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BRCA Mutations and Breast Cancer, New Recommendations

By Esther Entin, MD

Many people are aware that actress Angelina Jolie underwent a double mastectomy to prevent breast cancer, but far fewer understand the genetic mutation behind her decision.

Genetic testing for breast and ovarian cancer risk is an option for certain women, but just knowing about the option of genetic testing has left many women, who have no symptoms of these diseases, wondering how it fits in with mammograms and other forms of breast cancer screening.

The United States Preventative Services Task Force (USPSTF) recently updated their guidelines on breast cancer screening, and they confirm that screening isn’t appropriate for everyone and should be only be done following careful consideration and thorough counseling.

The USPSTF is an independent panel of experts composed of primary care providers. It reviews scientific evidence and develops recommendations for primary care clinicians and health systems regarding the best ways to prevent and treat disease. The BRCA screening guidelines are part of this work.

Why the BRCA Genes Are Important

The idea behind genetic screening is to definitively assess and reduce the risk of cancer in women with potentially harmful mutations by implementing medical interventions when they show the BRCA1 (Ms. Jolie's form) or BRCA2 mutations that so often lead to cancer.

“My doctors estimated that I had an 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer, although the risk is different in the case of each woman,” the actress wrote in her opinion piece in the New York Times.

The BRCA1 and BRCA2 genes produce proteins that suppress the formation of tumors, helping to prevent abnormal growths. When mutations to either of these genes cause them to malfunction, cell DNA may not be repaired properly and the unchecked growth of cancer cells may develop.

There are inherited mutations of these two genes that are known to lead to an increased risk of some cancers. BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and around 15 percent of ovarian cancers overall.

The cancers that are associated with these mutations usually occur at younger ages than the cancers that are considered sporadic (occurring without a known genetic predisposition or family history).

In the general population, 12.3% of women will develop breast cancer during their lifetime and 1.4% will develop ovarian cancer. With a known BRCA mutation, a woman’s risk for breast cancer increases to 45%-65% by age 70.

Mutations in BRCA 1 increase ovarian cancer risk to 39% by age 70 and BRCA 2 mutations increase ovarian cancer risk to 10-17% by age 70. The combined prevalence of BRCA 1 and BRCA 2 mutations is also much higher in Ashkenazi Jewish women.

Mutations Seen in Both Men and Women

The BRCA1 or 2 gene mutations can be inherited from either a mother or a father. When either parent carries the abnormal gene, a child has a 50% chance of inheriting the same mutation.

Men and women who inherit harmful BRCA1 or BRCA2 mutations, whether or not they develop cancer themselves, may pass the mutations on to their sons and daughter. If a person learns that he or she has inherited a harmful BRCA1 or BRCA2 mutation, this will mean that each of his or her siblings has a 50% chance of having inherited the mutation as well.

Thinking about Screening and Genetic Testing

The USPSTF recommends that women with a family history of breast, ovarian, tubal, or peritoneal cancer first be screened by their primary care providers to pinpoint aspects of family history that may be associated with an increased risk for BRCA1 or BRCA2 mutations.

Family history factors associated with increased likelihood of these potentially harmful gene mutations include: breast cancer diagnosis before age 50, bilateral breast cancer, a family history of breast and ovarian cancer, the presence of breast cancer in more than one male family member, multiple cases of breast cancer in the family, more than one family member with two primary types of BRCA-related cancer, and Ashkenazi Jewish ethnicity.

Women with histories that meet the USPSTF guidelines should be screened when they reach age 18, and should be re-screened at least every five to ten years, as family health histories may change over time.

In order to gather accurate information, the screening tools are standardized questionnaires that explore a family’s health history and include questions such as:

  • Did any of your first-degree relatives have breast or ovarian cancer?
  • Did any of your relatives have bilateral breast cancer?
  • Did any man in your family have breast cancer?
  • Did any women in your family have breast and ovarian cancer?
  • Did any women in your family develop breast cancer before age 50?
  • Do you have two or more relatives with breast and/or ovarian cancer?
  • Do you have two or more relatives with breast and/or bowel cancer?

If a woman’s family history is suggestive of a BRCA1 or 2 mutation — if any of the answers to these questions are “yes” — her primary care provider should refer her to a genetic counselor for further assessment and discussion of the risks and benefits of genetic testing.

Task Force chair Virginia Moyer, M.D., M.P.H. put it this way: “Too many American women and families are faced with the challenge of dealing with cancer diagnosis and treatment. We have great hope in the science of genomics to improve screening practices and even prevent some cancers. At this point, the evidence shows that most American women will not benefit from genetic counseling or the test for gene mutations in BRCA1and BRCA2.

“For women who have a family history that might be associated with an increased risk for these mutations, we found that some may benefit from in-depth genetic counseling that thoroughly reviews their family history and, if indicated and after weighing the pros and cons of BRCA testing, receiving the test.”

The task force stresses that genetic testing should not be undertaken without referrals for pretest and post-test counseling, as the results can have significant implications for the lives of the patient and her extended family.

A genetic counselor will describe the possible outcomes of the test, potential interventions if the test is positive, and the implications for extended family members. This can help the patient decide whether or not she wants to continue with the process of genetic testing.

