NORD gratefully acknowledges Jennifer Litton, MD, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, for assistance in the preparation of this report.
Hereditary breast and ovarian cancer (HBOC) syndrome is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. Additionally, to a lesser degree, there is also an increased risk of developing other types of cancer including prostrate cancer, melanoma, and pancreatic cancer. HBOC syndrome is most commonly associated with variations (mutations) in the either the BRCA1 gene or the BRCA2 gene. In HBOC syndrome, there is usually a family history of cancer and the variant gene is inherited. The underlying causes of cancer are not completely understood and while inheriting a variation in the BRCA1 or BRCA2 gene greatly increases a person’s risk of developing certain cancers, it does not mean that the people will definitely develop cancer. Some people with variations in these genes never develop cancer. How these gene variants affect individuals and families will be different. Most likely, there are additional genetic (e.g. variations in other genes) or environmental factors (e.g. smoking) that influence whether and how cancer develops.
Most forms of cancer develop sporadically. When cancer occurs sporadically, it is usually because of aging and other factors besides genetics. With sporadic cancer, there is a single occurrence of that form of cancer in the family and the affected person is usually older (often more than 60 years old). Sometimes, cancer is familial. This means that two or more first-degree relatives have the same type of cancer. Cancer usually develops after the age of 50 and there are several, moderate-to-minor genetic factors involved. In addition, there is often an environment factor or factors as well. HBOC syndrome is a genetic disorder in which multiple members in multiple generations are affected. Cancer often develops before the age of 50. The affected family members have a variation in a single major cancer susceptibility gene, most often the BRCA1 or BRCA2 gene.
HBOC syndrome is a cancer predisposition syndrome in which individuals are at a greater risk of developing certain cancers, particularly breast or ovarian cancer. Signs and symptoms are associated with the development of cancer, and depend upon the type and location of cancer. HBOC syndrome can cause cancer in multiple family members over several generations in one family. It can also be associated with more than one cancer in the same person.
The exact percentage of risk for specific types of cancer in HBOC syndrome varies greatly depending on the specific gene that is altered and the specific alteration (i.e. mutation). Some people with a variation in these genes will never develop cancer. Female breast cancer is the most common type of cancer associated with a variation in the BRCA1 or BRCA2 genes. The risk for breast in the general population is about 12%, but for women with a BRCA1 gene variation it can be between 46%-87%, and between 38%-84% for women with a BRCA2 variation. There is also an increased risk of having a second primary breast cancer.
In HBOC syndrome, ovarian cancer includes cancer of the fallopian tubes. Primary peritoneal cancers can also occur. These are cancers that develop in the thin layer of tissue that lines the abdomen (peritoneum). The risk for ovarian cancer in the general population is about 1%-2%, but about 39%-63% with BRCA1 gene variations and 16.5%-27% with BRCA2 variations.
There is an increased risk for male breast cancer, which affects about .1% of the population. In men with a BRCA1 gene variation, there is a 1.2% risk and an 8.9% risk in men with a BRCA2 gene variation. In general, the relative risk for male breast cancer is greatest in men in their 30s and 40s and decreases with advancing age.
There is a risk of prostate cancer of 6% before the age of 69 in the general population. There is an 8.9% by 65 years of age in men with a BRCA1 variation and a 15% risk by age 65 in men with a BRCA2 variation. The lifetime risk for prostate cancer is about 20%-25%.
The risk of pancreatic cancer in the general population is about .5%. With a BRCA1 variation the risk is about 1%-3%, and with a BRCA2 variation the risk is about 2%-7%.
Other cancers including melanoma, cervical and uterine cancer have all been reported as having higher rates in affected individuals. Further studies are needed to confirm which additional cancers are definitively associated with variations in these genes.
HBOC syndrome is caused by a variation in a single major cancer-causing gene, most often the breast cancer susceptibility gene 1 (BRCA1) or the breast cancer susceptibility gene 2 (BRCA2). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The gene variation in HBOC syndrome is a germline mutation (as opposed to a sporadic mutation). A germline mutation is a genetic change that occurs in the body’s reproductive cells, either the egg or the sperm. Germline mutations can be passed on from parents to children. A sporadic mutation is one that occurs after fertilization at some other point in life. Most likely, the gene is somehow damaged or changed due to many different factors.
