BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer
Clinical characteristics BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes 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 exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant. Diagnosis/testing The diagnosis of BRCA1 and BRCA2 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: National Comprehensive Cancer Network guidelines suggest that women with a BRCA1/2 pathogenic variant could consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer. Treatment of ovarian and other cancers in individuals with a BRCA1/2 pathogenic variant is similar to that for sporadic cancers. 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 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 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 prostate cancer 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 early intervention when a cancer is identified. Genetic counseling Germline pathogenic variants in BRCA1 and BRCA2 are 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 of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from prophylactic surgery, or early death, not all individuals with a BRCA1 or BRCA2 pathogenic variant have a parent affected with cancer. Offspring of an individual with a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the variant. Prenatal testing is possible for a pregnancy at increased risk if the cancer-predisposing variant in the family is known; however, requests for prenatal testing for adult-onset diseases are uncommon and require careful genetic counseling.