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Overview

Several years ago, the actress Angelina Jolie revealed that she had lost her mother to ovarian cancer and had learned, through genetic testing, that she carried a BRCA gene mutation. She decided to have elective double-mastectomy surgery and breast reconstruction, as well as a procedure to remove her ovaries and fallopian tubes. By writing and talking about her situation, Jolie raised public awareness about BRCA genetic testing and an inherited disorder called hereditary breast and ovarian cancer syndrome, or HBOC.

HBOC is what is known as an inherited cancer susceptibility syndrome. It is caused by harmful mutations to the BRCA1 or BRCA2 genes, which are passed down through families. Though not everyone who has HBOC develops cancer, those with the syndrome have a substantially increased lifetime risk of breast and ovarian cancer, as well as a number of other types of cancer.

Although HBOC is rare—it affects less than 1% of the population—it is linked to 5 to 10% of breast cancers in women and around 15% of ovarian cancers in the U.S. every year. If you find out you have a BRCA1 or BRCA2 mutation, you may be able to take some preventive measures to reduce your risk for cancer or increase your chances of catching cancer early, when it is most treatable.   

“There’s value in BRCA genetic testing if you are a healthy person with a strong family history of BRCA-related cancers, or if you have been diagnosed with a cancer associated with BRCA,” says Yale Medicine medical oncologist Erin Hofstatter, MD. “For the healthy patient with a positive genetic result, there’s a lot that can be done with screening and prevention, starting as young as 25 years old. For those with cancer, certain drugs and treatments appear to be more effective in patients with BRCA mutations. We are essentially providing more personalized medicine.” 

What is hereditary breast and ovarian cancer syndrome?

HBOC is an inherited genetic condition that significantly increases the risk of developing certain types of cancer, most notably breast and ovarian cancer. These cancers often occur at younger ages than in people who do not have the condition. Though its name may suggest that it affects only women, men and transgender people can have HBOC. The condition is linked to increased risk for several other types of cancer including cancers of the prostate, fallopian tubes, pancreas, male breast, and peritoneum (the membrane that lines the abdominal cavity).

People get HBOC when they inherit a mutation, or change, in the BRCA1 or BRCA2 genes, from their parents. These genes get their name from “BReast CAncer,” and they are sometimes referred to as breast cancer susceptibility genes 1 and 2. Mutations in other genes can also increase the risk of breast and ovarian cancers, but BRCA1 and BRCA2 make up the majority of cases. BRCA1 and BRCA2 are both members of a special category of genes known as “tumor suppressor genes.” Everyone inherits copies of these genes from their parents, and when they are functioning properly, they make proteins that regulate the growth of cells and suppress—or prevent—the development of tumors. If a harmful mutation occurs in these genes, however, their ability to regulate cell growth is impaired. This can result in uncontrolled cell growth which in turn can lead to the development of cancerous cells and tumors.  

Who is at risk of hereditary breast and ovarian cancer syndrome?

Researchers estimate that around 1 in 300 to 1 in 800 people have a harmful mutation in the BRCA1 or BRCA2 genes. Some groups, however, are more likely to have mutations in these genes. For instance, approximately 1 in 40 people of Ashkenazi Jewish descent have a mutation in BRCA1 or BRCA2.

Because HBOC is an inherited syndrome, family history of breast, ovarian, and certain other cancers is an important risk factor. If one parent has a BRCA1 or BRCA2 mutation, each of their children will have a 50% chance of inheriting the mutation.

What is the risk of breast, ovarian, and other types of cancer for those who have hereditary breast and ovarian cancer?

Several factors play a role in determining one’s cancer risk including age, type of cancer, and whether the mutation affects BRCA1 or BRCA2. On average, however, the risk that someone with HBOC will develop several types of cancer by age 70 is as follows:

  • Breast cancer. The lifetime risk of breast cancer among women in the U.S. is around 12%. The risk rises to 55-70% for women with BRCA1 mutations and 45-70% for BRCA2.
  • Ovarian cancer. The lifetime risk of ovarian cancer is approximately 1%. For carriers of BRCA1, however, the risk is around 40% and for carriers BRCA2, approximately 15%.
  • Prostate cancer. Male carriers of BRCA1 have around a 15-20% risk of prostate cancer, while the risk for those with BRCA2 is about 30-40%. By contrast, in the general population the risk ranges from around 14–19%.
  • Breast cancer in men. On average, men in the U.S. have about a 0.1% risk of breast cancer. Men with BRCA1 and BRCA2 mutations, however, have a 1% and 8% risk, respectively.
  • Pancreatic cancer. The average lifetime risk for pancreatic cancer in the U.S. is 1.5%. For BRCA1 carriers the risk rises to 2-4%, while those with a BRCA2 mutation have a 5% risk.

