is between 24 and 54% for BRCA1 and 11 and 27% for BRCA2 mutation carriers. 6,7,8,9 The chances to develop breast cancer begin increasing when a woman is in her mid 20 s. 9 The risk of ovarian cancer begins to increase in the mid 30 s, but becomes most significant in the 50 s and beyond. Additional cancers in women include fallopian tube carcinoma, primary peritoneal carcinoma, and endometrial serous carcinoma. 10,11,12 The lifetime risk for breast cancer in male BRCA1/2 mutation carriers is increased. Men with BRCA2 mutations have a 4-7% risk for male breast cancer. 1,14 The risk for BRCA1 mutation carriers is increased, although not well defined. 1,14,15 The risk for other malignancies has been reported in families with mutations in BRCA1 or BRCA2, including prostate cancer 4

7 BRCA1/2-Associated Lifetime Risks by Cancer Type 100 BRCA1* 57-87% 41-84% BRCA2 80 Probability (%) % 11-27% 20-34% % 5-7% 0 Female Breast Male Breast* Ovarian Pancreatic* Prostate* Cancer Type *Individuals with BRCA1 mutations have increased risks for male breast, prostate, and pancreatic cancers, however the exact risks are not well-defined. in men as well as pancreatic cancer in both men and women. Men with BRCA2 mutations have up to a 34% risk of prostate cancer 16 and both men and women with BRCA2 mutations have a 5-7% risk of pancreatic cancer. 17,18 Individuals with BRCA1 mutations have increased risks for these cancers, although the exact risks are not well-defined. 1,15,19,20 The relative risk of prostate cancer has been shown to be greater in BRCA1/2 carriers under the age of Lastly, the risk to develop melanoma skin cancer is increased in men and women with BRCA2 mutations. 1,18 Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. This risk may depend on the age at which the first breast cancer was diagnosed. Table 1 describes the risk of a second primary breast cancer based on age of diagnosis of the first breast cancer. The majority of BRCA1-related breast cancers are invasive ductal carcinomas. These tumors are also more likely to be of higher histologic grade. Triple negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and lacking HER2/neu overexpression) CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2 5

8 Age of Diagnosis of First Breast Cancer Risk of second primary breast cancer Within 10 years Under age % 63% Between ages 40 and % 44-49% Within 25 years After age % 17-20% Table 1: Risk of second primary breast cancer based on age of diagnosis of first breast cancer in BRCA1/2 positive women 13 is also more common in BRCA1 mutation carriers compared to patients with sporadic breast cancer. BRCA2-related breast cancers are usually hormone receptor-positive. 21 Ovarian cancers related to BRCA1 or BRCA2 mutations are usually serous adenocarcinomas and more likely to be high grade compared to ovarian cancers in non-carriers. 22,23 BRCA2-associated prostate cancer is more likely to have a high histologic grade compared to sporadic tumors. 24 High grade tumors are often more responsive to chemotherapy, and do not necessarily portend a worse prognosis with appropriate treatment. 25,26 Management of BRCA1/2-positive Patients There are a variety of management strategies available to patients who test positive for a disease-causing mutation in BRCA1 or BRCA2. Various guidelines outline available options and recommendations for patients who have a positive BRCA1 or BRCA2 test result. These options include increased screening, surgery and chemoprevention. The guidelines below are examples of current recommendations as of Please visit for the most up-to-date recommendations, including ages to begin surveillance and current recommended screening frequencies. Increased Screening: For women, increased screening includes the following: Increased breast awareness including self breast exam Routine clinical breast exam 6

9 Breast MRI and mammogram starting at an early age Consider transvaginal ultrasound of the ovaries and CA-125 blood tests Consider full body skin exam Consider pancreatic cancer screening For men, increased screening includes the following: Increased breast awareness including self breast exam Routine clinical breast exam Consider baseline mammogram with repeat imaging if gynecomastia or parenchymal/glandular breast density is noted on baseline study Routine prostate cancer screening starting at an early age Consider full body skin exam Consider pancreatic cancer screening Risk Reducing Surgery: Consider prophylactic mastectomy; mastectomy reduces the chance of developing breast cancer by at least 90%. Salpingo-oopherectomy is recommended (as early as the 30s-40s) once a woman has completed childbearing; this reduces the risk of ovarian cancer by approximately 80% and, if performed prior to natural menopause without hormone replacement, reduces the risk of breast cancer by up to 50%. Medication to Reduce Cancer Risk: Consider the use of breast cancer chemoprevention (such as tamoxifen and raloxifene), which may reduce the risk of breast cancer. Consider the use of oral contraceptives, which may reduce the risk of ovarian cancer by 45-50% in BRCA1 mutation carriers and by 60% in BRCA2 mutation carriers. Risks and benefits should be carefully considered, given conflicting evidence on the impact of oral contraceptives on breast cancer risk. Genetic Counseling Pre-test counseling is recommended for individuals who are either interested in understanding their risks and/or meet the clinical criteria and are considering testing for BRCA1/2. If a disease-causing mutation has CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2 7

