BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Excerpt

Clinical characteristics: BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The risk of developing an associated cancer varies depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.

Diagnosis/testing: The diagnosis of BRCA1- and BRCA2-associated HBOC is established in a proband by identification of a heterozygous germline pathogenic variant in BRCA1 or BRCA2 on molecular genetic testing.

Management: Treatment of manifestations: Treatment of breast cancer per oncologist with consideration of bilateral mastectomy as a primary surgical treatment of breast cancer because of elevated rate of ipsilateral and contralateral breast cancer; PARP inhibitors may be considered in BRCA1- and BRCA2-related tumors. Melanoma treatment per dermatologist and oncologist.

Prevention of primary manifestations: Prophylactic bilateral mastectomy, prophylactic oophorectomy, and chemoprevention (e.g., tamoxifen) have been used for breast cancer prevention, but have not been assessed by randomized trials in high-risk women. Prophylactic salpingectomy followed by delayed oophorectomy or salpingo-oophorectomy for ovarian cancer prevention.

Surveillance: Breast cancer screening in women relies on a combination of monthly breast self-examination, annual or semiannual clinical breast examination, annual mammography, and breast MRI. Annual transvaginal ultrasound and serum CA-125 concentration beginning at age 35 years may be considered for ovarian cancer screening. However, this screening has not been effective in detecting early-stage ovarian cancer, either in high-risk or average-risk women. For men, breast cancer screening includes breast self-examination education and training and annual clinical breast examination beginning at age 35. Annual serum prostate-specific antigen and digital rectal exam screening should begin at age 40 in men heterozygous for a BRCA2 pathogenic variant and should be considered in men heterozygous for a BRCA1 pathogenic variant. Screening for melanoma should be individualized based on the family history. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended.

Evaluation of relatives at risk: Once a cancer-predisposing BRCA1 or BRCA2 germline pathogenic variant has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial pathogenic variant and thus need increased surveillance and specific treatments when a cancer is identified.

Genetic counseling: BRCA1- and BRCA2-associated HBOC is inherited in an autosomal dominant manner. The vast majority of individuals with a BRCA1 or BRCA2 pathogenic variant inherited it from a parent. However, because the penetrance of breast, ovarian, and other cancers associated with pathogenic variants in BRCA1 and BRCA2 is less than 100%, not all individuals with a BRCA1 or BRCA2 pathogenic variant have a parent affected with cancer. The offspring of an individual with a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the pathogenic variant. Once a cancer-predisposing BRCA1 or BRCA2 germline variant has been identified in a family, prenatal and preimplantation genetic testing are possible.