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 45. 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 have 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.
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