Genetic testing can find BRCA1 and BRCA2 mutations — then what?


By Linda Liu, MD

Although the clear majority of the approximately 240,000 new breast cancers diagnosed annually are not caused from a genetic mutation, it's important to identify the small percentage that are. The most common and well known mutations associated with breast and ovarian cancers are the BRCA1 and BRCA2 mutations. Finding these mutations — or, in fact, any genetic mutation linked to tumor formation — is a powerful weapon to prevent additional cancers in these patients, in their relatives and in future generations.

What is a genetic mutation?

genetic mutation - BRCA 2 and BRCA 3 - HonorHealth

The BRCA1 and BRCA 2 genes normally function as tumor suppressor genes. They help repair DNA damages that could lead to cancer formation. When there's a harmful mutation — an alteration in either of these genes — the ability to defend against cancer formation is greatly weakened. Individuals with one of these mutations are more likely to get a cancer at a much earlier age than expected and develop multiple tumors, sometimes in different organs.

These faulty genes are then inherited by their children, and a characteristic pattern of hereditary cancer arises in these families: numerous relatives with cancers, often occurring at young ages, with the same individual sometimes having several different kinds of cancers.

Of the many gene mutations that can cause hereditary breast and ovarian cancer, the BRCA1 and 2 mutations are the most common. They may account for up to 10 percent of all breast and ovarian cancers, especially when they occur in young patients or those with a strong family history of both breast and ovarian cancers.

These mutations are not common and are found in 1 in 400 patients. One in 40 patients of Ashkenazi Jewish heritage can carry three specific BRCA1 and 2 mutations that appear with greater frequency in this group.

Higher risk of breast and ovarian cancers

Although individuals with the BRCA1 or 2 mutations clearly have a higher risk of getting breast and ovarian cancer, the predicted risk is a wide range, rather than a precise number. Why? Because there are many interacting environmental and biologic factors that can influence an individual's risk of getting a cancer.

In general, a woman's lifetime risk of getting breast cancer is 12 percent, and ovarian cancer is less than 2 percent. With a BRCA1 or 2 mutation, those lifetime risks greatly increase to 40-80 percent for breast cancer and 15-40 percent for ovarian cancer. Faulty genetic defenses enable breast cancers to develop at much younger ages, sometimes in patients in their 20s, 30s or 40s.

Men with BRCA mutations also have a higher risk of getting cancers, but at much lower percentages. This allows the presence of the mutation to remain "hidden" in male family members. Male breast cancer occurs in less than 0.1 percent of healthy men. With the BRCA mutation, the risk is comparatively much higher, from 2 to 8 percent. That's still so infrequent overall that hereditary cancer patterns go unrecognized.

Given its rarity, male breast cancer should automatically prompt BRCA mutation testing. Prostate cancer can occur more frequently and at slightly younger ages in men with the mutation. In both sexes, there's a slight increase of pancreatic cancer and melanoma.

Identifying the presence of the BRCA mutation empowers individuals to understand their chance of getting future cancers. Most importantly, it allows prevention or detection much earlier. This knowledge can help patients recently diagnosed with cancer and family members who do not have cancers but are concerned about their risk.

When to get genetic testing

Done as a simple blood or saliva test, genetic testing is usually covered by insurance if the patient meets the criteria for testing. History that should prompt genetic testing in patients diagnosed with cancer include:

  • Breast cancer in patients less than 50 years of age.
  • Triple negative breast cancer, a more aggressive form that's not responsive to estrogen or progesterone and does not have extra HER2/neu protein markers.
  • Multiple breast tumors in the same patient, either simultaneous, distinctly different tumors, or a history of multiple episodes of breast cancer occurring at different times.
  • Ashkenazi Jewish ancestry.
  • Ovarian cancer: Either a personal history of ovarian cancer in the past or a relative with ovarian cancer.
  • Male breast cancer diagnosed in the patient or in a family member.
  • Pancreatic cancer: A personal history or in family members.
  • A strong family history of breast cancer with multiple relatives on the same side or an unusual pattern with relatives who developed cancer at an early age — less than 50 — or multiple times.

Patients who have not had a breast or ovarian cancer, but who have a concerning family history, should have genetic testing based on the following criteria:

  • A relative with a confirmed BRCA mutation.
  • A strong family history of breast cancer that is striking in:
    • The number of relatives — at least three on the same side of the family.
    • An unusual history of breast cancer at less than 50 years of age or individual relatives who had multiple cancers. "Red flag" cancers are uncommon cancers that should also raise a suspicion to test — a relative with ovarian cancer, male breast cancer or pancreatic cancer.

It's always best to test first a family member who has been diagnosed with a cancer; unfortunately, that's not always possible. If an affected relative is not available, then the next best person to test is an unaffected family member higher in the family tree. A negative result in that person clears all of his or her children from having a mutation.

