Familial breast cancer

Most cases of breast cancer occur sporadically in people with little to no family history of the condition. They are due to random changes (mutations) that occur only in the cells of the breast. These mutations (called somatic mutations) accumulate during a person's lifetime and are not inherited or passed on to future generations.

Approximately 15-20% of women diagnosed with breast cancer have a significant family history of breast cancer (two or more first- degree or second- degree relatives with breast cancer) but have no identifiable mutation in a gene known to cause a hereditary predisposition to breast cancer. These clusters of breast cancer are likely due to a combination of gene(s) and other shared factors such as environment and lifestyle.

An additional 5-10% of breast cancer is considered "hereditary." These cases are thought to be caused by an inherited predisposition to breast cancer that is passed down through a family in an autosomal dominant manner. In some of these families, the underlying genetic cause is not known. However, many of these cases are part of a hereditary cancer syndrome. The following cancer syndromes are associated with an increased risk of breast cancer and several other types of cancer:

• Hereditary breast and ovarian cancer syndrome due to mutations in the BRCA1 or BRCA2 gene is the most common known cause of hereditary breast cancer
• Cowden syndrome is caused by mutations in PTEN gene
• Li Fraumeni syndrome is caused by mutations in the TP53 gene
• Hereditary Diffuse Gastric Cancer is caused by mutations in the CDH1 gene
• Peutz-Jeghers syndrome is caused by mutations in the STK11 gene

Of note, some research suggests that inherited mutations in several other genes (including CHEK2, BRIP1, ATM, PALB2, RAD51, BARD1, MRE11A, NBN, _and RAD50_) may also be associated with an increased risk for breast cancer. However, the risk associated with many of these genes is not well understood. Most are termed "moderate- or low- penetrant" genes which means that, on their own, they would be expected to have a relatively small effect on breast cancer risk. However, in combination with other genes and/or environmental factors, these genes may lead to a significant risk of breast cancer.

Most cases of breast cancer occur sporadically in people with little to no family history of the condition. However, approximately 5-10% is thought to be inherited in an autosomal dominant manner. In these cases, a person is born with a mutation in a gene known to cause a hereditary predisposition to breast cancer and has a 50% chance with each pregnancy of passing along the mutated gene to his or her child. A person only needs a mutation in one copy of the responsible gene in each cell to have an increased risk for breast cancer. In some cases, a person with familial breast cancer inherits the mutation from a parent who has had or has familial breast cancer. Other cases may result from new (de novo) mutations in the gene.

An additional 15-20% of women who are diagnosed with breast cancer have a significant family history of breast cancer (two or more first- degree or second- degree relatives who have or have had breast cancer) but the cancer follows no clear pattern of inheritance. These cases of breast cancer may be due to inherited gene(s); shared factors such as environment and lifestyle; or a combination of all these factors.

Management of familial breast cancer is generally focused on high-risk cancer screening to allow for early detection and treatment of cancer. In general, the National Comprehensive Cancer Network recommends high- risk breast cancer screening for women who have: (1) a personal and family history suggestive of a hereditary cancer syndrome that is associated with breast cancer or (2) a greater than 20% risk of developing breast cancer in their lifetime based largely on family history. The recommended screening protocol includes:

• Breast awareness and breast self-exams
• Clinical breast exams every 6-12 months beginning at age 30 or individualized based on the earliest breast cancer diagnosis in the family
• Annual mammogram and breast MRI beginning at age 30 or individualized based on the earliest breast cancer diagnosis in the family
• Discussion of other risk reduction strategies such as chemoprevention and/or prophylactic surgeries

If the familial breast cancer is part of a known hereditary cancer syndrome, management will also include screening for the other associated cancers. Please click on the following links for more information regarding the treatment and management of each condition:

• Hereditary Breast and Ovarian Cancer
• Cowden syndrome
• Li Fraumeni syndrome
• Hereditary Diffuse Gastric Cancer
• Peutz-Jeghers syndrome