by Dr. C.H. Weaver M.D. 10/2022
What is hereditary breast and ovarian cancer syndrome?
The average risk of a woman in the United States for the development of breast cancer in her lifetime is about 13%, or a one in eight chance. It is estimated there will be 281,550 individuals diagnosed in the U.S. in 2022.
Up to 10% of breast cancers are hereditary - there are 11 breast cancer predisposition genes with BRCA1, BRCA2 and PALB2 conferring the highest risk of developing breast cancer.
Hereditary breast and ovarian cancer (HBOC) is one of the most commonly inherited breast and ovarian cancer syndromes, and increases the risk of developing breast or ovarian cancer significantly. HBOC is due to mutations, or changes, in the BRCA1 and BRCA2 genes, also called the BRCA genes. (BRCA1 and BRCA2 stand for breast cancer gene 1 and breast cancer gene 2.) About 1 in 500 people in the United States has HBOC syndrome due to mutations in the BRCA1 or BRCA2 gene.
Women with alterations in the BRCA1 or BRCA2 gene have an increased risk for developing breast and ovarian cancer. Hereditary breast cancer is responsible for 5-10% of all invasive breast cancers and an increased risk of Triple Negative Breast Cancer and Ductal carcinoma in situ (DCIS).1,4
People with HBOC have an increased lifetime risk of developing certain types of other cancers. An individual with HBOC has up to an 80 percent lifetime risk of developing breast cancer and up to a 40 percent lifetime risk of developing ovarian cancer. Cancers that develop as a result of the HBOC syndrome generally occur at an earlier age compared with those that develop in people who do not have the syndrome; a woman can develop more than one breast cancer in her lifetime if she has this condition. Other cancers associated with HBOCs include prostate cancer, male breast cancer, fallopian tube cancer, pancreatic cancer, and melanoma (skin cancer).1
What causes HBOC?
HBOC is caused by a genetic mutation called a deleterious mutation, or a disease-causing mutation, in either the BRCA1 or the BRCA2 gene. To understand the HBOC syndrome, it is helpful to know a few basics about genetics. A gene is a hereditary unit of DNA. Genes carry directions to cells and tell them to make specific proteins that perform and regulate all functions of the body. Genes are capable of replicating themselves at each cell division.
A mutation is a change in the usual DNA sequence of a particular gene. Mutations can be beneficial, harmful, or neutral. Many diseases, including cancer, begin in the genes. Genetic mutations can be inherited from a parent or can be a random event that occurs in one single cell during cell division—or even in response to environmental factors and exposures. In the case of HBOC, we know that there is a deleterious mutation that causes the BRCA1 or BRCA2 gene to work incorrectly.
How would I know if my family has HBOC?
First, awareness of your family and personal health history is key. We know that families with hereditary cancer syndromes often have a family history that includes multiple generations affected by specific types of cancer that fit a certain pattern. And these cancers are often diagnosed at younger ages. Individuals in these families will often develop multiple cancers in their lifetime.
Red flags in a family history that might indicate HBOC include breast cancer diagnosed under the age of 45; ovarian cancer diagnosed at any age; breast and ovarian cancer diagnosed in the same woman; bilateral breast cancer diagnosed in a woman of any age; male breast cancer in any member of the family; and Ashkenazi Jewish ancestry (individuals of Ashkenazi Jewish ancestry have a much higher chance of carrying a mutation in either their BRCA1 or BRCA2 gene).
If I think my family may have HBOC, what steps should I take?
First meet with a genetic counselor. A professional will have the tools to take a good family history and determine whether you meet criteria for genetic testing and what type of genetic testing you would need.
To prepare for a meeting with a genetic counselor, make sure that you have spoken with your family and understand your family history; the genetic counselor will take a detailed family history as a first step. Next, the genetic counselor will review the history for certain patterns in the family, including early onset of cancers and multiple cancers in the family (especially breast, ovarian, fallopian tube, pancreatic, melanoma, and prostate cancers). Based on these patterns, genetic testing may be recommended. In some cases, it may not be you who is ultimately recommended for genetic testing but rather another family member who would be a better candidate. This may be a relative who has already been diagnosed with a cancer, as it is more likely that a genetic mutation would be revealed in someone who already has cancer.
Does the risk of breast cancer among BRCA1/2 carriers vary across families?
The answer appears to be yes. To explore whether and how risk of breast cancer varies among women with a BRCA1 or BRCA2 mutation, researchers evaluated breast cancer risk among female first-degree relatives (mothers, sisters, daughters) of breast cancer patients with a BRCA1 or BRCA2 mutation.4
Information was available for 598 female first-degree relatives (350 from BRCA1 families and 248 from BRCA2 families). Relatives of women who were diagnosed with breast cancer at a younger age were more likely to develop breast cancer themselves. The estimated risk of breast cancer by the age of 70 was 52% for relatives of women diagnosed before the age of 35 and 36% for relatives of women diagnosed between the ages of 45 and 55.
