What is the significance of a BRCA (Breast Cancer Gene) positive result in breast cancer?

From the Guidelines

BRCA-positive breast cancer significantly increases the risk of developing breast cancer, with lifetime risks of 55-72% for BRCA1 carriers and 45-69% for BRCA2 carriers, and management typically involves more aggressive treatment approaches, including surgery, chemotherapy, and PARP inhibitors, as well as risk-reducing strategies such as prophylactic bilateral mastectomy and salpingo-oophorectomy 1.

Key Points

• BRCA mutations are inherited in an autosomal dominant pattern, meaning each child has a 50% chance of inheriting the mutation 1
• Risk-reducing strategies for unaffected BRCA carriers include prophylactic bilateral mastectomy and salpingo-oophorectomy after childbearing is complete, with a substantial reduction in the risk of breast and ovarian cancer 1
• Enhanced surveillance with alternating mammography and breast MRI every 6 months is recommended for those who decline surgery 1
• PARP inhibitors such as olaparib (300mg twice daily) or talazoparib (1mg daily) are specifically effective in BRCA-mutated breast cancers and may be used in metastatic settings 1

Treatment Approaches

• Standard treatment includes surgery (either breast-conserving surgery with radiation or mastectomy), chemotherapy (often including platinum agents like carboplatin), and for hormone receptor-positive cancers, endocrine therapy 1
• Tamoxifen has been shown to reduce the risk of ER-positive breast cancer in women with an increased risk based on the Gail model, but has not been well studied in women with a known or suspected familial cancer syndrome 1

Risk Reduction

• Risk-reducing salpingo-oophorectomy (RRSO) is recommended by age 35–40, or earlier if either child bearing is complete or there is indication based on the family history, with a substantial reduction in the risk of ovarian cancer and breast cancer if carried out before menopause 1
• Prophylactic mastectomy may also be considered due to the high lifetime cancer risk and increased risk of secondary breast cancers, with discussion of a nipple-sparing approach 1

From the FDA Drug Label

Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious gBRCAm using a clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx® BRCA mutation status [breast cancer susceptibility gene 1 (BRCA1)-positive or breast cancer susceptibility gene 2 (BRCA2)-positive] was similar across both treatment arms.

A BRCA positive result in breast cancer signifies that a patient has a deleterious or suspected deleterious germline BRCA mutation, which is associated with an increased risk of breast cancer. In the context of the EMBRACA study, patients with a BRCA positive result were more likely to benefit from treatment with talazoparib compared to chemotherapy, as demonstrated by a statistically significant improvement in progression-free survival (PFS) 2. This suggests that a BRCA positive result can inform treatment decisions and predict response to certain therapies, such as PARP inhibitors like talazoparib. Key points include:

• BRCA mutation status is a significant factor in breast cancer treatment
• Deleterious or suspected deleterious germline BRCA mutations are associated with increased breast cancer risk
• Talazoparib may be a beneficial treatment option for patients with a BRCA positive result 2

From the Research

Significance of BRCA Positive Result

• A BRCA positive result indicates that an individual has a deleterious mutation in the BRCA1 or BRCA2 tumor suppressor genes, which are the most commonly encountered pathogenic germline variants (PGVs) in breast cancer patients 3.
• Individuals with BRCA1 or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers, with a 50-80% risk of developing breast cancer 4, 5.
• The presence of a BRCA mutation affects the management of breast cancer, with options including risk-reducing interventions such as mastectomy and salpingo-oophorectomy, as well as special treatment regimens like platinum-based chemotherapy and PARP inhibitors 3, 6.

Management Options

• Prophylactic breast surgery, such as bilateral mastectomy, can reduce the risk of breast cancer by over 90% in high-risk patients with BRCA mutations 6.
• Surveillance with multiple modalities is also an option for managing breast cancer risk in BRCA-positive patients, although the decision to undergo surveillance or prophylactic surgery is highly personal and depends on various factors 5.
• Factors that influence the decision to undergo prophylactic mastectomy include having a family member with breast cancer before the age of 50, cancer-related death of a relative younger than 50 years old, and prophylactic oophorectomy before planned mastectomy 5.

Treatment and Prevention

• PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells, and have been shown to improve outcomes in BRCA-mutant, metastatic breast cancer patients 4.
• Risk-reducing strategies, such as chemoprevention and prophylactic surgeries, are standard options for the effective medical management of BRCA mutation carriers 7.
• Personalized management is based on enhanced clinical and radiological monitoring, the use of predictive tools, and surgical options, and must be individualized considering the patient's history, therapeutic needs, and preferences 6.