What is Hereditary Breast and Ovarian Cancer?
Hereditary Breast and Ovarian Cancer (HBOC) should be considered when there are multiple cases of breast cancer and/or ovarian cancer on the same side of the family. The chance that a family has HBOC increases in any of these situations:
- One or more women are diagnosed at age 45 or younger
- One or more women are diagnosed with breast cancer before age 50 with additional family history (such as prostate cancer, melanoma, and pancreatic cancer)
- There is breast or ovarian cancer in multiple generations on the same side of the family (such as a mother and a daughter)
- A woman is diagnosed with a second breast cancer in the same or the other breast or has both breast and ovarian cancers
- A male relative is diagnosed with breast cancer
- There is a history of breast cancer or ovarian cancer and pancreatic cancer on the same side of the family
- There is a history of breast and/or ovarian cancer and Ashkenazi Jewish ancestry
What causes HBOC?
HBOC is an inherited genetic condition. This means that the cancer risk is passed from generation to generation in a family. Two genes are associated with HBOC: BRCA1 and BRCA2 (BRCA stands for BReast CAncer), although other less common genes have been associated with an increased risk of developing breast and other cancers, such as mutations in the p53 tumor suppression gene. A mutation (alteration) in either BRCA1 or BRCA1 gives a woman an increased lifetime risk of developing breast and ovarian cancers. Men with these gene mutations also have an increased risk of breast cancer and for prostate cancer. Not all families with multiple cases of breast and ovarian cancer have mutations in BRCA1 or BRCA2. Research is ongoing to identify other genes associated with HBOC.
How is HBOC inherited?
Normally, every cell has two copies of each gene: one inherited from the mother and one inherited from the father. HBOC follows an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting that disease. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a mutation also has a 50% chance of having the same mutation.
How common is HBOC?
Current estimates are that less than 1% of the general population has a mutation in the BRCA1 or BRCA2 genes, and only 10% to 15% of women diagnosed with breast cancer have mutations in one of these genes. Nine to 28% of women under the age of 60 diagnosed with “triple negative” breast cancer (cancers that are negative for estrogen and progesterone receptors and HER2/neu) will have a BRCA1 gene mutation; therefore international guidelines recommend that these women be referred for genetic counseling and gene testing (see below). HBOC is most frequently diagnosed when there are multiple cases of breast cancer and/or ovarian cancer on the same side of the family. In families with four or more cases of breast cancer diagnosed before age 60, the chance of HBOC is approximately 80%. To compare, the chance of finding HBOC when only one woman has had breast cancer diagnosed under age 50 is estimated to be 10% or less.
Individuals with Ashkenazi Jewish ancestry have an increased chance of having HBOC. Three specific gene mutations are common in this group:
- 185delAG in BRCA1 (also reported as 187delAG)
- 5382insC in BRCA1
- 6174delT in BRCA2
It is estimated that about one in 40 individuals with Ashkenazi Jewish ancestry has one of these three 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. If a person with Ashkenazi Jewish ancestry is found to have a BRCA2 mutation, it is important for their partner to also be tested prior to pregnancy. If both parents carry a BRCA2 gene mutation, there is a 25% risk with each pregnancy of having a child with Fanconi anemia (an inherited disorder associated with physical abnormalities, an increased risk of blood cancers, and other serious problems).
For women without a previous diagnosis of breast or ovarian cancer, the U.S. Preventive Services Task Force (USPSTF) developed guidelines in 2005 for referral for genetic counseling to determine if gene testing is indicated; these are summarized below and are expected to be updated in late 2013. The phrase “first-degree relatives” include parents, siblings, and children. “Second-degree relatives” include aunts/uncles, grandparents, grandchildren, and nieces/nephews. The full USPSTF guidelines can be found online at: http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrgen.htm.
