Hereditary Breast and Ovarian Cancer (BRCA1/BRCA2)
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Last updated April 2016
Bottom line: Breast cancer is relatively common in the general population (12% lifetime risk) and the majority of cases occur sporadically. About 5-10% of breast cancer is due to an inherited gene change. Mutations in the genes BRCA1 or BRCA2 are the most common cause of hereditary breast and ovarian cancer (HBOC) and BRCA1 and BRCA2 mutation carriers have a significant increased lifetime risk for breast and ovarian cancer in addition to other cancers. Risk-reducing surgeries and, for some women, chemoprevention, can reduce mortality from breast and ovarian cancers in both BRCA1 and BRCA2 carriers. Individuals with family histories of breast or ovarian cancer that are at high risk (generally >10%) to carry a BRCA1 or BRCA2 gene mutation can be offered referral to genetics services for a discussion of the benefits, harms and limitations of genetic testing, while women whose family histories suggest a low risk of carrying a BRCA1 or BRCA2 gene mutation, can be reassured and offered screening following provincial guidelines. This GECKO Messenger will chiefly focus on HBOC caused by mutations in BRCA1 or BRCA2.
Approximately 80% of breast cancer occurs sporadically. About 10-15% of breast cancer is familial (when shared familial risk factors e.g. genes, environment, cause a higher incidence of cancer) and about 5-10% is hereditary (due to a single gene mutation). Harmful mutations in BRCA1 and BRCA2 appear to account for ~30% of high-risk breast cancer families. There are other hereditary cancer syndromes that cause an increased risk of breast and/or ovarian cancer. 1
Figure 1. Distribution of breast cancer etiology.
Figure 2. Proportion of genes contributing to hereditary breast cancer.1
What do I need to know about the genetics of HBOC?
More than 2600 pathogenic mutations have been found in the BRCA1 and BRCA2 genes, both of which are tumour suppressor genes. A mutation in one of these genes leads to the inability of a cell to regulate apoptosis (cell death) and to uncontrolled cell growth leading to cancer.
It is estimated that the general population prevalence of pathogenic mutations in the BRCA1 and BRCA2 genes is 1 in 300 to 1 in 5002. Founder mutations are observed in individuals of Ashkenazi Jewish ethnicity occurring at an estimated frequency of about 1 in 502.
Pattern of inheritance
HBOC is an autosomal dominant cancer predisposition syndrome. Individuals with HBOC have a high risk for breast and ovarian cancers and a moderate risk for other cancers (Table 1). Not all individuals who inherit a mutation in BRCA1 or BRCA2 will develop cancer (reduced penetrance) and the signs and symptoms, type, and age of onset of cancer will vary within families (variable expressivity).
Usually the decision to offer genetic testing is made in the setting of a genetics consult at a hereditary cancer program or a general genetics clinic. Click to connect to your local genetics centre or hereditary cancer program.
If possible, testing is first offered to the affected individual in the family at highest risk to carry a mutation in order to maximize the likelihood of detecting a mutation. For example, this might be the youngest individual with breast cancer in a family with multiple cases of breast and ovarian cancer.
How do I assess my patient’s risk?
Family and personal history factors associated with increased risk for Hereditary Breast /Ovarian cancer
These are general guidelines to identify patients at high risk for HBOC. You should consider referring your patient to your local genetics centre or hereditary cancer program for further assessment if s/he has a family or personal history of: 2-5, local genetics centres
Breast cancer diagnosis at a young age (<35-45 years) [both invasive and ductal carcinoma in situ]
Ovarian cancer at any age [epithelial]
Male breast cancer
Multiple primaries in the same individual e.g. bilateral breast cancer (particularly if the diagnosis was before age 50), breast and ovarian cancer
Breast cancer diagnosis AND a family history of two or more additional HBOC-related cancers, including breast, ovarian, prostate (Gleason ≥7) and pancreatic cancer
High risk ethnicity (Ashkenazi Jewish, Icelandic) and a personal and/or family history of breast, ovarian or pancreatic cancer
Triple negative breast cancer diagnosed <age 60
OR if s/he has a personal
Probability of 10% or higher to carry a BRCA mutation
Eligibility criteria for genetic testing vary among organizations. In general, criteria are based on clinical features that increase the likelihood of a hereditary cancer susceptibility syndrome.
If possible, the affected individual in the family at highest risk to carry a mutation is offered testing first in order to maximize the likelihood of detecting a mutation.
