Familial cancer syndromes - BRCA1 and 2
Description
- Hereditary breast and ovarian cancer syndrome - AD, high-penetrance tumour suppressor genes
- BRCA1 chr 17q21; BRCA2 chr 13q12
Lifetime cancer risk to age 80
| BRCA1 | BRCA2 | Population | |
|---|---|---|---|
| Breast (female) | ~65-72% | ~45-69% | ~12% |
| Contralateral breast @20 yr | ~40% | ~26% | |
| Ovarian/tubal/peritoneal | ~44% | ~17% | ~1.5% |
| Male breast | ~1% | ~7% | 0.1% |
| Prostate | modest inc | inc, aggressive | |
| Pancreas | small inc | ~3-5% | |
| Melanoma | - | small inc |
Tumour phenotype - the discriminator
- BRCA1 -> triple-negative (ER-/PR-/HER2-), high grade, basal-like, younger, medullary features
- BRCA2 -> resembles sporadic: ER-positive, HER2-negative, luminal
- Ovarian: high-grade serous in both
Epidemiology
- Combined carrier frequency ~1:400 in unselected populations
- Ashkenazi Jewish founder mutations ~1:40 - 185delAG and 5382insC (BRCA1), 6174delT (BRCA2)
- Account for ~5-10% of breast and ~15-20% of ovarian cancer
- Other founder populations: Icelandic, Polish, French-Canadian
Aetiopathogenesis
- BRCA1/2 proteins mediate homologous recombination repair of DNA double-strand breaks
- Germline loss of one allele + somatic second hit -> HR deficiency
- -> reliance on error-prone non-homologous end joining -> genomic instability
- Synthetic lethality = the therapeutic principle
- PARP repairs single-strand breaks; PARP inhibition -> unrepaired SSB -> replication-fork collapse -> DSB
- A normal cell repairs it by HR; a BRCA-mutant cell cannot -> selective tumour death
- Biallelic germline BRCA2 -> Fanconi anaemia (FANCD1); biallelic BRCA1 -> a Fanconi-like syndrome
- Reversion mutations restoring HR are the commonest mechanism of PARP inhibitor resistance
Diagnosis
Who to test - refer to a familial cancer service
- Multiple relatives with breast and/or ovarian cancer on the same side
- Breast cancer <40-45 yr; triple-negative breast cancer <=50 yr
- Male breast cancer - test regardless of family history
- Any non-mucinous epithelial ovarian, tubal or primary peritoneal cancer - test all, at any age
- Bilateral breast cancer, or breast + ovarian in the same person
- Ashkenazi Jewish ancestry with any breast/ovarian cancer
- Metastatic or high-risk prostate cancer; pancreatic cancer
- Known familial mutation -> predictive cascade testing
- Test the affected relative first wherever possible - a negative result in an unaffected person is uninformative unless the familial variant is known
The test
- Germline sequencing + MLPA for large rearrangements on blood or saliva
- Usually a multigene panel now (PALB2, TP53, PTEN, CDH1, STK11, ATM, CHEK2, mismatch repair)
- Somatic (tumour) testing also used in ovarian/prostate/pancreatic cancer to guide PARP inhibitors - detects HRD and somatic BRCA
- *Variant of uncertain significance (VUS) must NOT drive management* - manage on family history alone and re-contact as classification changes
Management
A. Surveillance - unaffected carrier
- Breast MRI annually from age 30 (from 25-30 in BRCA1), more sensitive than mammography in dense young breasts
- Add annual mammography from ~40 (or 30 if MRI unavailable)
- Clinical breast examination 6-12 monthly; breast awareness
- No effective ovarian cancer screening - CA-125 + TVUS does NOT reduce mortality and is not recommended as a substitute for surgery
- Prostate: PSA surveillance from 40 in male BRCA2 carriers
- Pancreatic surveillance only within a research protocol / strong family history
B. Risk-reducing surgery - the intervention that works
- Risk-reducing bilateral salpingo-oophorectomy (RRSO)
- BRCA1: age 35-40; BRCA2: age 40-45 (ovarian cancer occurs ~8-10 yr later in BRCA2)
- dec ovarian/tubal cancer risk ~80-90% and all-cause mortality
- Residual primary peritoneal carcinoma risk ~1-4%
- Always send the tubes for SEE-FIM protocol sectioning
- Bilateral risk-reducing mastectomy - dec breast cancer risk >90%
- Choice, not a recommendation - discuss with reconstruction
- HRT after RRSO until ~age 51 in a woman without breast cancer - does not negate the breast-risk reduction of mastectomy and offsets surgical menopause
- Salpingectomy alone with delayed oophorectomy remains investigational
C. Chemoprevention
- Tamoxifen or raloxifene dec ER-positive breast cancer - of less value in BRCA1 (tumours are ER-negative)
- Combined oral contraceptive dec ovarian cancer risk ~50% (small breast risk increase)
D. Treatment of established cancer
- Adjuvant olaparib 1 year in HER2-negative high-risk early breast cancer with a germline BRCA mutation, after chemotherapy (OlympiA: inc iDFS and OS)
- PARP inhibitor maintenance (olaparib, niraparib) after platinum response in high-grade serous ovarian cancer
- Platinum sensitivity - BRCA-mutant tumours respond well
- Metastatic breast: olaparib or talazoparib
- Prostate: olaparib in metastatic castrate-resistant disease with HRR mutation
- Consider bilateral mastectomy rather than breast conservation at the time of a new diagnosis, given contralateral risk
E. Reproductive and family
- 50% transmission - PGD and prenatal diagnosis available
- Fertility preservation before RRSO
- Cascade testing of all first-degree relatives, including men
Associations
- Fanconi anaemia (biallelic BRCA2 / FANCD1)
- Pancreatic adenocarcinoma, gastric and biliary cancer (BRCA2)
- Aggressive prostate cancer (BRCA2 > BRCA1)
- Uveal and cutaneous melanoma (BRCA2)
- Platinum and PARP inhibitor sensitivity
- Other HR genes with overlapping phenotype: PALB2 (breast risk approaching BRCA2), ATM, CHEK2, RAD51C/D, BRIP1 (ovarian)
Natural history & complications
- Risk is age-dependent and cumulative - rises steeply from the mid-30s (BRCA1) and 40s (BRCA2)
- Contralateral breast cancer risk ~2-3%/yr after a first primary - dominates decision-making at diagnosis
- RRSO before 45-50 also reduces breast cancer risk, though the magnitude is debated and smaller than once claimed
- Stage-for-stage breast cancer survival is similar to sporadic disease; ovarian cancer survival is better (platinum sensitivity)
- Psychosocial burden is substantial - surveillance anxiety, body image, surgical menopause, communicating risk to children
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