What is the difference between BRCA1 (Breast Cancer Gene 1) and BRCA2 (Breast Cancer Gene 2) in terms of cancer risk and management for individuals with a known family history of breast or ovarian cancer?

Key Differences Between BRCA1 and BRCA2 Mutations

BRCA1 and BRCA2 mutations both confer high breast cancer risk (65-80% for BRCA1, 45-85% for BRCA2 by age 70), but BRCA1 carriers face substantially higher ovarian cancer risk (37-62% versus 11-23%) and develop more aggressive, triple-negative breast cancers, while BRCA2 is strongly associated with male breast cancer and prostate cancer. 1, 2, 3

Cancer Risk Profiles

Breast Cancer Risk

• BRCA1: 65-80% lifetime risk, with bilateral disease occurring in nearly half of cases 1, 3
• BRCA2: 45-85% lifetime risk, similar magnitude to BRCA1 but with different tumor biology 1, 3
• Both genes account for 5-10% of all breast cancer cases overall 1

Ovarian Cancer Risk

• BRCA1: 37-62% lifetime risk (range 16-63% in earlier estimates), representing the most distinctive difference between the two genes 1, 2, 3
• BRCA2: 11-23% lifetime risk, substantially lower than BRCA1 1, 2, 3
• After breast cancer diagnosis, 15-year ovarian cancer risk remains 12.2% for BRCA1 versus only 2.0% for BRCA2 4

Male Breast Cancer

• BRCA2: 5-10% lifetime risk, making male breast cancer a hallmark clinical feature suggesting BRCA2 mutation 1, 2, 5
• BRCA1: Lower risk than BRCA2, though still elevated above population baseline 2
• Male breast cancer with family history of breast/ovarian cancer is a specific criterion for BRCA testing 1, 5

Other Cancer Risks

• BRCA1: Increased colorectal cancer risk (4-fold), prostate cancer (29% cumulative lifetime risk) 1, 2
• BRCA2: Elevated pancreatic cancer risk (up to 2%), prostate cancer (60% cumulative lifetime risk—notably higher than BRCA1), stomach, and head/neck cancers 1, 2

Tumor Biology and Pathology

BRCA1-Associated Breast Cancers

• Triple-negative phenotype: Predominantly estrogen-receptor negative, progesterone-receptor negative, and HER-2 negative 1, 3
• Basal-like subtype: High histologic grade (grade 2-3), with basal epithelial features on immunohistochemical profiling 1, 3
• Medullary features: 13% show medullary or atypical medullary histology (versus 1-3% in sporadic cases), with pushing tumor margins and tumor-infiltrating lymphocytes 1
• Prognosis: May have worse outcomes than BRCA2 or sporadic breast cancers of similar stage 1

BRCA2-Associated Breast Cancers

• Hormone receptor positive: Up to 80% are estrogen-receptor positive, more closely resembling sporadic tumors 1, 3
• High grade: Typically grade 2-3, but less distinctive pathologically than BRCA1 tumors 1
• Prognosis: May have slightly better outcomes than BRCA1-associated cancers 1

Clinical Recognition Patterns

Family History Clues

• BRCA1 mutation: Occurrence of both breast AND ovarian cancers within the same family or individual strongly suggests BRCA1 1
• BRCA2 mutation: Male breast cancer in the pedigree is the hallmark feature 1, 5
• Both genes: Early age at onset, bilateral breast cancer, multiple affected family members across generations 1

Management Implications

Surveillance Differences

• Both require intensive screening: monthly self-examination, clinical breast exam twice yearly, annual mammography and MRI starting age 25-30 1
• BRCA1 carriers: Given the 37-62% ovarian cancer risk, risk-reducing salpingo-oophorectomy is particularly critical and reduces both breast and ovarian cancer risk by 75% 2
• BRCA2 carriers: While ovarian cancer risk is lower (11-23%), prophylactic oophorectomy is still recommended given poor ovarian cancer prognosis 1, 4

Treatment Considerations

• BRCA1 tumors: Despite being predominantly ER-negative, adjuvant tamoxifen reduces contralateral breast cancer risk by 50% 1
• DNA repair deficiency: Both BRCA1 and BRCA2 null cells show increased sensitivity to platinum-based chemotherapy and DNA cross-linking agents due to impaired double-strand DNA break repair 1, 6, 7
• Contralateral breast cancer risk reaches 40% within 10 years of initial diagnosis for both genes 1

Population-Specific Mutations

• Ashkenazi Jewish population has three founder mutations: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2, with prevalence of 1/50 versus 1/800-1/1000 in general population 1, 3

Critical Pitfalls

• Do not assume low ovarian cancer risk in BRCA2: While lower than BRCA1 (11-23% versus 37-62%), this still represents substantial elevation requiring prophylactic surgery 1, 2, 3
• Do not withhold tamoxifen from BRCA1 carriers: Despite ER-negative primary tumors, tamoxifen significantly reduces contralateral breast cancer 1
• Male relatives matter: BRCA2 confers 5-10% male breast cancer risk and 60% prostate cancer risk, requiring cascade testing and surveillance 2, 5
• Negative testing does not eliminate risk: Over 70% of familial breast cancer remains genetically unexplained; strong family history warrants continued high-risk surveillance regardless of BRCA1/2 results 1, 3