Risk elevation from BRCA mutations

Increased cancer risks with BRCA mutations cover a broad range. The risks are influenced by the particular mutation, family history and other complex factors.

Cancer risk over lifetimeGeneral populationBRCA1 or 2 mutation
Breast (female)12%45-80%
Second breast cancer5-15%30-50%
Male breast cancer0.1%2-8%
Ovarian cancer<2%20-40%
Pancreatic cancer<1%1-7%

Effective strategies for prevention or early detection can reassure individuals with a BRCA mutation that they don't need to feel vulnerable and anxious. For patients diagnosed with breast cancer, awareness of an underlying BRCA mutation can more precisely guide their surgery choice.

Lumpectomy is the usual surgical treatment for small cancers because it's a minimal surgery that removes only the tumor with a small rim of surrounding tissue. It's equally safe when compared to a more complicated mastectomy surgery, and there's a low 5-10 percent lifetime risk of developing another cancer in that breast.

However, in female BRCA-positive patients, a lumpectomy may not be the best choice because the risk of another breast cancer is significantly higher because the mutation is more likely to misbehave later, in a different breast cell, and allow a distinctly new cancer to form in either breast. Because the risk of a second new breast cancer can be as high as 50-60 percent over a patient's lifetime, most BRCA-positive women choose mastectomy on both sides to prevent new cancers from developing.

Reconstruction and possible nipple preservation can be done at the same time as the mastectomy. Some BRCA-positive breast cancer patients still opt to minimize surgery to lumpectomy only, but these patients need to be more carefully watched with an annual MRI along with the usual mammograms. These patients likely would take anti-estrogen medication to help prevent future cancers.

When to have a mammogram, other tests

BRCA-positive patients who do not have a breast or ovarian cancer can ease the burden of having hereditary cancer with a proactive strategy for risk reduction or early detection. All BRCA-positive patients should undergo increased surveillance unless they opt for preventive surgery. In the general population, mammograms are recommended at age 40 with annual exams by clinicians.

Earlier and more thorough examinations are encouraged in patients with hereditary breast and ovarian cancer genes. For women, these exams include:

  • Monthly breast self-examinations starting at 20.
  • Examination by clinicians every six months.
  • Breast MRI, if available, for greater detection starting in the 25-29 age range. Mammograms are difficult in young patients because they have dense breast tissue, but they should start at 30. Ultrasound is also helpful if MRIs are difficult.
  • Screening for ovarian cancer is difficult and of questionable value. Transvaginal ultrasound and measuring tumor markers (found in the blood or body tissue of some people with cancer) can be considered. Pelvic exams should begin by age 30.

Men should perform breast exams by age 35, but they don't necessarily need mammograms unless they have large amounts of breast tissue. Men should undergo earlier prostate screening.

Medications, surgery reduce your risk of breast cancer

Risk reduction involves the use of medication to decrease the chance of cancer formation or prophylactic (preventive) surgery to remove tissue before it can develop a cancer:

  • Taking tamoxifen for five years blocks estrogen activation of breast cancers, reducing them 40-50 percent. A downside is that tamoxifen can cause menopausal symptoms. Men don't take tamoxifen for prevention, but might take it if they develop a breast cancer.
  • Oral contraceptives may reduce the risk of ovarian cancer.
  • Oophorectomy, surgical removal of ovaries and fallopian tubes, is strongly recommended because ovarian cancer is difficult to detect. The surgery decreases both ovarian and breast cancers. It reduces the risk of ovarian cancer by 90 percent and is recommended when the patient is done with childbearing, between the ages of 35 and 44 — earlier for BRCA 1 carriers. When this surgery is performed when a woman is in her 30s or 40s, the estrogen reduction can effectively decrease breast cancer 30-60 percent.
  • Mastectomies, the surgical removal of both breasts, reduces breast cancer risk 90-95 percent. Reconstruction often can be done during the same surgery, sometimes keeping the nipple and areola for the best cosmetic effect. Excellent aesthetic results can be achieved with reconstruction. Having mastectomies is optional and can be done at any age when the individual feels ready. However, these surgeries can be emotionally and physically challenging. Patients should receive thorough counseling to help guide the decision for surgery versus the option of continued close surveillance. Mastectomies are not recommended in men.

The success of risk reduction depends on many factors. Ovary removal is more effective in reducing the risk of breast cancer if done earlier, under age 45. Ovary removal is strongly encouraged in all BRCA-positive patients, but mastectomies should be performed on an individualized basis.

Cancer risk reduction strategies

Lifetime cancer riskBRCA mutation0ophorectomy (ovary removal)MastectomiesTamoxifenOral contraceptives
Breast cancer40-80%Reduce by 30-50%Reduce by 90%Reduce by 30-50%No increased risk
Ovarian cancer20-40%Reduce by 90%------Possible reduction

With greater understanding of the many gene mutations that can cause hereditary breast and ovarian cancer, doctors can order full panels of genetic tests to detect less common mutations, in addition to the BRCA mutations.