Testing an unaffected individual should only be considered if an affected individual is not available for testing. There are significant limitations to interpretation of test results in an unaffected individual. Unaffected individuals can be referred for genetic counselling for risk assessment and information. It is important to note that any individual of Ashkenazi Jewish ethnicity or French Canadian ethnicities can be offered genetic testing for the mutations commonly found in these ethnic groups (e.g. 3 common mutations in those of Ashkenazi Jewish ethnicity). A negative result in this situation only rules out those ethnic-specific mutations.
See the GEC-KO point of care tool which can be used in your practice to help identify patients who would benefit from referral to genetics or your local hereditary cancer program. The tool is based on the Referral Screening Tool6 which was designed for use in primary care settings and demonstrated an overall sensitivity of 81.2% and a specificity of 91.9%.
If your patient does not meet any of the criteria above, but you are suspicious of a hereditary cancer syndrome, consult your local genetics centre or hereditary cancer program. In general, suspicion of a hereditary cancer syndrome should be raised if:
There are multiple related family members with related cancers
Cancers occur on the same side of family
Cancer diagnoses occur at a younger than expected age
Several generations are affected (demonstrating an autosomal dominant pattern – typical of most hereditary cancer syndromes)
Multiple primary cancers are diagnosed in same individual, with early age of onset
Usually the decision to offer genetic testing is made in the setting of a genetics consult at a hereditary cancer program or general genetics clinic. To assess if your patient could be eligible for genetic testing see Who Should Be Offered Genetic Testing? Click to connect with your local genetics centre or hereditary cancer program and find their referral criteria. If your patient does not have cancer, genetic testing of a relative with cancer will be recommended as a first step.
How is genetic testing done?
Testing for mutations in BRCA1 and BRCA2 involves a blood test, which is usually available at regional genetic centres and some cancer centres. The test is covered by most provincial health plans if there is substantial probability of identifying a mutation. If a mutation has already been identified in a family, testing for this specific mutation is available for all at-risk relatives.
Click to connect to your local genetics centre or hereditary cancer program.
Note that hereditary cancer programs/general genetics centres vary with regards to the referrals they choose to accept. You may want to contact your local genetics centre or hereditary cancer program for more information.
Include all relevant information with your referral (e.g. family history, cancer history, pathology results, genetic test results, and results of investigations such as colonoscopies). Encourage your patient to collect this information, if you do not have it, to facilitate a productive genetic counselling session and to prevent unnecessary delays when further clarification is needed before an appointment can be booked.
If your patient is found to carry a mutation in the BRCA 1 or BRCA2 gene, a positive result, s/he has an increased lifetime risk to develop certain cancers (Table 1). This also means that family members are at risk of carrying the same mutation and of having similar cancer risks.
If a mutation is not identified in someone from a family with a known mutation, this is a true negative result. You can provide reassurance to your patient; however these individuals may still need to follow modified screening recommendations based on their family history and/or personal history factors (e.g. BMI, age at menarche, personal benign breast disease). Consult your local genetics centre or hereditary cancer program.
If a mutation is not identified in an affected patient who has no known familial mutation this result is uninformative.
A variant of uncertain significance (VUS) could be identified, which is a gene change that has not yet been categorized as benign or as pathogenic. Some variants may be interpreted as ‘likely pathogenic’, generally meaning greater than 90% certainty of being disease causing.7 In these instances screening and management may be modified, and other family members may be offered genetic testing to try to track the familial gene change and to see if it is associated with cancer. Variants are periodically re-classified and patients are often encouraged to recontact their genetics clinic to see if this is the case. In some circumstances, genetic testing for other hereditary cancer syndromes may be considered. In both of these circumstances, the diagnosis of HBOC is neither confirmed nor ruled out, especially in families with a strong history of breast and/or ovarian cancer.
Table 1. Significant lifetime cancer risks for individuals who have inherited a mutation in the BRCA1 or BRCA2 gene as compared to the general population.
