Manuel A. Torres-Salichs MD,FACS Surgical Oncology, Breast Surgeon

Edileidis Tarrio, ARNP-BC, OCN





Inherited Breast Cancer Gene Mutations

Defects in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer (HBOC) syndrome. Only about 5% of breast cancer cases are due to inheritance of cancer susceptible genes.

BRCA1 and BRCA2:

Although breast cancer is relatively common, only about 5% to 10% of cases are due to the inheritance of cancer susceptible genes. The majority of inherited breast cancers are caused by mutations in the BRCA1 and BRCA2 genes. Mutations in these genes cause a significantly increased lifetime risk for cancer compared to the general population. Every cell in the human body is made up of thousands of genes. These genes are made up of DNA which is the genetic material inherited from our parents. Some genes are classified as tumor suppressor genes. They prevent cells from becoming cancerous. BRCA genes are tumor suppressor genes involved in the repair of DNA as a response to damage. A mutation or alteration on these genes makes them defective and unable to prevent cells from becoming malignant. The most susceptible organs affected by these defective genes are the breasts and ovaries. Most hereditary breast cancers are associated with mutations in the tumor suppressor gene called breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2). They account for 60% to 80% of all inherited breast cancers. These genes were discovered in 1994 and 1995 respectively. In North America one in every 300- 500 persons is estimated to harbor a BRCA gene mutation. In the Ashkenazi Jewish population it is as high as 1 in 40.
To put it in perspective, the lifetime risk for breast cancer and ovarian cancer in the general population is 12% and 1% respectively. There is a lifetime breast cancer risk of 50% to 85% among BRCA1 and BRCA2 mutation carriers. There is a lifetime ovarian cancer risk of 36% to 46% among BRCA1 mutation carriers and 10% to 27% among BRCA2 mutation carriers. Another important clinical feature of BRCA mutations is the preponderance of early-onset and multiple cancers. Both BRCA1 and BRCA2 mutation carriers have a 40% to 60% lifetime risk, or approximately 3% per year risk of developing a second cancer in the contralateral breast.
Men can also inherit a deleterious mutation in the BRCA genes. The lifetime risk for male breast cancer is approximately 6% among BRCA1 mutation carriers and 7% among BRCA2 mutation carriers. The occurrence of male breast cancer diagnosed at any age should prompt consideration of BRCA1 and BRCA2 genetic testing.

The Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2) were cloned in 1994 and 1995 respectively. The BRCA1 gene is located in chromosome 17 and the BRCA gene is located in chromosome 13. These genes are responsible for producing several proteins that have been implicated in protecting cells from turning into cancer.

The damaged BRCA1 or BRCA2 gene can be inherited from either the mother or the father. Each offspring of an individual found to carry a mutation has 50% chance of carrying the same mutation. A person who is born with a mutation has one affected gene out of two. An event that occurs during a lifetime can damage the second gene of the pair, leading to the formation of cancer.

Other Hereditary Cancer Syndromes:

These syndromes are also associated with an increased risk for breast cancer:

Ataxia-Telangiectasia: It is associated with the ATM gene The affected individuals have a 2 to 5 fold increased risk for breast cancer
Hereditary Diffuse Gastric Cancer: It is caused by mutations in the CDH1 gene.The affected individuals have up to an 80% lifetime risk of diffused gastric cancer and a 39% lifetime risk for lobular breast cancer
The Cowden Syndrome: It is caused by mutations in the PTEN gene.There is a 25% to 50% lifetime risk for breast cancer, a 10% lifetime risk for thyroid cancer and a 5% to 10% lifetime risk for endometrial cancer
The Li Fraumeni Syndrome: It is caused by mutations in the p53 gene.This syndrome is associated with a variety of   cancers, including breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, adrenocortical carcinomas and, leukemia
The Peutz-Jeghers Syndrome: It is caused by mutations in the STK11 gene.Patients are at increased risk for breast, gastrointestinal, pancreatic, gynecologic, and testicular cancers

Carriers of BRCA mutations also have an increased risk of other cancers such as ovarian cancer, malignant melanoma, pancreatic cancer, colon cancer, stomach cancer, and gallbladder and bile duct cancer.

BRCA Mutations and Other Hereditary Cancers

There are other types of cancers associated with BRCA1 and BRCA2 mutations:

Prostate Cancer: The lifetime risk for prostate cancer is approximately 20% among BRCA2 mutation carriers and it is slightly increased among BRCA1 mutation carriers
Pancreatic Carcinoma: Pancreatic carcinoma has been associated with BRCA2 mutation. The lifetime risk for pancreatic cancer is about 5%
Melanoma: There is a slight increased risk of malignant melanoma. In particular melanoma affecting the eye. (uveal melanoma)

A woman affected with a BRCA mutation is given several treatment options including close surveillance, chemoprevention or risk-reducing surgeries.

BRCA1 and BRCA2 Medical Interventions Strategies

Risk Assessment:

Every breast cancer patient or a person considered to be high risk for develop breast cancer should undergo a thorough risk assessment in order to identify individuals who may carry a BRCA gene mutation. A complete personal and family history should be obtained prior to considering genetic testing. A 3-generation family history should be constructed. This information should be reviewed by the health care provider or genetic counselor to determine whether there are any features that are consistent with the known hereditary cancer syndromes.