10 already been identified in a family member, testing of the specific mutation is appropriate. If a disease-causing mutation has never been identified, an affected family member with the highest likelihood for a positive result (early onset disease, bilateral disease or multiple primaries) is ideally the best candidate for initial testing within a family. If an affected family member is not available for testing, testing of an unaffected family member with the highest likelihood of testing positive for a mutation is recommended. Once patients make the decision to undergo testing, post-test genetic counseling is recommended to understand the implications of the results. Genetic counseling services across the country can be found at: More information about risk assessment and genetic counseling for hereditary breast and ovarian cancer can be found at: Resources for Patients Bright Pink: FORCE: NCI: National Society of Genetic Counselors: Sharsheret: Susan G. Komen: References 1. Liede A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the literature. J Clin Oncol Feb;22(4): Ford D, et al. Risk of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet Mar;343(8899): Claus EB, et al. The genetic attributable risk of breast and ovarian cancer. Cancer Jun; 77(11): Whittemore AS, Gong G, and Itnyre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three U.S. population-based case-control studies of ovarian cancer. Am J Hum Genet Mar; 60(3): Chen S and Parmigiani G. Meta-anlaysis of BRCA1 and BRCA2 penetrance. J Clin Oncol Apr; 25(11): Ford D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet Mar; #62(3):

11 7. Risch HA, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: A kin-cohort study in Ontario. J Natl Cncer Inst Dec; #98(23): Antoniou A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet May; 72(5): King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science Oct; 302(5645): Levine DA, et al. Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol Nov; 21(22): Biron-Shental T, et al. High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol Dec; 32(10): ) 12. Pennington KP, et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer Jan; 119(2): Graeser MK, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol Dec; 27(35): Tai YC et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst Dec;99(23): Brose MS et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst Sep;94(18): Thompson D, Easton D, Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet Feb;68(2): Ozcelik H, et al. Germline BRCA26174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet May; 16(1): The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst Aug; 91(15): Leongamornlert D et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer May 8;106(10): Thompson D, Easton DF, and the Breast Cancer Linkage Consortium. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst Sep;94(18): van der Groep P, van der Wall E, and van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol Apr; 34(2): Berchuck A, et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res Oct; 4(10): Rubin SC, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Eng J Med Nov; 335(19): Gallagher DJ, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res Apr; 16(7): Bolton KL, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA Jan; 307(4): Chetrit A, et al. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: The national Israeli study of ovarian cancer. J Clin Oncol Jan; 26(1):20-5 CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2 9

12 How can I order this test? You can order this test by taking the following steps: 1. Download the OncogeneDx test requisition form from the GeneDx website: 2. Complete all the forms with required information 3. Ship completed forms along with either two 4ml lavendar top tubes of blood OR saliva collected in mouthwash using our oral rinse collection kit and send to the following address: Accessions GeneDx 207 Perry Parkway Gaithersburg, MD We provide shipping kits to physicians upon request. To place an order for shipping kits, please visit our website: or us at: wecare@genedx.com About GeneDx GeneDx is a highly respected genetic testing company, founded in 2000 by two scientists from the National Institutes of Health (NIH) to address the needs of patients and clinicians concerned with rare inherited disorders. Currently, GeneDx offers whole exome sequencing, oligonucleotide microarray-based testing for detecting chromosomal abnormalities, testing for inherited eye disorders and autism spectrum disorders and gene panels for testing various forms of inherited cardiac disorders, mitochondrial disorders, neurological disorders and inherited cancer disorders. At GeneDx, our technical services are matched by our scientific expertise and customer support. Our growing staff includes more than 80 geneticists and genetic counselors specialized in clinical genetics, molecular genetics, metabolic genetics and cytogenetics who are just a phone call or away. We invite you to visit our website: to learn more about us and the services we offer. 207 Perry Parkway Gaithersburg, MD T F E wecare@genedx.com GeneDx. All rights reserved /15 Information current as of 1/2015