NOTE: The literature suggests that there is also an increased lifetime risk for other cancers such as melanoma and pancreatic cancer in BRCA mutation carriers. 4,15
If a mutation is identified (a positive test result):
- Clinical intervention can improve outcomes.17,18 (See Screening and Management for more)
- Risk-reducing mastectomy lessens the risk of breast cancer by at least 90%
- Annual magnetic resonance imaging plus mammography increases detection rate for breast cancer
- Risk-reducing salpingo-oophorectomy decreases the risk of ovarian cancer by at least 80% and, if performed prior to menopause, can reduce the risk of breast cancer by at least 50%
- Chemoprevention, e.g. tamoxifen, may be considered for some women as a risk-reducing option
- Other at-risk family members can be identified and given accurate risk assessments19
- Positive health behaviours can be reinforced19
If a mutation is not identified and testing was for a known familial mutation (true negative):
- Your patient is not considered to be at increased risk of developing hereditary cancer but may still be at increased risk of cancer depending on family history
- You can provide reassurance to your patient and her/his children
If a mutation is identified (a positive test result)19:
- Your patient may experience psychological distress knowing s/he is at increased risk to develop cancer, and/or over the possibility s/he may have passed the mutation to her/his children
- Family issues such as confidentiality concerns may inhibit the transfer of information between relatives
- Your patient may face insurance (life, disability, long-term) or job discrimination, although the increased risk over and above that associated with a strong family history of cancer may be small
- Incomplete penetrance – being identified as having a mutation does not mean one will develop cancer
If a mutation is not identified in an unaffected patient and testing was for a known familial mutation (true negative)19,20:
- Depending on family dynamics (some siblings may have tested positive while some have not) or extensive family history of cancer, your patient may experience psychological distress such as ‘survivor guilt’ or ‘identity loss’
- Your patient may develop a complacent attitude to health and screening
If no mutation is identified in an affected patient who has no known familial mutation (uninformative result) or when a variant of uncertain significance (VUS) is identified19:
- The diagnosis of HBOC is neither confirmed nor ruled out, even in families with a strong history of breast and/or ovarian cancer
- Screening recommendations will be based on a combination of factors, such as family history and, in cases where a VUS was identified, information about the VUS
- Please consult your patient’s specialist, also see Screening and Management
Screening recommendations for high risk women (carriers of a mutation in BRCA1 or BRCA2 gene and their first degree relatives who have not yet had genetic testing) vary according to provincial guidelines and access to imaging technologies. The literature demonstrates life expectancy gains with the use of breast MRI in addition to digital mammography22. The age at which to begin screening varies but generally is between 25 and 30 years4,21,22. For details about screening provincial/territorial breast cancer recommendations see Canadian breast cancer screening programs table in Public Resources or consult your local hereditary cancer program for details about high risk screening.
Generally, breast awareness should be encouraged, starting at age 18, and breast changes should be reported to primary care providers.
High risk men: There are limited data on the use of imaging in men. Breast awareness should be encouraged.
Screening for ovarian cancer has limited evidence of utility. Risk-reducing surgery, bilateral salpingo-oophorectomy (BSO), is recommended for women who have completed childbearing4,21. Women who elect not to have prophylactic BSO may be screened by pelvic examination, transvaginal ultrasound and CA-125 serum tumour marker every 6-12 months starting at age 30 or 5-10 years before the earliest diagnosis of ovarian cancer in the family4,21. Women should be counselled about the limitations of these screening techniques as they have not been shown to be effective strategies for cancer detection4.
Screening according to provincial guidelines (e.g. annual digital rectal examination +/- prostate specific antigen), should begin at age 404,21.
Women with no current or past diagnosis of breast cancer and who have a life expectancy of greater than 10 years can be counselled by their multidisciplinary healthcare teams about options for reducing lifetime risk of BRCA1 and BRCA2 related cancers.
Individuals should be encouraged to maintain a healthy lifestyle with proper diet, healthy BMI, regular exercise and limited alcohol consumption, in addition to staying up-to-date on current screening recommendations.
Bilateral total mastectomy provides a high degree of protection against breast cancer (at least 90% reduction) in BRCA1 and BRCA2 mutation carriers4,21. BRCA1 and BRCA2 mutation carriers also have an increased lifetime risk of ovarian cancer and, in the absence of reliable early detection and the poor prognosis of ovarian cancer, bilateral salpingo-oophorectomy (BSO) can be offered to these women after completion of childbearing34,21. BSO has been shown to reduce the risk of ovarian cancer by about 80% in BRCA1 and BRCA2 mutation carriers4,21. If BSO is performed prior to menopause, a woman’s breast cancer risk can also be reduced by about 50%, likely because of decreased hormonal exposure4,21. The residual risk for primary peritoneal carcinoma is estimated to be 1-4%4,21.