There was a suggestion that relatives of women who had a second breast cancer diagnosed in the opposite breast (contralateral breast cancer) were more likely to develop breast cancer themselves. The estimated risk of breast cancer was 51% for relatives of women with contralateral breast cancer and 40% for relatives of women with unilateral (one-sided) breast cancer. This difference did not meet the criteria for statistical significance, however, suggesting that it could have occurred by chance alone.
Even after accounting for factors such as age at diagnosis and presence of contralateral breast cancer, risk of breast cancer varied across BRCA1/2 families.
The researchers conclude that there is broad variation in risk of breast cancer among carriers of BRCA1 and BRCA2 mutations.
Genetic Risk Assessment Recommendations
In the United States, the National Comprehensive Cancer Network (NCCN) recommends genetic risk assessment, counseling, and management for women diagnosed with triple-negative breast cancer at age 60 or younger. Women with other personal or familial characteristics suggestive of a BRCA1 or BRCA2 mutation may also be candidates for testing.5,6
Polygenic Breast Cancer Risk Assessment Test for Women of All Ancestries Announced at ASCO 2021.
Data from a new study with more than 275,000 women validating the use of a new method for polygenic breast cancer risk assessments in women of all ancestries was releases at ASCO 2021. According to the study author Holly Pederson, M.D., director of Medical Breast Services at Cleveland Clinic, “The polygenic risk score (PRS) is one of the most powerful risk prediction tools in the field of breast cancer, and until now a validated model had not been available to assess women of all ancestries” The PRS delivers a personalized genomic breast cancer risk assessment to any and all interested women.
What does genetic testing involve?
Genetic testing is a simple process: it involves either a blood draw or a saliva sample, which is then sent to a genetic laboratory, where BRCA1 and BRCA2 genes are examined for any mutations or changes that would cause them not to work correctly. With new genes being discovered all the time, we are finding that the BRCA1 and BRCA2 genes are not the only genes that cause hereditary cancer conditions. The genetic counselor may recommend that you undergo panel testing, wherein multiple genes are tested to see if you carry various known mutations (including BRCA1 and BRCA2) that might lead to cancer. Panel testing is a more efficient method to carry out genetic testing and is becoming the standard process.
What do my test results mean?
There are a variety of results you may receive after undergoing genetic testing. The following is a brief summary of potential outcomes and what they mean.
Positive. A “positive” result means that a deleterious mutation has been discovered in either your BRCA1 or BRCA2 gene, which is the cause of your and your family’s cancers. This result would mean that you have HBOC.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
Negative. A “negative” result means that no mutation was discovered in your BRCA1 or BRCA2 gene, although this result does not always mean that you are free of HBOC. As of right now, genetic testing is not 100 percent accurate, and there are instances in which mutations are missed due to limitations of genetic testing. It is important that you meet again with the genetic counselor to discuss whether there is additional recommended testing or if, based just on your family history, there are certain types of screening that he or she would recommend even if you have a negative test result.
Variant of uncertain significance (VUS). A “VUS” result means that a mutation was found but it is unclear what that mutation does to the gene; we don’t know if it changes the function and causes it not to work or if it does nothing to the gene at all. If you receive this result, the genetic counselor or medical provider will generally plan to continue to monitor your health, as a definitive diagnosis is not possible. As a patient it is important that you continue to follow up with the genetic counselor to track any changes or reclassifications in that VUS.
What about risk from other mutations?
Moderate-risk gene mutations that confer a 20%-30% lifetime risk include ATM and CHEK2. CHEK2 serves the body as a tumor suppressor, but when mutated, it can be linked to cancer, including breast and prostate cancer.
Women carrying the CHEK2 mutation have a moderate risk for developing breast cancer, ranging from 23%-48% depending on their variant and family history and men with CHEK2 have an increased risk of developing prostate cancer. More than 2,500 variants of CHEK2 exist, with 270 of those classified as likely or definitely disease-causing
You have HBOC. What’s next?
If you do find out that you have HBOC, there are steps you can take to reduce your risk of developing related cancers.
Breast cancer screening. Women who have tested positive for HBOC should become very familiar with their breasts through breast self-exams (recommended beginning at age 18) so that they can be aware of any changes as soon as possible. In addition, women with HBOC are advised to undergo an annual clinical breast exam, mammogram, and breast magnetic resonance imaging (MRI) scan, starting at age 25. The recommended schedule for these screening tools is to alternate the mammogram and MRI every six months.
Ovarian cancer screening. Ovarian screening tools are limited, and there is no consensus as to their value; however, despite conflicting recommendations, some physicians still recommend ovarian cancer screening. Current screening options include transvaginal ultrasound and a CA- 125 blood test, which may reveal a specific marker in the blood associated with ovarian cancer. Experts agree that it is most important to be aware of the often subtle signs and symptoms of ovarian cancer. Understanding these vague early indicators of ovarian cancer provides a better chance of catching ovarian cancer at an earlier stage.