- Both maternal (mother’s) and paternal (father’s) family medical histories are important
- For non–Ashkenazi Jewish women:
- two first-degree relatives with breast cancer, one with a diagnosis at age 50 years or younger
- A combination of three or more first- or second-degree relatives with breast cancer regardless of age at diagnosis
- A combination of both breast and ovarian cancer among first- and second- degree relatives
- A first-degree relative with bilateral breast cancer
- A combination of 2 or more first- or second-degree relatives with ovarian cancer regardless of age at diagnosis
- A first- or second-degree relative with both breast and ovarian cancer at any age
- A history of breast cancer in a male relative
- For women of Ashkenazi Jewish heritage, an increased-risk family history includes:
- Any first-degree relative (or two second-degree relatives on the same side of the family) with breast or ovarian cancer.
- About 2% of adult women in the general population have an increased-risk family history using these definitions.
- Women with none of these family history patterns have a low probability of having a mutation in BRCA1 or BRCA2 genes.
How is HBOC identified?
Families with multiple women diagnosed with breast cancer before age 50 and families with both breast and ovarian cancers might be at risk for having HBOC. Mutations in the BRCA1 or BRCA2 genes can be identified through a blood or saliva test. Since most breast and ovarian cancers are sporadic, genetic testing is recommended primarily for people who have a personal family history that suggests HBOC. While standard gene sequencing identifies the majority of mutations, there are other types of mutations called rearrangements (also called deletions or duplications) in BRCA1 and BRCA2 that also may cause an increased risk for these cancers. Testing for large rearrangements in BRCA1 and BRCA2 is now available. If the result of your initial BRCA1 and BRCA2 testing was negative, meaning no mutation was detected, or a variant of uncertain significance was identified, there may be additional testing that would be now recommended. Talk with your doctor for more information. Most, but not all, insurance companies are now covering the cost of complete BRCA1 and BRCA2 testing, including Medicare and Medicaid.
However, women under the age of 60 with “triple negative” (see above; estrogen receptor negative, progesterone receptor negative, and HER2 negative) breast cancer have a risk of having a BRCA1 mutation, regardless of family history. Testing for mutations in the BRCA1 or BRCA2 genes may not be beneficial for the average woman.
What are the estimated cancer risks associated with HBOC?
Cancer risks for women with HBOC
- Lifetime risk of breast cancer 50% to 85%
- Risk of breast cancer before age 50 30% to 50%
- Lifetime risk of ovarian cancer
- BRCA1 gene mutation 25% to 50%
- BRCA2 gene mutation 15% to 30%
- Developing a second breast cancer 40% to 60% (The risk of breast cancer occurring in the other breast rises
approximately 2% to 3% per year)
Cancer risks for men with HBOC
- Lifetime risk of breast cancer
- BRCA1 gene mutation 1% to 2% (10-fold increase over the general population)
- BRCA2 gene mutation 6%
- Risk of prostate cancer
- BRCA1 gene mutation some increased risk
- BRCA2 gene mutation 20%
- Men with a BRCA2 gene mutation have a significantly increased risk of developing more aggressive prostate cancer before age 65 and therefore screening should begin at age 40.
Breast cancer subtypes and inherited mutations
Cancers diagnosed in individual with BRCA mutations often have specific characteristics:
- 80% to 90% of the breast cancers in women with a BRCA1 mutation are “triple negative” (estrogen and progesterone receptor negative, HER2/neu negative).
- 80% of the breast cancer in women with a BRCA2 mutation are estrogen receptor positive, progesterone receptor positive, and HER2/neu negative
Other cancer risks for people with HBOC
Both men and women with mutations in the BRCA2 gene may be at an increased risk of other types of cancer, including melanoma and pancreatic, stomach, esophageal, and bile duct cancers. Rare mutations in other genes may be associated with an increased risk of developing breast and other cancers, including the Li-Fraumeni syndrome (p53 gene), Cowden syndrome (PTEN gene), and others. The pattern of cancers in the family is often a clue to the specific gene that would explain the hereditary cancer for that family. Recently, new panels of multiple genes have been developed for use when a patient with a strong personal and family history has a negative test result for BRCA1 and BRCA2. Mutations in other genes may cause a more moderate increase in the risk of cancer and/or their effects have not been fully studied. New testing technology -- sometimes referred to as “next generation sequencing,” “massively parallel sequencing,” or “deep sequencing” -- has made it faster and less expensive to test for mutations in multiple genes at the same
time. Several laboratories are now offering genetic testing “panels” that offer testing of several genes at once. If a genetic mutation is found, this could explain the cancers in a family and provide information about which family members are at risk and what type of monitoring and prevention/risk reduction methods are appropriate.