When a change (variation) in a gene causes a disease, it is called a pathogenic (or disease causing) variant. However, some variations in a gene do not cause problems. Sometimes, doctors discover a variation in a gene and they do not know whether or not it causes disease. This is called a variation of unknown significance. Having a pathogenic variation in one of these two genes greatly increases a person’s risk of developing cancer, but how these variations affect every person in a family can be very different. Most families with a pathogenic variation have higher cancer incidence rates, while others do not. Not every person who has a pathogenic variation will definitely develop cancer. Whether cancer develops, the type of cancer that develops, and the age that cancer develops can be different in people in the same family with the same variation in one of these genes. Whether and to what degree a BRCA1 or BRCA2 gene variation causes cancer in an individual or family is called “penetrance.” This means that other factors, most likely additional genetic factors or environmental ones play a role in the development of cancer in people with variations in their BRCA1 or BRCA2 genes.
The BRCA1 and BRCA2 genes are tumor suppressor genes. These genes help to regulate cell growth. They normally limit or stop the growth of cells. When the tumor suppressor genes are altered, cells can multiply (proliferate) wildly, causing cancer. When the normal versions of these genes are present, they appear to prevent cancer from developing.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a dominant pattern occur when only a single copy of a gene variation is necessary to cause a particular disease. The gene variation can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Sometimes de novo variations of the BRCA1 or BRCA2 gene have been reported. However, this is rare. This type of gene variation occurs as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The variation can then be passed on by the affected person in an autosomal dominant pattern.
HBOC syndrome can affect both men and women and occurs in people from all ethnic and racial backgrounds. In fact, HBOC syndrome is the most common cause of hereditary breast and ovarian cancer in all ethnic and racial backgrounds. The prevalence, which is the number of people with a disorder at a given time, is not known, but estimated to be somewhere between 1 in 200 to 1 in 800 people in the general population. In certain populations, the prevalence is higher. In individuals of Ashkenazi Jewish descent, HBOC syndrome affects about 1 in 40 people. Sometimes, this is due to a founder effect. A founder effect is when a small, isolated population of people expands over several generations leading to a high prevalence of a genetic trait.
Several different groups have put out guidelines for screening and diagnostic criteria for HBOC. These guidelines help to identify individuals who would most benefit from screening for variations in the BRCA1 or BRCA2 genes. One of the most commonly referenced guidelines was created by the National Comprehensive Cancer Network (NCCN). Information on these guidelines can be found at: https://www.nccn.org/professionals/physician_gls/default.aspx
Generally, HBOC syndrome may be suspected in women with breast cancer before 50 years of age, in men with breast cancer, in women with ovarian cancer, in people with multiple primary breast cancers in one or both breasts, and the association of pancreatic or prostate cancer or both with breast or ovarian cancer or both. Additionally, HBOC syndrome may be suspected when two or more relatives have breast cancer before the age of 50, when three or more relatives develop breast cancer, or if there is a previously identified variation in the BRCA1 or BRCA2 gene in the family. HBOC syndrome should be considered in anyone of Ashkenazi Jewish heritage who develops breast cancer. Specific breast cancer subtypes may have different indications for testing. For example, triple negative breast cancer may be suspected in individuals who develop the disorder before age 60.
Clinical Testing and Workup
Molecular genetic testing can confirm a diagnosis. This involves taking a blood or saliva sample and testing it for variations in the BRCA1 and BRCA2 genes known to cause HBOC syndrome. However, molecular genetic testing is available only as a diagnostic service at specialized laboratories. Additionally, if someone tests negative for BRCA1 or BRCA2 gene variations, they can still develop sporadic forms of cancer, or cancer because of a different hereditary cause.
In people who have an identified variation in the BRCA1 or BRCA2 genes periodic screening tests may be performed. Women may routinely undergo magnetic resonance imaging (MRI) and/or mammography. Data suggests that the use of both imaging techniques is more sensitive. An MRI can also be used to help to determine the extent and exact location of cancer associated with HBOC syndrome. Mammography is a different, specialized imaging technique that uses low-dose x-rays to see inside the breasts to find any tumors.
The treatment of HBOC syndrome is highly individualized, which means that the specific treatment options and recommendations will vary among affected individuals. The therapeutic management may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), oncology nurses, psychiatrists, and other healthcare specialists. Psychosocial support for the entire family is essential as well.
Genetic counseling is extremely important in HBOC syndrome. Understanding the risk of cancer based on variations in the BRCA1 and BRCA2 is critical to allow affected individuals, along with their medical team, to make the best decisions concerning their health. Genetic counseling by appropriately trained medical personnel including genetic counselors is recommended by multiple organizations that deal with cancer.
