BRCA

BRCA1 and BRCA2

BRCA1

• Autosomal dominant
  • Mutation in the Breast Cancer Type 1 gene on 17q21
  • Penetrance 80-100%
• Cancer susceptibility gene
  • Regulates gene expression, probably tumour suppressing
  • Mutations generally inactivates the tumour suppressor gene
  • Not all mutations are pathogenic
• 1:800 of population are carriers of mutation
  • Up to 1% in Ashkenazi Jew population
• Risk
  • Cumulative risk of breast cancer
    • 20% at 40
    • 50% at 50
    • 70% at 70
    • 60% risk of Contralateral Ca (higher than non-BRCA Ca)
  • Cumulative risk of ovarian cancer
    • 40-60% at 70
  • Cumulative risk of other cancers
    • Colorectal Ca 6% by age 70
    • Prostate Ca 15-20% by age 70
    • Pancreatic 1-3%
• Accounts for 45% hereditary early onset breast cancer
  • 4-5% of all breast cancers
• Median age of onset 45, frequently bilateral, worse histoprognostic factors
  • More likely to be ER/PR –ve
  • 70% chance of triple negative high grade cancers
  • BUT - No difference in recurrence or death rate c.f. non-BRCA tumours

BRCA2

• Autosomal Dominant
  • Mutation in the Breast Cancer Type 2 gene on 13q12/13
  • Penetrance 80%
• Cancer susceptibility gene
  • Tumour suppressor, mutations inactivate this function
• Accounts for 70% of remaining (non-BRCA1) hereditary breast cancer
• Risk
  • Cumulative risk of breast cancer
    • 45-70% at 70
    • 60% risk of Contralateral Ca (higher than non-BRCA Ca)
  • Cumulative risk of ovarian cancer
    • 10-20% at 70
  • Cumulative risk of other cancers
    • Pancreatic Ca 2-5% by age 70
    • Prostate Ca 30-40% by age 70
    • Male Breast Ca - 80% of inherited (as opposed to BRCA 1)
      • Lifetime Risk: 7%
    • Laryngeal
    • Bladder
• Cancer histological subtypes not as poor as BRCA 1
  • More likely to be ER/PR+

BRCA1 and BRCA2

• Life-time risk of developing Breast Ca 70% (Ovarian Ca 10-40%)
  • Combined CA risk 4% per year
• Incidence of Breast Ca in BRCA carriers is high in pre-menopausal women
  • NB: This approaches the population incidence in post-menopausal women
    • But not so for Ovarian Ca, incidence continues to ↑ from age 40

BRCA1 and BRCA2 Screening

• Age 30-40: Annual MRI +/- USS
• Age 40-50: Annual MRI +/- MMG +/- USS
• Age > 50: Annual MMG +/- USS (Consider MRI if dense breasts)
• For Ovarian Ca
  • Do not offer CA125 or TV USS.
    • Data to show screening improves outcome is lacking.
  • BSO should be done

Cancer type	Lifetime risk to age 70 in carriers*	Lifetime risk to age 70 in general population¶	Comments
Breast (female)	BRCA1: 60-70% BRCA2: 45 to 70%	9%	In most studies, lifetime risk in BRCA1 carriers is higher than that observed in BRCA2 carriers. The incidence of breast cancer diagnosed younger than 50 years of age is higher in BRCA1 carriers compared with BRCA2 carriers, but both groups have an increased risk of premenopausal breast cancer.
Contralateral (opposite) breast (female)	Up to 63% at 25 years postdiagnosis but highly dependent on age at diagnosis of first breast cancer	0.4% annual risk and 10% at 25 years postdiagnosis	Risk is affected by other factors such as tamoxifen use and oophorectomy. Mutation carriers who have had lumpectomy have increased ipsilateral risks over long follow-up periods.
Ovarian	BRCA1: 40 to 60% BRCA2: 10 to 20%	1%	The incidence of ovarian cancer diagnosed younger than 50 years of age is higher in BRCA1 carriers and overall rare in all carriers younger than 40 years old. Risk of fallopian tube cancer is also substantially elevated.
Prostate	BRCA1: Approximately 15 to 20% BRCA2: Approximately 30 to 40%	6% White Americans 10% Black Americans	Risk appears to be higher in BRCA2 carriers and in males younger than 65 years old.
Breast (male)	BRCA1: 0.2 to 1% BRCA2: 2 to 7%	0.1%	Risk before age 50 is very low.
Pancreatic	BRCA1: 1 to 3% BRCA2: 2 to 5%	0.6%
Colon	Not well defined	2%	Studies have not been consistent about whether risk is elevated. If elevated, risk is likely to be small.
Melanoma	Not well defined	Approximately 2% White Americans 0.1% Black Americans	Increased risk for ocular melanoma in BRCA2 carriers.
Other sites	Not well defined	Varied	These sites may include cancer of the stomach, gall bladder, and biliary tree in BRCA2 carriers, as well as uterine serous carcinoma in BRCA1 and BRCA2 carriers.

These risks are estimates based upon review of the literature that focuses on individuals identified based on a positive family history. Risk may differ (ie, may be lower) in individuals with a negative family history, although data are extremely limited. Specific studies have reported risks that are lower or higher than the ranges or estimates quoted; however, the estimates reported here are representative of findings from high-quality studies in BRCA1 and BRCA2 families. Risks will also vary based on an individual’s current age and other risk factors. (Refer to UpToDate topics on cancer risks and management of BRCA1/2 carriers without cancer.)

• Risk to individuals over age 70 is higher, but data are generally unavailable.

Risk reduction surgery

• Risk-Reducing Bilateral Mastectomy - reduces risk in BRCA patients by 90%
  • Skin-Sparing Mastectomy with Preservation of nipple-areola complex + Immediate Reconstruction
  • Greatest benefit of surgery if before age 40
  • No proven survival benefit
  • Should not be encouraged but can be discussed about options to reduce risk
  • Need to emphasize does not reduce risk to 0%
  • Need to be clear on all potential complications, changes to cosmesis and sensation
• Early risk reducing BSO + Peritoneal Lavage –
  • Consider around age 40 once family complete
  • BRCA
    • BRCA 1 – Should be performed by age 35-40
    • BRCA 2 – Can be delayed until age 40-45
  • Reduces risk of ovarian cancer by 80% and mortality by 60%
  • Health Considerations related to Premature Surgical Menopause:
    • Osteoporosis risk
    • Cardiovascular disease
    • Possible cognitive decline
    • Vasomotor symptoms, reduced libido, vaginal dryness, dyspareunia – may not be fully relieved by oestrogen therapy
  • Use of HRT – though unopposed oestrogen HRT seems to carry no increased risk of breast cancer, though long term effects are not known
    • Usually given until age of natural menopause at age 50
  • Consider hysterectomy at the same time - individualised.
    • Risk of uterine cancer low
    • Can give unopposed Estrogen HRT