Male screening guidelines. Men with HBOC should have a baseline mammogram so that any changes in breast tissue are apparent in any follow-up screening; in addition, prostate cancer screening is recommended, starting at age 40.
Skin cancer screening. Men and women with HBOC—especially those with a BRCA2 mutation—should undergo annual skin exams with a dermatologist to screen for melanoma.
Chemoprevention. Chemoprevention is the use of drugs to prevent cancer. The chemopreventive drugs tamoxifen or Evista® (raloxifene)—drugs that are known as selective estrogen receptor modulators—may be used to reduce the risk of breast cancer in women at high risk of the disease. Oral contraceptive drugs may also be used as chemopreventive agents, as they have been found to reduce the risk of ovarian cancer.
Risk-reducing surgery. A bilateral mastectomy, or the removal of both breasts, can reduce a woman’s risk of breast cancer by greater than 90 percent. (A woman’s risk of breast cancer cannot be completely ruled out because some breast tissue may remain after the bilateral mastectomy.)
A bilateral salpingo-oophorectomy (BSO), a surgical procedure to remove a woman’s fallopian tubes and ovaries, is another risk-reducing surgery. This procedure is typically recommended for premenopausal women who have completed child bearing or by the age of 40. When a woman chooses to have her ovaries and fallopian tubes removed and the procedure is completed before menopause, she dramatically reduces her risk of ovarian cancer by at least 90 percent and reduces her risk of breast cancer by about 50 percent.
Women with BRCA mutations can reduce their risk of developing breast cancer by losing weight.
A multi-institutional study conducted to evaluate the effects of body mass, or body weight, on outcomes in women with BRCA mutations found that a weight loss of more than 10 pounds between the ages of 18-30 years reduced the risk of developing breast cancer by the age of 30-49 years by 65% in women with a BRCA1 mutation. However, changes in weight later in life, between the ages of 30-40 years, did not seem to affect the risk of developing breast cancer. This weight loss appeared to have the greatest effect on women with BRCA1 mutations: Those with BRCA2 mutations who lost the same amount of weight during the ages 18-30 years only experienced a 12% reduction in risk.8
BRCA and Breast Cancer Treatment
Does BRCA influence treatment outcomes?
According to research published in the New England Journal of Medicine, women with breast cancer who have BRCA1 or BRCA2 mutations have similar outcomes compared to patients without these mutations.7
HBOC Is A Family Affair
It is very important that you share your genetic information with your family members, as they are also at risk of HBOC. There are things that they can do to prevent or greatly reduce their risk of cancer if they know that they have the condition (chemoprevention, cancer screening, risk-reducing surgeries). Even if family members have already had cancer, it is important that they be informed of genetic-testing results that may affect them because there are certain clinical trials investigating preventive and treatment strategies that could provide benefit.
Results of genetic testing can be shared via e-mail, a phone call, the family communication tool KinTalk.org, or face-to-face, depending on your comfort level. When you share the results, it is a good idea to also recommend that family members see a genetic counselor.
Join the conversation and connect with others dealing with hereditary cancers in the CancerConnect Genetic testing and cancer screening community.
This Ask the Expert Series is made possible through support from the Personalized Medicine Foundation, CancerConnect and the UCSF Cancer Risk Program at The Helen Diller Comprehensive Cancer Center. Ask the Expert content and programs are not intended to be a substitute for healthcare professional medical advice, diagnosis, or treatment. Information should be used to further an individuals discussion with their managing healthcare team or providers. Speak to your healthcare provider about any questions you may have regarding your health.
Bergfeldt K, Rydh B, Granath F, et al. Risk of ovarian cancer in breast-cancer patients with a family history of breast cancer or ovarian cancer: a population-based cohort study. The Lancet. 2002;360:891-894.
- Begg CB, Haile RW, Borg A et al. Variation of breast cancer risk among BRCA1/2 carriers. Journal of the American Medical Association. 2008;299:194-201.
- Malone KE, Begg CB, Haile RW et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. Journal of Clinical Oncology. [early online publication]. April 5, 2010.
- Claus E, Petruzella S, Matloff E, et al. Prevalence of BRCA1 and BRCA2 Mutations in Women Diagnosed with Ductal Carcinoma Situ. Journal of the American Medical Association. 2005;293:964-969.
Fostira F, Tsitlaidou M, Papadimitriou C et al. Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study. Breast Cancer Research and Treatment. 2012;134:353-3
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: breast and ovarian. V.1.2012. Accessed August 21, 2012.
Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical Outcomes of Breast Cancer in Carriers of BRCA1 or BRCA2 Mutations. New EnglandJournal of Medicine. 2007;357:115-123.
Kotsopoulos J, Olopado O, Ghadirian P, et al. Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research. 2005; 7: R833-R843. doi:10.1186/bcr1293