Genetic Testing for Hereditary Breast Cancer-Related Disorders

Criteria for Genetic Testing

• The National Comprehensive Cancer Network recommends genetic testing for individuals with a personal history of breast cancer diagnosed at age ≤45 years 1
• The National Comprehensive Cancer Network suggests genetic testing for individuals with a personal history of breast cancer diagnosed at age ≤50 years with one or more close blood relatives with breast cancer diagnosed at age ≤50 years 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a personal history of breast cancer at any age with one or more close blood relatives with epithelial ovarian/fallopian tube/primary peritoneal cancer 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a personal history of two breast primaries when the first breast cancer diagnosis occurred before age 50 years 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a personal history of breast cancer at any age with two or more close blood relatives with breast and/or epithelial ovarian cancer at any age 1
• The National Comprehensive Cancer Network and the Journal of Clinical Oncology recommend genetic testing for individuals with a personal history of epithelial ovarian/fallopian tube/primary peritoneal cancer 1, 3
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a personal history of male breast cancer 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a close male blood relative with breast cancer 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a first- or second-degree blood relative meeting any of the above criteria 1
• The National Comprehensive Cancer Network recommends genetic testing for individuals with a third-degree blood relative with breast cancer diagnosed at age ≤50 years with two close blood relatives with breast and/or ovarian cancer 1
• The National Comprehensive Cancer Network and the Journal of the National Comprehensive Cancer Network recommend genetic testing for individuals with a family member with a known BRCA1/BRCA2 mutation or other breast cancer susceptibility gene mutation 1, 2
• The Journal of Clinical Oncology and the Annals of Internal Medicine recommend genetic testing for individuals of Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer at any age 3, 4

Benefits of Genetic Testing

• Genetic testing identifies individuals at high risk for developing specific cancers, allowing for enhanced surveillance and early detection, as recommended by the Annals of Oncology and the Journal of Clinical Oncology 5, 6
• The National Comprehensive Cancer Network recommends that genetic testing enables consideration of risk-reducing interventions such as prophylactic mastectomy and/or oophorectomy for mutation carriers 2
• The Journal of Clinical Oncology recommends that genetic testing informs treatment decisions for those already diagnosed with cancer 3
• The Annals of Oncology recommends that genetic testing provides prognostic information and helps guide management decisions 5

Approach to Testing

• The National Comprehensive Cancer Network recommends that initial testing should ideally be performed on an affected family member with the highest likelihood of carrying a mutation 2
• The Annals of Internal Medicine recommends that if no affected family member is available, testing may be performed on an unaffected individual, though interpretation of negative results may be more challenging 4
• The National Comprehensive Cancer Network recommends that for individuals of Ashkenazi Jewish descent, testing for the three common founder mutations should be performed first 2
• The National Comprehensive Cancer Network recommends that if founder mutation testing is negative or the individual has mixed ancestry, full sequence testing should be considered 2
• The Annals of Oncology recommends that when multiple genes could explain an inherited cancer syndrome, multigene panel testing is appropriate and may be more cost-effective 5

Post-Testing Management

• The National Comprehensive Cancer Network recommends that a positive test result should lead to implementation of enhanced screening protocols and consideration of risk-reducing interventions 2
• The National Comprehensive Cancer Network recommends that a variant of uncertain significance should lead to offers of research and individualized recommendations based on personal and family history 2
• The National Comprehensive Cancer Network recommends that a negative test result with a known familial mutation should lead to follow-up with general population screening guidelines 2
• The National Comprehensive Cancer Network and the Annals of Internal Medicine recommend that a negative test result without a known familial mutation should lead to management based on personal and family history risk assessment 2, 4

Important Considerations and Potential Pitfalls

• The Journal of Clinical Oncology and the Annals of Internal Medicine recommend that genetic testing should include pre-test and post-test counseling to discuss risks, benefits, and limitations 3, 4
• The Annals of Oncology recommends that a negative test result does not rule out hereditary cancer risk if the family history remains suggestive 7
• The Annals of Oncology recommends that large genomic rearrangements may not be detected by standard sequencing techniques 7
• The Annals of Oncology recommends that testing sensitivity is not 100%, and other undiscovered genes may contribute to cancer risk 7
• The Journal of Clinical Oncology recommends that family history should be periodically reassessed as new cancer events may occur 6
• The Journal of Clinical Oncology recommends that primary cancer treatment should not be delayed for genetic counseling referral 3