BRCA1 and BRCA2 Mutations

Etiology

The incidence of BRCA1 or BRCA2 mutations within the general population is infrequent and only found in 1 out of every 300 to 800 people [6]. Certain populations exhibit a higher likelihood of harboring genetic mutation than the general population. These include Ashkenazi Jewish patients, male patients who develop breast cancer, and patients younger than 30 years old who develop breast cancer. Founder mutations are particular mutations passed down between family members descendant from the same genetic lineage. The specific mutations found in members of Ashkenazi Jewish lineage include 185delAG and 5385insC in the BRCA1 genes and 6174delT in the BRCA2 gene at a rate of 1 in 40 [6].

While the risk for the development of breast cancer is the highest of the epithelial malignancies (between 40% to 80%), the likelihood of developing other cancers including ovarian, pancreatic, and prostate is also increased in patients with BRCA1 and BRCA2 mutations [7].

Epidemiology

The normal risk for cancer development in the general population is 12.5% for female breast cancer, 0.1% for male breast cancer and 1% to 2% for ovarian cancer [2][4]. The incidence and associated risk for cancer development by age 70 for BRCA1 and BRCA2 mutations are listed below [8][9].

BRCA 1 Mutation

• Responsible for approximately 35% of hereditary breast cancer
• Increased risk of developing breast cancer by age 70 to 44% to 78%
• Increased risk of developing ovarian cancer by age 70 to 18% to 54%
• Increased risk of developing male breast cancer by age 70 to 0.22 to 2.8%

BRCA 2 Mutation     

• Responsible for approximately 25% of hereditary breast cancer
• Increased risk of developing breast cancer by age 70 to 31% to 56%
• Increased risk of developing ovarian cancer by age 70 to 2.4% to 19%
• Increased risk of developing male breast cancer by age 70 to 3.2% to 12%

Pathophysiology

Tumor suppressor genes are integral for normal tissue growth control. These genes encode proteins that function to limit proliferation. However, if the tumor suppressor genes are inactivated by a point mutation, deletion or loss of expression, there is no longer any restraint on tissue growth. Both BRCA1 and BRCA2 are thought to act as tumor suppressor genes. Over the decades, it has been shown that mutations in the BRCA genes can lead to the development of breast, ovarian, prostate and colon cancer. In excess of 100 discrete germline mutations in BRCA1 and BRCA2 have been identified. Over the lifetime, there is a very high penetrance of germline BRCA mutations.

History and Physical

The United States Preventive Service Task Force recommends that primary care physicians evaluate women who are candidates for hereditary cancer genetic testing by inquiring about family history of breast, ovarian, tubal or other cancers during annual examinations. If questioning reveals increased risk, referral to a certified genetic counselor (CGC) for possible testing is indicated (Grade B recommendations). Certified genetic counselors and breast surgeons may also aid in the decision regarding tests for BRCA alone, or for different genetic mutations related to other hereditary cancers [5].

BRCA1 mutations are seen in about 7% of families with multiple breast cancers and in about 40% of families with ovarian and breast cancer. BRCA2 mutations are found in 20% of families at high risk for ovarian and breast cancers but in less than 3% of women with earlt onset breast cancer. Other cancers associated with BRCA2 mutations include:

• Pancreas
• Prostate
• Stomach
• Bile duct
• Gallbladder
• Melanoma

Evaluation

American Society of Breast Surgeons emphasizes the importance of thorough patient history and uses the following criteria (similar to the NCCN guidelines for genetic risk evaluation).

Criteria for testing in patients with a personal history of breast cancer and one or more of the following (from the NCCN and the American Society of Breast Surgeons Consensus Guideline on Hereditary Genetic Testing) [4][5]:

1. Age of onset less than or equal to 50
2. Triple negative tumor (ER-PR-HER2-) and age less than or equal to 60
3. Ashkenazi Jewish heritage and breast cancer at any age
4. Two or more primary breast cancer (either asynchronous, synchronous, bilateral, or multicentric)
5. A first-degree relative with breast cancer diagnosed at age less than or equal to 50
6. Two relatives on the same side of the family with breast cancer and/or pancreatic cancer
7. Family or personal history of ovarian cancer, fallopian cancer, or primary peritoneal cancer
8. Male breast cancer
9. Known mutation carrier in the family

Testing patients who have not been diagnosed with cancer is typically reserved for situations when the affected family member or members cannot be tested. Criteria for testing patients without a personal history of breast cancer but with one or more of the following (from the NCCN and American Society of Breast Surgeons Consensus Guideline on Hereditary Genetic Testing) [5]: 

1. A first-degree or second-degree relative with age onset of breast cancer less than or equal to 45
2. Ashkenazi Jewish heritage and family history of breast cancer at any age
3. Two or more primary breast cancer (either asynchronous, synchronous, bilateral, or multicentric) in a single family member
4. Two or more relatives on the same side of the family with breast and/or pancreatic cancer
5. Family or personal history of ovarian, fallopian, or primary peritoneal cancer
6. Male breast cancer
7. Known mutation carrier in the family

In addition to the above criteria, likelihood or risk assessment models such as the BRCAPRO, BOADICEA, Penn II, and IBIS can also be used to determine whether a patient is at an increased risk for carrying BRCA mutations and thus indicate the need for genetic testing or referral to a genetic counselor or breast surgeon. Though these models estimate the risk of developing breast cancer, no particular test or level of risk determines the need for or against BRCA testing.

Treatment / Management

Surveillance for Patients with BRCA1 and BRCA2 Mutations

An increased level of monitoring is mandatory for all patients with known BRCA mutations. The NCCN guidelines are widely accepted in the management of patients with BRCA mutation. The main goal of monitoring is early detection of malignancy and high-risk premalignant lesions. Early detection begins with breast awareness and self-breast examination beginning at age 18 and annual or semiannual clinical breast examination at age 25 (though neither of these has shown to benefit survival) [5].

Breast MRI increases sensitivity from approximately 33% to approximately 80% sensitivity in the detection of malignancy in patients with a familial or hereditary predisposition and has proven especially useful in this younger subset of patients. According to the NCCN guidelines, annual screening breast MRI with contrast is recommended annually from age 25 to 29 if available, or mammogram annually, if not. From age 30 to 75, annual mammogram and MRI of the breast with contrast is performed [5].

The treatment is personalized for each patient who is found to have a BRCA1 or BRCA2 mutation. This may include increased surveillance only, chemoprevention using tamoxifen or raloxifene, bilateral prophylactic salpingo-oophorectomy and or bilateral prophylactic mastectomy. Bilateral prophylactic mastectomy reduces the risk of developing breast cancer by 90% to 95% [10]. Referral to a breast surgeon for discussion regarding the option of risk-reducing mastectomy is indicated.(A1)

Differential Diagnosis

• Breast abscesses and masses

• Breast cancer

• Breast fibroadenoma imaging

• Ductal carcinoma

• Duct ectasia

• Fibrocystic disease

• Hyalinized fibroadenoma

• Inflammatory carcinoma

• Mastitis

• Papilloma

Prognosis

Patients with BRCA1 and BRCA2 mutation experience worse breast cancer-specific survival when compared to BRCA-negative patients. BRCA1 carriers have a worse overall survival than BRCA2 patients [11].

Studies do show that women who carry BRCA mutations are more likely to develop secondary cancer - either in the same breast or the contralateral breast. For these women, prophylactic bilateral mastectomy is recommended. More important, studies show that women who do undergo surgery are less likely to die from breast cancer compared to women who were treated with unilateral mastectomy.