Payal D. Shah, Kenneth Offit, and Mark Robson
Biology
• Genes: BRCA 1 on chromosome 17q, BRCA 2 on 13q
• Function: TSGs; proteins function in double-stranded DNA damage repair by homologous recombination (HR)
• Germline Mt types: Point Mt, small indels, LGRs
• Inheritance: Autosomal dominant
• Ashkenazi Jewish (AJ) Mt: Founder Mt include BRCA 1 187delAG & 5385insC, BRCA 2 6174delT; AJ populations less likely to have LGRs
Epidemiology
• Incidence: ∼5% of all breast CA & 90% of all inherited breast CA attributable to BRCA Mt
• Penetrance: 50–85% risk of BC by age 70; BRCA 1 confers 30–50% risk of ovarian CA, 10–30% for BRCA 2 carriers
• Population differences: Higher prevalence of BRCA Mt in AJ individuals
Clinical Presentation
• BRCA 1 risks conferred: Breast, ovarian, 2nd 1° BC, likely pancreas, possibly others
• BRCA2 risks conferred: Breast, ovarian, 2nd 1° breast, pancreatic, prostate, possibly melanoma, male BC (BRCA 2 > BRCA 1)
• Prognosis: Outcomes of BRCA 1 Mt carriers similar to those of sporadic breast CA Pts (J Clin Oncol 2012;30:19)
Pathology
• BRCA 1-associated breast CA: More likely hormone receptor- & Her2-negative (basal-like subtype, 80%), higher grade; ∼15% medullary carcinomas
• BRCA2-associated breast CA: More varied pathology, spectrum more similar to sporadic CA; more hormone receptor-positive (luminal subtype), lobular carcinomas (Cancer Epidem Biomar 2012;21:134)
• A/w ovarian serous carcinoma
Risk Assessment
• Consider genetic risk evaluation: 2+ breast primaries in 1 individual or in 2 individuals from same side of family; >1 ovarian 1° from the same side of family; self, 1st or 2nd-degree relative w/BC ≤age 45; triple negative BRCA Mt; male BC, BC + BRCA-related malignancies on same side of family; modify criteria for higher risk populations (eg, AJ) (NEJM 2007;357:154)
• Risk assessment models:
• Empirical models: Estimate probability that testing will detect a BRCA1/2 Mt (NCI, Myriad, University of Pennsylvania models)
• Genetic risk models: Estimate Mt carrier probabilities & CA
Risks (BRCAPro, Tyrer-Cuzick, BOADICEA)
• Genetic counseling: Important before genetic testing to ensure that Pt warrants testing, understands benefits as well as risks & potential unanticipated findings from testing; important following testing to guide interpretation, reproductive options
Genetic Testing
• Most commercial testing occurs through Myriad Genetics
• Components: Comprehensive clinical testing includes full sequencing of BRCA 1/2 & testing for specific large genomic rearrangements
• NCCN recommendation is to test all at risk for large genomic rearrangements (LGRs) if negative sequencing
• If AJ & known familial Mt, first test for known familial Mt + AJ founder Mt
• If AJ & no known familial Mt, first test for AJ founder Mt; further testing if negative
Screening
• Self-breast exam: NCCN recommends education & training on SBE beginning age 18 to promote breast self-awareness
• Breast CA screening: CBE q6–12mo beginning age 25, annual mammogram + annual breast MRI beginning age 25 or younger based on earliest onset in affected family member; consider U/S as adjunct to mammography for women w/dense breasts, w/c limits Se of mammography, though questionable utility if performing MRI
• Ovarian CA screening: No definitive evidence supporting screening, but can consider transvaginal U/S + CA-125 q6mo beginning age 30 or earlier depending on earliest onset in family
• Other malignancies (endometrial, prostate, pancreas): Age-appropriate malignancy screening, to be initiated early depending on FHx
• Male carriers: Breast self-exam training & education beginning age 35; CBE q6–12mos beginning age 35; consider mammogram age 40, prostate evaluation starting at 40
• Recommendations for relatives: Encourage genetic counseling & possible genetic testing
Risk Reduction
• Risk-reducing mastectomy: ↓ breast CA risk by ≥90%; recommend discussing w/all known BRCA Mt carriers
• Risk-reducing salpingo-oophorectomy: ↓ ovarian CA risk by 85–90% & breast CA risk by approximately 50% if performed premenopausally; a/w lower all-cause, breast CA-specific, & ovarian CA-specific mortality (JAMA2010;304:967); guidelines recommend RRBSO after completion of child-bearing, ideally between ages 35–40
• Chemoprevention: If risk-reducing medical intervention is desired, can consider tamoxifen, though limited evidence
• Lifestyle measures: Avoid hormone Rx, limit EtOH consumption to maximum of 1 drink daily, weight loss
Treatment
• Surgery: Same as for non-Mt carriers, though may more strongly consider bilateral (risk-reducing) mastectomy during surgical tx
• Chemotherapy: Agents, indications & dosing same as for nonMt carriers; evidence suggests anthracycline/taxane combination w/benefit in BRCA 1 Mt carriers as in sporadic triple-negative carriers; BRCA-associated breast CA may be particularly sensitive to platinum compounds (investigational question)
• PARP inhibitors: Promote synthetic lethality in BRCA-associated breast CA (deficient in homologous repair) (Lancet 2010;376:235); studies pending
• Endocrine Rx: Agents, indications & dosing same as for nonMt carriers
• Her2-targeted Rx: Agents, indications & dosing same as for nonMt carriers