Risk reduction - What can I do to reduce my risk of developing cancer of the breast or ovary if I have a BRCA gene mutation?
Risk reducing surgery
A risk reducing, bilateral skin-sparing mastectomy (removal of both breasts) can reduce the risk of breast cancer by more than 90%. A special protocol for the pathology with fine sectioning of all tissue should be followed. Only about 3% of breast cancers associated with BRCA mutations are diagnosed before age 30, so that surgery could be considered over the age of 30 for most women.
Risk reducing salpingo-oophorectomy (removal of the ovaries and fallopian tubes) at age 35 to 40 or when child-bearing is complete can reduce the risk of ovarian cancer by approximately 90%. If this surgery is completed in premenopausal women, it is also associated with a 50% decrease in breast cancer risk.
Tamoxifen (Nolvadex, Soltamox) taken for five years by individuals with BRCA2 mutations reduces the risk of breast cancer by 50%. There is less data regarding the impact of tamoxifen in those with BRCA1 mutations, as tamoxifen is unlikely to reduce the risk of developing a “triple negative” breast cancer.
Oral contraceptives taken for five years by individuals with BRCA1 or BRCA2 mutations may be associated with a decreased risk of ovarian cancer. This must be balanced by a potential slight increase in the risk of breast cancer.
Screening - What are the screening options for HBOC?
It is important to talk with your doctor about the following screening options, as each individual is different:
Screening for women with a BRCA1 or BRCA2 gene mutation
- Monthly breast self-examinations, beginning at age 18
- Biyearly clinical breast examinations (examination performed by a doctor or nurse), beginning between the ages of 25 to 30
- Yearly magnetic resonance imaging (MRI) scans of both breasts, beginning at age 25
- Yearly MRI alternating every 6 months with mammograms, beginning at age 30
- Pelvic examination, transvaginal ultrasound with color doppler, and CA-125 blood test every 6 months, beginning at age 30
- Consideration for risk reducing oophorectomy at 35 or when child-bearing is done (screening for ovarian cancer is not yet able to identify the majority of early cancers)
Screening for men
- Monthly breast self-examinations, beginning around age 30
- Yearly clinical breast examinations, beginning around age 30
- Baseline mammogram at age 35 for men with a BRCA2 gene mutation
- Yearly prostate cancer screening with digital rectal exam and PSA blood test, beginning at age 40
Screening options may change over time as new technologies are developed and more is learned about HBOC. It is important to talk with your doctor about appropriate screening tests for you.
Learn more about what to expect when having common tests, procedures, and scans.
Questions to ask the doctor
- What is my risk of developing breast and ovarian cancers?
- What can I do to reduce my risk of cancer?
- What are my options for cancer screening?
If you are concerned about your family history and think your family may have HBOC, consider asking the following questions:
- Does my family history increase my risk of breast cancer or ovarian cancer?
- Should I meet with a genetic counselor?
- Should I consider genetic testing?
National Comprehensive Cancer Network Guidelines: Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancers
National guidelines updated annually, directed towards physicians and other professionals
Facing Our Risk of Cancer Empowered (FORCE)
Information for women who are at a high risk of developing ovarian cancer and/or breast cancer.
Young Survival Coalition
National Ovarian Cancer Coalition
Foundation for Women’s Cancers
National Cancer Institute
American Cancer Society
To find a genetic counselor in your area, ask your doctor or visit the following websites:
National Society of Genetic Counselors
National Cancer Institute: Cancer Genetics Services Directory