Genetic Counseling:

Counseling is provided to convey complex medical and genetic information to patients. This process allows patients to make informed decisions regarding genetic testing when appropriate, and to weigh the risks and benefits of various screening tests and risk-reduction options. When genetic testing is indicated the genetic counselor or health care provider should discuss the risks, benefits, limitations, and possible results of the genetic tests. The discussion should include the testing process, the cost of the test, and which family member is the best candidate for genetic testing. An informed consent must be obtained. For BRCA-associated breast cancer, the risk of getting cancer by the age of 50 is nearly 50%. The lifetime risk of a second primary breast cancer may be as high as 50%.

All women diagnosed with breast cancer under the age of 50 are advised to undergo genetic counseling to discuss testing for BRCA1 and BRCA2, particularly if they have relatives with breast or ovarian cancer. A deleterious mutation in these genes is also associated with an increased risk of ovarian cancer, pancreatic cancer, melanoma, and prostate cancer in men.

Gene Mutation Analysis:

The BRCA gene mutation test is typically performed with a blood sample or buccal swabs, which are swabbed inside the mouth.

Ethical and Legal Issues Associated with Genetic Testing:

Given the sensitive nature of genetic information and concerns about the misuse of genetic testing both federal and state laws have been enacted to protect patients against genetic discrimination. The Genetic Information Nondiscrimination Act (GINA) was signed into law in May 2008 and enacted in 2009.

Medical Interventions Strategies:

Medical Interventions Strategies:

Women who carry a genetic mutation may elect to undergo close follow up and defer preventative surgical intervention. The goal is to be able to detect the cancer at its earliest stages before it spreads. As a general rule the earlier a cancer is diagnosed the better the chances for a cure. The following schedule is suggested for women who carry the genetic mutation and have elected close monitoring.

Surveillance for Breast Cancer:

• Monthly breast self examination at age 18 years
• Semiannual clinical breast examinations beginning at age 25
• Annual mammography and breast MRI beginning at age 25 or earlier depending on family history

Surveillance for Ovarian Cancer:

Ovarian cancer screening remains controversial because it has not shown to lead to earlier diagnosis or reduced mortality. Despite the lack of literature to document decreased mortality, BRCA mutation carriers are advised to undergo annual or semiannual transvaginal ultrasound with color doppler and serum CA- 125 levels at age 25- 35.


Chemoprevention is defined as the use of medications to reduce the risk of, delay the development of, or recurrence of cancer. Tamoxifen has been shown to be effective in preventing breast cancer in patients with BRCA mutations. Studies have shown a 50% reduction in breast cancer risk. The reduction is greater in BRCA2 carriers who have tumors with estrogen receptors. Chemoprevention is also effective in lowering ovarian cancer risk. The long-term use of oral contraceptives has been shown to reduce the risk of ovarian cancer, even in women with BRCA mutations.

Prophylactic Surgery:

Some women would elect to undergo prophylactic surgeries to reduce their risk of dying from breast and ovarian carcinoma. Women do not want to wait for the future development of cancer. They want to try and catch it early. Women actually want to be proactive and try to reduce the risk of getting breast and ovarian carcinoma. For those women, risk-reducing surgery is a good option.

Bilateral Prophylactic Mastectomy:

Prophylactic mastectomy in women who carry the BRCA gene mutation is the best way to reduce the risk of developing breast cancer. The surgery is protective. It is risk reducing but not 100% risk eliminating. There is a 90% reduction in breast cancer risk in BRCA1 and BRCA2 mutation for women who undergo bilateral prophylactic mastectomy.

Bilateral Salpingo-Oophorectomy:

BRCA mutation carriers are strongly advised to have their ovaries and fallopian tubes removed after the age of 35 or after childbearing is complete. Prophylactic bilateral salpingo-oophorectomy has been shown to reduce the ovarian cancer-specific mortality rate by 95%. It also provides protection against breast cancer by cutting a major source of hormone production. It reduces the risk of breast cancer by 50%. Prophylactic bilateral salpingo-oophorectomy may be the most important intervention available for these high-risk women due to the accumulation of evidence demonstrating a reduction in the combined risk of breast and ovarian cancer.

Hereditary Breast and/or Ovarian Cancer Syndrome Testing Criteria

NCCN Clinical Practice Guidelines in Oncology - Version I.2009

Individual from a family with a known BRCA1/BRCA2 mutation.
Personal history of breast cancer (Invasive and Ductal Carcinoma In Situ should be included) plus one or more of the following:

Diagnosed age ≤ 45 y
Diagnosed age ≤ 50 y with ≥ 1 close blood relative with breast cancer ≤ 50 y and/or ≥ 1 close blood relative with epithelial ovarian/fallopian tube/primary peritoneal cancer
Two breast primaries (including bilateral disease or cases where there are two or more clearly separate ipsilateral primary tumors) when first breast cancer diagnosis occurred prior to age 50
Diagnosed at any age, with ≥2 close blood relatives with breast and/or epithelial ovarian/fallopian tube/primary peritoneal cancer at any age
Close male blood relative with breast cancer
Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer
For an individual of ethnicity associated with higher mutation frequency (i.e., founder populations of Ashkenazi Jewish, Icelandic, Swedish, Hungarian or other)
No additional family history may be required
Personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer
Personal history of male breast cancer
Family history only-Close family member meeting any of the above criteria

Close Family Members Include First, Second, and Third Degree Relatives:

First Degree relatives include the parents, brothers, sisters, or children of an individual
Second Degree relatives include the aunts, uncles, grandparents, grandchildren, nieces, nephews, or half-siblings of an   individual
 Third Degree relatives include great grandparents, great grandchildren, great aunts, great uncles, first cousins, grand   nieces, and grand nephews of an individual