Breast cancer genetics

Epidemiology

• Associated with 5-10% of all breast cancers, but 25% of cases in women <30yo
• Overall rare (BRCA found in 0.1% of USA population, and up to 1% of Ashkenazi Jews)
• Estimate individual risk of carrying mutation with https://canrisk.org/canrisk_tool/

List of syndromes and associated lifetime cancer risk

• TP53 - 85%
• BRCA 1 and 2 - 70%
• PALB - 55%
• ATM - 50%
• PJS - 45%
• Cowden syndrome - 40%
• CDH1 - 35%
• NF1 - 30%
• CHEK2 - 30%

Specific genes

BRCA

• • Breast CAncer genes
  • Lifetime breast cancer risk 70% for both
  • Overall mortality rates are similar to sporadic breast cancer of same type
  • Tumour suppressor genes which encode proteins that repair dsDNA breaks - Homologous Recombination (HR)
  • Leads to cells with loss of HR repair and therefore general genetic instability. BRCA-mutated cells accumulate other mutations in critical genes, including p53.
    • BRCA1 is also involved with cell-cycle checkpoint regulation, preventing cells with damaged DNA from dividing
  • The genetic risk is transmitted in heterozygotic state, with a second hit occurring and subsequent complete loss of function. Therefore autosomal dominant.
  • There is also a higher risk of DCIS at a younger age than in the general population
  • BRCA1
    • Accounts for about 40% of familial breast cancer
    • Chromosome 17
    • Associated with basal type triple negative cancer, often high-grade (20% of patients with triple negative have BRCA1); however 38% of cancers are other phenotypes
    • 45% lifetime risk of ovarian cancer for carriers - do the oophorectomy by 40
    • Male breast cancer risk 0.2-1.2%
  • BRCA2
    • Accounts for 30% of familial breast cancers
    • Chromosome 13
    • Cancer risks
      • Hormone-sensitive breast cancer
        • Mostly luminal A or B
      • Ovarian/endometrial cancer 20%
        • Do the oophorectomy by 45
      • Male breast cancer (2-7%)
      • Melanoma
      • Pancreatic cancer 2-5%
      • Prostate cancer 30%
  • Treatment options
    • Intense surveillance - MRI encouraged
      • PBS approved MRI annually from age 25 for all BRCA carriers - on the first scan, find and mark the fibroadenomas
      • Baseline mammogram at age 35, then start doing them annually from 40yo
    • Chemoprevention - efficacy unclear, especially with BRCA1, however likely worthwhile especially pre-menopausal, based on retrospective data
    • Breast cancer treatment differences
      • Recommend mastectomy as opposed to BCS + radiotherapy, due to high risk of local recurrence
    • Contralateral prophylactic mastectomy
      • Risk of cancer on the other side is about 25%
      • CPM generally offered to prevent this
    • Bilateral prophylactic mastectomy - highly effective
      • Salpingo-oophorectomy reduces risk of ovarian cancers from 5.8% to 1.1%, and also reduces breast cancer-specific mortality
      • Overall chance of dying of breast cancer is about 10% if no risk-reducing surgery
      • Once that's done, no formal surveillance but keep an eye on it

TP53

• • Accounts for 70% of Li Fraumeni syndrome
  • High risk of breast cancer especially for <30yo women
  • High risk of brain tumours, sarcomas and other malignancies
  • See separate topic

Ataxia telangiectasia (ATM)

• • Moderate-risk: 2-3x

CHEK2

• • Moderate-risk: 15-40%
  • Chromosome 22

PALB2

• • 4-7x risk

CDH1

• • Mutated e-cadherin (same as DHGC)
  • Always lobular cancer
  • See separate topic

RAD51C and RAD51D

• • Preponderance of triple negative cancers

Indications for genetic testing (based on eviQ Australian guidelines)

• Manchester Score can be used to evaluate who gets government funding through PBS - need a score >10, but can also use eviQ criteria
• Known breast/ovarian cancer genetic susceptibility in the family
• Triple negative diagnosed <60yo
• Individual characteristics:
  • Male breast cancer
  • Breast cancer and Jewish ancestry
  • Two primary breast cancers in the same person, where the first occurred at <60yo
  • Breast cancer and another associated cancer in the same person at any age (pancreatic, ovarian, prostate)
  • Breast cancer diagnosed <=40yo
  • Lobular breast cancer AND diffuse-type gastric cancer (in the same person or in the same family)
  • Breast cancer diagnosed <50yo with limited family structure or knowledge
  • Breast cancer and a personal or family history suggestive of:
    • PJS
    • PTEN hamartoma syndrome
    • Li-Fraumeni
    • NF1
• Family characteristics
  • Two first or second-degree relatives with breast or ovarian cancer on the same side of the family, AND:
    • Additional relatives
    • Breast cancer diagnosed <50yo
    • >1 primary breast cancer in the same person
    • Breast and ovarian cancer in the same person
    • Jewish ancestry
    • Male breast cancer
    • Pancreatic cancer
    • High-grade (Gleason 7) or metastatic prostate cancer

iPrevent familial risk assessment tool is the recommended way to assess familial risk in Australia