The data are limited with regards to effectiveness of chemoprevention in BRCA1 and BRCA2 mutation carriers. The selective estrogen receptor modulator (SERM), Tamoxifen, has been shown to decrease the risk of contra-lateral breast cancer in BRCA1 and BRCA2 mutation carriers by at least 50%4,21. Limited data have shown that Tamoxifen can reduce breast cancer risk by about 62% in healthy BRCA2 mutation carriers, who have a greater likelihood of developing ER-positive tumours, but with no effect on BRCA1 mutation carrier breast cancer risk. There are insufficient data to recommend use of Tamoxifen in women under 35 years.
The results of various studies looking at the effect of the oral contraceptive pill (OCP) on increased breast cancer risk, particularly for BRCA1 and BRCA2 mutation carriers are not consistent. Overall, the risk for breast cancer associated with OCP does not seem to be greater for high-risk women (e.g. BRCA1 and BRCA2 mutation carriers) than for average risk women. The literature does show that OCP decreases the risk for ovarian cancer in average and in high risk women (a greater effect for BRCA1 than BRCA2 mutation carriers) and could be considered for some pre-menopausal women who have not yet completed childbearing .23
See www.geneticseducation.ca for the more concise version, GECKO on the run, and for a point of care tool. For general guidelines on HBOC management contact your local genetics centre.
For a recent review article see US Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. US Preventive Services Task Force recommendation statement. JAMA 2019;322(7):652-665.
- Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 2014;343(6178):1466-70
- Moyer VA, U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 160(4):271-81
- Carroll JC, Heisey R, Warner E. Family history and breast cancer. CMAJ 2012; 184(12):1391
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/familial high risk assessment: Breast and ovarian V.1.2015© National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [26/05/2015]. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
- National Institute for Health and Clinical Excellence: Guidance. Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2013 Jun.
- Bellcross CA, Lemke AA, Pape LS, et al. Evaluation of a breast/ovarian cancer genetics referral screening tool in a mammography population. Genet Med 2009;11(11):783-9
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-23
- Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25(11):1329-33
- Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2012), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2015, based on the November 2014 submission. Tables 4.17 (female breast cancer), 21.10 (ovarian cancer) and 23.10 (prostate cancer) http://seer.cancer.gov/csr/1975_2012/browse_csr.php (accessed 2015 Jun 01).
- Tai YC, Domchek S, Parmigiani G, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2007; 99(23):1811-4
- Evans DG, Susnerwala I, Dawson J, et al. Risk of breast cancer in male BRCA2 carriers. J Med Genet 2010;47(10):710-1
- Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013; 31(14):1748-57
- Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 2010; 16(7):2115-21
- Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 2004; 22(4):735-42
- Mersch J, Jackson MA, Park M, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 2015; 121(2):269-75
- Moran A, O’Hara C, Khan S, et al. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer 2012; 11(2):235-42
- Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol 2005; 23(8):1656-63
- Horsman D, Wilson BJ, Avard D, et al. Clinical management recommendations for surveillance and risk-reduction strategies for hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation. J Obstet Gynaecol Can 2007; 29(1):45-60.
- Riley B, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counselling, and testing: Updated recommendations of the National Society of Genetic Counselors. J Genet Counsel 2012; 21: 151-161
- Valverde K. Why me? Why not me? J Genet Counsel 2006; 15(6): 461-463
- Berliner JL, Fay AM, Practice Issues Subcommittee of the National Society of Genetic Counselors’ Familial Cancer Risk Counseling Special Interest Group. Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. J Genet Couns 2007; 16(3):241-60.
- Lowry KP, Lee JM, Kong CY, et al. Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis. Cancer 2012; 118(8):2021-30
- Davidson BA, Moorman PG. Risk-benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer. Expert Opin Drug Saf 2014; 13(10):1375-82
Canadian Cancer Society: a national, community-based organization of volunteers whose mission is the eradication of cancer and the enhancement of the quality of life of people living with cancer.
Willow – Breast and Hereditary Cancer Support: a national, not-for-profit organization. Willow provides free-of-cost support, insight and information to anyone affected by breast cancer or hereditary cancer.
FORCE (Facing Our Risk of Cancer Empowered) : an American-based organization dedicated to improving the lives of individuals and families affected by hereditary breast and ovarian cancer.
Authors: S Morrison MS CGC, C Cremin MS CGC, E Tomiak MD FRCPC, JE Allanson MD FRCPC and JC Carroll MD CCFP
GEC-KO Messenger is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.