Cancer Genetics

BRCA1/2

Payal D. Shah

Kenneth Offit

Mark Robson

Biology

Genes: BRCA1 on chromosome 17q, BRCA2 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 BRCA1 187delAG & 5385insC, BRCA2 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; BRCA1 confers 30-50% risk of ovarian CA, 10-30% for BRCA2 carriers
Population differences: Higher prevalence of BRCA Mt in AJ individuals

Clinical Presentation

BRCA1 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 (BRCA2 > BRCA1)
Prognosis: Outcomes of BRCA1 Mt carriers similar to those of sporadic breast CA Pts (J Clin Oncol 2012;30:19)

Pathology

BRCA1-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 <age 60; family member w/known 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 BRCA1/2 & 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

Genetic Testing Outcome & Clinical Significance/Screening Recommendation
Deleterious Mt	Pt is at higher than population risk of CA. Screening as below.
Variant of uncertain significance	Pt may be at higher than population risk of CA. Offer research & individualized recommendations.
No Mt found, known familial Mt	True negative (TN). Pt is at population risk of CA. Screen as per general population guidelines.
No Mt found, no known familial Mt	Uninformative. Pt is at unclear risk of CA. Offer research & individualized recommendations based on family & personal hx.

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 (JAMA 2010;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 BRCA1 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