Genetic Risk Factors for Breast Cancer

Main menu:

• Genetics Overview
• How do physicians test for BRCA mutations?
• Who should consider genetic testing?
• Preventing breast cancer in BRCA-positive women
• HER2 (or HER2/neu)
• p53 Tumor Suppressor
• Additional Resources and References

Genetics Overview

DNA (deoxyribonucleic acid), a chemical found on cell chromosomes, is responsible for carrying genetic information. Chromosomes are threadlike structures present within the nuclei of cells. DNA’s double helix structure allows the chromosomes to be replicated during cell division. Genes (segments of DNA) contain instructions for controlling when cells should grow, divide, and die. Certain genes called tumor suppressors slow down the process of cell division, causing cells to die.

Changes in DNA can sometimes cause normal cells to become cancerous by de-activating the tumor suppressor genes. Researchers are still investigating how and why some genes mutate but have discovered that inherited DNA changes may cause cancers to occur more frequently in some families. However, most DNA mutations that cause breast cancer are not inherited; they occur during a woman’s life and may be caused by a variety of factors (many still unknown to medical experts). These factors may include exposure to certain chemicals (such as Aldrin, Alachlor, and Acetamide), high dose radiation (from atomic bombs or from certain types of radiation therapy used to treat other cancers), other environmental exposures, diet, and smoking.

BRCA1 (breast cancer gene 1) and BRCA2 (breast cancer gene 2) are two tumor suppressor genes that, when functioning normally, help repair damage to DNA (a process that also prevents tumor development). In 1994, researchers discovered that women who carry mutations of BRCA1 or BRCA2 are at higher risk of developing both breast and ovarian cancer than women who do not have these genetic mutations. Currently, women with BRCA1 mutations account for 5% of all breast cancer cases.

Dr. Sandhya Pruthi, MD, a Breast Health Specialist at the Mayo Clinic, estimates that 20% of women who carry BRCA1 mutations will develop breast cancer by age forty, 51% by age fifty, and 87% by age sixty.

How do physicians test for BRCA mutations?

To test for BRCA1 or BRCA2 mutations, a small sample of blood is drawn, and the DNA is analyzed for BRCA defects. In addition to being at higher risk for developing breast cancer, women who test positive for BRCA defects are at a 20% to 60% greater risk of developing ovarian cancer. BRCA1 mutations may also lead to a higher lifetime risk of colon or prostate cancer, while BRCA2 mutations may raise lifetime risk of these and possibly other cancers.⁽¹⁾

Presently, there are over 2000 genetic mutations associated with BRCA1 and BRCA2 genes. Women who test positive for BRCA defects will not necessarily develop breast cancer; they are merely at higher risk for the disease. Additionally, not all BRCA mutations carry the same risk of cancer. A new study conducted at Baylor College in Texas reveals that the protein ATM (ataxia telangiectasia) might be linked to breast cancer development in women who test positive for a mutated BRCA1 gene. Click here to learn more about the ATM protein study.

Who should consider genetic testing?

BRCA1 and BRCA2 genetic testing is a controversial topic among health care professionals. At many clinics, only women whose family histories place them at high risk of developing breast or ovarian cancers are eligible for genetic testing. Any woman considering genetic testing should discuss the process with a physician, nurse, or genetic counselor before proceeding with the testing.

Both men and women may inherit and pass on BRCA1 or BRCA2 mutations. According to the Mayo Clinic, families that typically pass on BRCA defects have the following characteristics:

• Breast cancer in two or more close relatives, such as a mother and two sisters
• Early onset of breast cancer in family members, often before age fifty
• History of breast cancer in more than one generation
• Cancer in both breasts in one or more family members
• Frequent occurrence of ovarian cancer
• Eastern and Central European (Ashkenazi) Jewish ancestry, with a family history of breast and/or ovarian cancer (researchers have identified two types of BRCA1 mutations and one BRCA2 mutation that are especially prominent in this group)

Genetic testing raises some complicated questions women should ask themselves before being tested. Genetic counselors can be very helpful.

• Would I want to know that I am at risk of developing a potentially life-threatening disease?
• How will knowing I am at increased risk of breast cancer change me emotionally?
• What can be done if I find out I may develop a potentially life-threatening disease?
• If I test positive for a BRCA mutation (i.e., an increased risk of breast cancer), should my children be tested?
• How will my family react if I test positive for a BRCA mutation?
• How will the female members of my family react if I find out I am at increased risk for breast cancer? Should they consider genetic testing too?
• How will the results of my genetic tests be used by physicians?
• What are the long term effects in terms of insurance coverage if you are found to carry the BRCA mutation?

Click here to learn more about candidates for BRCA gene testing.

Preventing breast cancer in BRCA-positive women

Women who test positive for BRCA1 or BRCA2 genetic mutations are at higher risk of developing breast cancer and may wish to consider preventive measures. The Mayo Clinic suggests that women at increased cancer risk limit alcohol consumption and exercise regularly. Additionally, increased breast screening helps to detect breast cancer at an early stage (when it is more easily treatable).

The American Cancer Society suggests the following guidelines to help detect breast cancer early:

• Women 20 years of age and older should perform breast self-examination (BSE) every month.
• Women 20-39 should have a physical examination of the breast (CBE or clinical breast exam) at least every three years, performed by health care professional such as a physician, physician assistant, nurse, or nurse practitioner. CBE may often be received in the same appointment as a Pap smear. Women 20-39 should also perform monthly BSE.
• Women 40 and older should have a physical examination of the breast (CBE or clinical breast exam) every year. CBE should be performed by a health care professional such as a physician, physician assistant, nurse, or nurse practitioner. CBE can often be performed in the same visit as a mammogram. Monthly BSE should also be performed.
• Women 40 years of age and older should have a screening mammogram every year in addition to annual CBE and monthly BSE.