Once the test results are received, the patient requires posttest counseling to understand the results. The results may be positive, negative, or ambiguous.

Interpreting the Test Results

A positive test, such as Angelina Jolie received, indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 gene and therefore, has an increased risk of developing certain cancers. A positive test result cannot tell whether an individual will actually develop cancer or when.

Many women (and men) who inherit a harmful BRCA1 or BRCA2 mutation will never develop breast or ovarian cancer. But they can pass it on to their children, and their siblings are at increased risk of also carrying the gene.

A negative test result requires a little more interpretation.

If a person knows that one of her close relatives — first degree: parents, siblings, or children; or second degree: grandparents aunts, uncles, nieces, nephews, half-siblings — has the BRCA1 or 2 mutation, but their own BRCA1 and 2 test is negative, they can be assured that they haven’t inherited the mutation themselves. Such a test result is called a “true negative.” A person with such a test result can be reassured that she has the same risk of cancer as someone in the general population.

If a person with a BRCA-mutation-suggestive family history doesn’t know for certain whether their family members have the BRCA mutation or not, it can be harder to interpret their own negative test.

Though unlikely, it is not impossible that the genetic testing will miss a known harmful BRCA1 or 2 mutation or that their family carries a new mutation which hasn’t been catalogued yet. Therefore, it can happen that a person in this scenario with a negative test result actually has an unknown harmful BRCA1 or BRCA2 mutation that has not been identified.

Ambiguous Results

There are other genes beside the BRCA 1 and 2 that increase the risk of cancer and sometimes genetic counselors will recommend more extensive testing depending on family history and outcome of first level tests.

It is also possible to have ambiguous test results. That occurs when a mutation is found on the BRCA genes, but it is not a mutation that is known to be associated with cancer at this time. One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of result.

BRCA testing and genetic testing for cancer in general are very much works in progress. As more people get tested and more data get collected, the significance of various findings for patients’ health will become clearer.

Making Decisions Based on Genetic Testing

As mentioned earlier, women who have BRCA1 or 2 mutations have a higher risk than the general population of developing cancer, but not every positive patient will get sick. The risks and benefits of the options following a positive test need to be considered carefully with the guidance of medical professionals.

There are three major areas of intervention, intensive screening, chemoprophylaxis, and risk-reducing surgery. More study is needed on all forms of interventions for BRCA mutation positive patients.


The goal of screening is to detect breast cancer at the earliest possible stages when it can be treated more successfully. Currently, the American Cancer Society recommends yearly screening and mammograms for women starting at age 40 and continuing for as long as a woman is in good health. They also recommend a clinical breast exam about every 3 years for women in their 20s and 30s and increasing in frequency to yearly for women 40 and over.

Women who test positive for BRCA1 and 2 mutations may wish to start screening early — around age 25 to 30 — with both yearly clinical breast exams and mammography. The benefits of early screening must be weighed against the risk of the increased radiation exposure from mammograms or x-rays. Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with mammography and MRI (which has no radiation risk) for women who have a high risk of breast cancer.

There are currently no effective methods of ovarian cancer screening. Some groups recommend transvaginal ultrasound examinations, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer.

The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 are also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography, as well as testing for prostate cancer.


Prophylactic or risk-reducing surgery such as that undergone by Angelina Jolie aims to remove as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (to reduce their risk of breast cancer) and/or surgery to remove a woman's ovaries and fallopian tubes to reduce her risk of ovarian cancer.

Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can stimulate the growth of some types of breast cancer.

Such surgeries cannot guarantee that cancer will never develop, but the risk reduction is substantial, with some studies reflecting an 85% to 100% decrease in breast cancer risk with mastectomy and a 37% to 100% reduction in ovarian cancer with removal of ovaries or ovaries and fallopian tubes.

For men with a BRCA 1 or 2 mutation or a family history of breast cancer, no evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk.


Chemoprevention, the use of drugs or vitamins or other agents to try to reduce the risk of, or delay the recurrence of, cancer is another possible response to the discovery of a BRCA mutiaton.

Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the FDA to lower the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear.

These medications have been shown to reduce the incidence of invasive breast cancer in high-risk women in the general population, but they have not been studied specifically in women who are BRCA mutation carriers. Additionally, they carry an increased risk of blood clots. Tamoxifen also can increase the risk of endometrial cancer, and raloxifene increases the risk of cataracts.

Oral contraceptives (birth control pills) may lower the risk of ovarian cancer in women with harmful BRCA1 or BRCA2 mutations.

Genetic testing for BRCA mutations is a multi-step process that begins with a consultation with the patient’s primary care provider and must be guided by medical providers at every level. The results have implications for the individual and their family and future generations to come.

Prophylactic interventions, such as mastectomy, for high-risk patients can be very effective but carry their own risks. As more research is done and a larger group of patients is followed, more information on risks, benefits, and alternatives will enhance clinical decision-making.

The U.S. Preventive Services Task Force Recommendation Statement is published in Annals of Internal Medicine and can be downloaded for free.

January 7, 2014

Source: TheDoctorWillSeeYouNow.com



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