Risk of a Second Cancer After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Breast cancer is the most common cancer among women worldwide. However, certain genetic factors increase the risk of a second primary cancer after breast cancer has been treated and the patient has recovered.

A second primary cancer is a new cancer that develops independently of the first cancer in a different tissue or organ.

In particular, pathogenic variants in BRCA1 and BRCA2 make this increase even more pronounced. A pathogenic variant is a change in the structure of a gene that can cause disease, or a mutation.

A large study conducted in England and published on October 29, 2024 in the Journal of Clinical Oncology showed that BRCA1/BRCA2 pathogenic variant carriers have a high risk of a second primary cancer after breast cancer. Its findings emphasize the need for these patients to take steps to prevent a second cancer.

A Study of Subsequent Cancer Risk in BRCA Mutation Carriers

The study involved people diagnosed with breast cancer at NHS Clinical Genetics Centres in England between 1995 and 2019: 25811 women and 480 men. The study investigated the presence of pathogenic variants in BRCA1 and BRCA2 in these individuals. Its findings showed that patients with BRCA variants face a high risk not only of cancer in the opposite breast but also of other cancer types after breast cancer.

A total of 1840 female BRCA1 and 1750 female BRCA2 pathogenic variant carriers were identified.

Comparison of Second Primary Cancer Risks After a Breast Cancer Diagnosis

People with genetic changes in BRCA1 and BRCA2 have, after breast cancer, a higher risk of developing another cancer than people without these changes. Here are some details of this increased risk:

Risks for BRCA1 Carriers:

• Cancer in the Opposite Breast: Women carrying a BRCA1 mutation were found to have approximately 3.6 times the risk of developing a new cancer in the opposite breast compared with noncarriers.
• Ovarian Cancer: These individuals have 33 times the risk of ovarian cancer.
• Other Cancers: BRCA1 carriers have 1.45 times the risk of developing other types of cancer.
• Colorectal Cancer: These individuals also have approximately 2.9 times the risk of bowel cancer.

Risks for BRCA2 Carriers:

• Cancer in the Opposite Breast: People carrying a BRCA2 mutation were found to have 2.4 times the risk of developing cancer in the opposite breast.
• Ovarian Cancer: The risk of ovarian cancer is increased 12-fold.
• Pancreatic Cancer: The risk of pancreatic cancer is approximately 3.6 times that of noncarriers.

Long-Term Cancer Risk: 10-Year Cumulative Rates

The study also provides 10-year cumulative risk rates after breast cancer, illustrating the long-term risk of cancer development:

• BRCA1 Carriers: 16% for the opposite breast, 6.3% for ovarian cancer, and 7.8% for cancers other than breast and ovarian cancer
• BRCA2 Carriers: 12% for the opposite breast, 3% for ovarian cancer, and 6.2% for cancers other than breast and ovarian cancer
• Noncarriers: 3.6% for the opposite breast, 0.4% for ovarian cancer, and 4.9% for cancers other than breast and ovarian cancer

Cancer Risk in Male BRCA2 Carriers

The study also found that male BRCA2 carriers are at risk of second primary cancers. Compared with male noncarriers, male BRCA2 carriers have 13.1 times the risk of cancer in the opposite breast (HR = 13.1, 95% CI = 1.19–1.46) and prostate cancer risk is 5.6 times higher (HR = 5.61, 95% CI = 1.96–16.0).

The Study's Importance and Conclusions

This large study shows that breast cancer patients carrying pathogenic variants in BRCA1 and BRCA2 require careful monitoring not only during post-treatment survivorship but also for other cancers over the long term. After breast cancer, these patients are advised to enter a more intensive screening program in view of their increased risk of cancer in the opposite breast and other cancers, including ovarian, pancreatic, and colorectal cancer.

The researchers stress that BRCA variant carriers are at high risk and should receive closer follow-up with measures aimed at cancer prevention or early diagnosis.