Women at high risk of developing breast cancer (in consultation with her physician) may begin screening mammography earlier age 40. Some experts suggest beginning screening ten years prior to the age at which a close relative (mother, sister) was diagnosed with breast cancer.

Click here for more information on the early detection of breast cancer.

"Chemoprevention" (the use of drugs, chemicals, vitamins, or minerals to treat breast cancer) is another option for women at increased risk of developing breast cancer. One type of chemoprevention involves the anti-cancer drug, tamoxifen. Tamoxifen has been used for twenty years to treat advanced breast cancer. More recently, tamoxifen has been used to treat early-stage breast cancer and to lower the risk of breast cancer in women who are at high risk for the disease.

In its first major breast cancer prevention trial (BCPT) from April 1992 to 1998, researchers for the National Surgical Adjuvant Breast and Bowel Project (NSABP) found a 49% decrease in the incidence of invasive breast cancer in women at increased risk for the disease who took tamoxifen therapy in comparison to those who did not receive the drug and received a placebo (an inactive pill) instead. The study showed that women taking tamoxifen also had fewer diagnoses of noninvasive breast cancer, such as ductal carcinoma in situ (DCIS). Click here for more information on the NSABP tamoxifen trials.

Some women at high risk of developing breast cancer may choose to have prophylactic mastectomy (preventive removal of the breasts). A recent study published in the Journal of Medicine revealed that prophylactic mastectomy reduced the risk of breast cancer by 90% in women at high risk for the disease. (Prophylactic mastectomy cannot reduce breast cancer risk by 100% because it is not possible to remove all of the breast tissue). The mortality rate from breast cancer was also reduced by 80% in the study.

Researchers are still not certain how women will be affected by prophylactic mastectomy, though. Preventive surgery may increase life expectancy in women with aggressive tumors. However, other women with BRCA1 or BRCA2 mutations never develop breast cancer and thus do not benefit from prophylactic mastectomy. Less invasive procedures (such as lumpectomy) may also be performed to treat breast cancer without having to remove the breast(s).

Though medical experts still do not recommend prophylactic mastectomy, the following women are candidates for the procedure:

• Mutated BRCA1 or BRCA2 genes
• Previous cancer in one breast
• Strong family history of breast cancer (mother or sister had breast cancer)
• Biopsy revealing lobular carcinoma in situ (LCIS)

Note: Women who do not have any of the above conditions should normally not consider having prophylactic mastectomy.

HER2 (or HER2/neu)

HER2 (human epidermal growth factor receptor 2) is another gene found on the surface of cells that plays a key role in regulating cell growth. When the HER2 gene is altered, extra HER2 receptors may be produced. This over-expression of HER2 causes increased cell growth and reproduction, often resulting in more aggressive tumor cells.

HER2 protein over-expression affects 25% to 30% of breast cancer patients. Women with HER2 over-expression may not be as responsive to standard breast cancer treatments, including certain regimens of chemotherapy.

The United States Food and Drug Administration (FDA) recently approved the drug Herceptin (generic name Trastuzumab) for use in breast cancer patients whose cancer has metastasized (spread) beyond the breast and underarm lymph nodes. Herceptin has been shown to slow the growth and spread of cancerous tumors in a number of clinical trials. In some cases, cancerous tumors have completely disappeared in patients taking Herceptin. Presently, only women who are HER2 positive (and have metastasized breast cancer) are candidates for treatment with herceptin. Click here for more information on Herceptin and HER2.

p53 Tumor Suppressor

Little is known about the p53 tumor suppressor except that, when mutated, the p53 gene also increases a woman's risk of developing breast cancer. A recent study published in the conducted by Dr. Ayman Linjawi of the Royal Victoria Hospital in Montreal, Quebec, Canada reveals that women with early-stage breast cancer who test positive for the mutated p53 tumor suppressor tend to have a poorer breast cancer prognosis than women who do not carry the mutated p53. Dr. Linjawi and colleagues found that the Stage I breast cancer patients with the mutant p53 had an average survival rate of 74% after five years compared with a survival rate of 83% who did not have the mutant p53. p53 mutation testing is available to high-risk women at specialized centers. However, according to the American Cancer Society, this testing has not been shown to be helpful in determining current patients' treatment at this point. Further research on p53 genetic testing is needed to determine whether it may one day have value in helping physicians choose a breast cancer patient's best course of treatment.

Additional Resources and References

• (1) The Mayo Clinic’s HealthOasis offers information on BRCA gene mutations and genetic testing at http://www.mayohealth.org/mayo/9910/htm/brca.htm.
• (2) The American Cancer Society provides information on genetic risk factors for breast cancer at http://www3.cancer.org/cancerinfo/main_cont.asp?st=pr&ct=5.
• For additional information on risk factors for breast cancer, please visit http://www.imaginis.com/breasthealth/bc_risks.asp.
• To learn more about HER2 and herceptin, please visit http://www.imaginis.com/breasthealth/herceptin.asp.
• For a complete list of "Chemicals Known to [California] State to Cause Cancer," please visit the Office of Environmental Health Hazard Assessment webpage at http://www.oehha.org/home.html
• Informed Medical Decisions provides risk assessment and informed medical decision-making based on family history.
• To learn more about candidates for BRCA gene testing, please visit http://www.imaginis.com/breasthealth/BRCA.asp

Updated: May 17, 2009