HBOC also increases the risk of melanoma (skin cancer) and, in women, cancer of the fallopian tubes, though the extent to which the risk is increased for these cancers is not yet well defined.

Who should be tested for BRCA1 and BRCA2 mutations?

Genetic testing for HBOC may be appropriate for people who have a personal or family history (in a 1st-, 2nd- or 3rd-degree relative) of certain types of cancer. The National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals who meet any of the following criteria should consider getting tested:

  • A previously identified BRCA1 or BRCA2 pathogenic, or harmful, mutation in the family
  • Two or more relatives with breast cancer, one under age 50
  • Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
  • Three or more relatives with breast cancer at any age
  • Multiple primary breast cancers either in one or both breasts
  • Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu [human epidermal growth factor receptor 2]-negative) breast cancer, particularly when diagnosed before age 60
  • Breast cancer diagnosed at or before age 50
  • Ovarian cancer (including fallopian tube cancer and primary peritoneal cancer)
  • Male breast cancer
  • The combination of pancreatic cancer and/or prostate cancer with breast cancer, and/or ovarian cancer

What does testing for BRCA1 , BRCA2 , or other gene mutations look like?

Getting tested for BRCA1, BRCA2, or other gene mutations requires a blood or saliva sample. This sample will be analyzed in a laboratory to determine if any known harmful gene mutations are present. In many cases, a multi-gene panel test is used. This test will check for mutations in BRCA1 and 2, as well as other genes associated with increased risk of cancer or other diseases.

A “negative” test result means no BRCA mutation was detected. A “positive” result means a known mutation in BRCA1 or BRCA2 was found.

In some cases, the test finds a “Variant of Uncertain Significance,” or VUS. This result means that the test detected a mutation in BRCA1 or BRCA2, but it does not match any known harmful mutations. For a VUS result, more testing may be necessary to determine if the mutation is harmful.

A genetic counselor can help patients interpret test results and clarify what they mean in terms of cancer risk and passing the mutation on to their children.

Is it possible to do BRCA testing with at-home DNA test kits?

Some at-home DNA test kits offer BRCA testing. At the moment, these tests are capable of detecting only three out of thousands of known BRCA variations. According to the National Cancer Institute (NCI), this means that an individual may test “negative” using an at-home kit, while in reality they may have a harmful mutation that the test did not recognize. What’s more, without the assistance of genetic counselor, interpreting the results may be difficult.

By contrast, genetic testing at a medical center like Yale Medicine searches for all known variants of BRCA1 and BRCA2, as well as other mutations in other genes, and genetic counselors are available to help patients understand their results.  

What preventative action can people with hereditary breast and ovarian cancer syndrome take?

Surgery, medication, and cancer screenings are all options that can help lower the risk of developing certain cancers or help detect cancer at an early stage, when it is easiest to treat.

  • Risk-Reducing Surgery. Women may choose to have surgery to remove both breasts (bilateral or double mastectomy) and/or ovaries and fallopian tubes (bilateral salpingo-oophorectomy). Bilateral mastectomy may lower the chance of developing breast cancer by 90%, and bilateral salpingo-oophorectomy may lower the risk of ovarian cancer by 80% and may also reduce the risk of breast cancer. Both of these procedures, however, can profoundly affect a woman’s physical and emotional health due, in part, to changes in hormones that could result when these organs are removed.   
  • Cancer Screening.
    • Women with HBOC can begin self-breast exams starting at age 18 and clinical breast exams with magnetic resonance imaging (MRI) studies twice a year beginning at age 25. Mammograms should be used starting at age 30. Screening for ovarian cancer can be done through twice yearly transvaginal ultrasounds and CA-125 blood tests beginning at age 30.
    • Men with a BRCA1 or BRCA2 mutation should perform a monthly breast self-exam and undergo an annual clinical breast exam beginning at age 35. In cases of gynecomastia (enlarged breasts), mammography should be considered. Starting at age 40, men should consider undergoing prostate cancer screening.
    • Depending on each patient’s individual situation and family history, regular melanoma and pancreatic screenings may be recommended.
  • Medications. Medications can lower the chance of developing breast or ovarian cancer. Tamoxifen, raloxifene, and aromatase inhibitors may help reduce the risk of breast cancer in patients who have not undergone a double mastectomy, and oral contraceptives can help reduce the risk of ovarian cancer (though they may increase the risk of breast cancer).  

What is unique about Yale Medicine’s approach to HBOC syndrome?

Our physicians are conducting research to better understand the complex relationship between BRCA mutations and cancer risks. “We aim to be a one-stop shop for patients who receive a positive genetic result. We have a team of physicians and nurse practitioners who are available for the planning and providing of longitudinal cancer screening and intervention care,” Dr. Hofstatter says.