Several organizations have released guidelines for the surveillance, screening and treatment of HBOC syndrome. Information on the guidelines published by the National Comprehensive Cancer Network (NCCN) can be found at: https://www.nccn.org/professionals/physician_gls/default.aspx.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the type of cancer; disease stage; tumor size; specific cancer subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgery, and/or other treatments should be made by physicians, genetic counselors, and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Specific surveillance recommendations have been made for women with intact breast tissue and a known hereditary risk of breast cancer. Other women, especially those with a confirmed disease-causing variation in the BRCA1 and BRCA2 gene may choose to have the breasts surgically removed as a preventive measure. This is called prophylactic mastectomy. This surgery may be recommended after counseling involving the specific cancer risk, degree of protection, and issues involving breast reconstruction. Doctors estimate that the cancer risk in unaffected women is reduced 90-95% following preventive mastectomy.
Another treatment option is chemoprevention. Chemoprevention involves using certain drugs such as tamoxifen to lower the risk of developing breast cancer. One large, clinical trial demonstrated an almost 50% decrease in the risk of breast cancer in unaffected women.
In 2018, the U.S. Food and Drug Administration (FDA) approved the drug olaparib (Lynparza®) for the treatment of BRCA-associated breast cancer that has spread (metastasized) to other areas of the body. Lynparza is a PARP, or poly (ADP-ribose) polymerase, is an enzyme that helps the body to repair DNA when it becomes damaged. Researchers believe that medications that stop or hinder (inhibit) the activity of PARP will prevent cancer cells from repairing themselves, and continuing to grow and spread. This is a targeted therapy, which means that it is targeting a specific molecule or substance (e.g. PARP) that contributes to cancer growth. Targeted therapies act by blocking the growth and spread of cancer rather than destroying cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy and are less likely to damage healthy cells.
Lynparza has also been approved by the FDA for women who have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have responded to treatment with a platinum-based chemotherapy medication (see Investigational Therapies below), but in whom the cancer has returned. Lynparza is also approved for advanced ovarian cancer in women who have received treatment with three or more prior chemotherapy medications.
In 2018, Talazoparib (talzenna) was approved to treat patients with deleterious or suspected deleterious germline BRCA gene mutations and HER2 negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on a companion diagnostic for talazoparib. FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients who are eligible for talazoparib. Talzenna is manufactured by Pfizer.
In 2018, the FDA approved the drug rucaparib (RuBRCAa®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.
In 2017, the FDA approved the drug niraparib (Zejula®) for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication.
A procedure called risk-reducing salpino-oophorectomy may be recommended for women with ovarian cancer. And for mutation carriers who do not have cancer. This is the surgical removal of the ovaries and the fallopian tubes. This is procedure significantly reduces the risk of ovarian cancer as well as somewhat reducing the risk of breast cancer. Women will not be able to have children after this procedure. Premenopausal women who undergo this surgery will begin to have menopausal symptoms. This surgery may be recommendation in women after counseling on reproductive issues, degree of protection, and hormonal and menopausal issues.
Some studies have shown that oral contraceptives have a duration-dependent protective effect against ovarian cancer. Duration-dependent means this protective effect exists while the contraceptive is being taken, but stops once women stop taking the medication. Oral contraceptive use may be associated with a slightly increased risk of breast cancer, however.
The use of hormonal therapy to treat menopausal symptoms is controversial and should be discussed in an individual setting based on personal history of cancer, prophylactic surgeries, etc. This therapy is used to help manage common symptoms of menopause and to protect bone health. However, long-term hormonal therapy is associated with an increased risk of breast cancer in women who have undergone normal menopause. Studies have also shown that short-term therapy with estrogen plus progestin increased breast cancer risk. Women who have gone through menopause because of surgery experience an abrupt rather gradual loss of hormones. Some studies have shown that short-term therapy has been used effectively in treating these abrupt symptoms and has not shown an increase in breasts cancer risk.
The treatment of other forms of cancer associated with HBOC syndrome generally follows the standard guidelines for individuals without BRCA1 or BRCA2 gene variations.
As of June of 2018, there are studies investigating the use of medications called PARP inhibitors in the treatment of HBOC syndrome. These studies include already-approved PARP inhibitors being tested for other forms of BRCA-associated cancer or new (novel) PARP inhibitors.
Research has shown that platinum-based chemotherapy is effective in treating some individuals with HBOC syndrome. Platinum-based chemotherapy includes drugs like cisplatin and carboplatin. These drugs bind to the DNA of cells, damaging the cells. Eventually the body cannot repair the cells and kills them off instead. Like all medications, platinum-based chemotherapy is associated with side effects. Platinum-based chemotherapy medications are often used for ovarian cancer, but are not as commonly used for breast cancer. Research is ongoing to determine the long-term safety and effectiveness of these medications for the treatment of BRCA-associated cancer.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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