Risk assessment in familial breast cancer

Risk assessment in familial breast cancer

Dr Fiona Lalloo
Consultant in Genetic Medicine
St Mary’s Hospital, Manchester, UK

Risk assessment in familial breast cancer

• Lifetime (10 year) risk of breast cancer
• Likelihood of BRCA1 or BRCA2 mutation

Risk assessment in familial breast cancer

Aims

• Individualised lifetime risk assessment
• Accurate
• Screening, chemoprevention, surgery
• Tool for decision re mutation testing

Risk assessment in familial breast cancer

• Highly penetrant dominant cancer predisposition
syndromes

– BRCA1/2
– Li Fraumeni

• Moderate penetrance syndromes

– CHEK2

• Familial aggregation

Risk assessment in familial breast cancer

• Classical features

– Early age of onset
– Multiple primaries
– May not be site specific

• Three generation family tree

– Remember sex limitation in males with respect to breast
cancer

• Confirm pathology if any doubt

Risk assessment

• Individual risk assessment

– Different models available
– Manual methods
– Computer programmes

Risk Assessment

• Appropriate models

• Gail
– 2852 women with invasive breast cancer and 3146
controls compared for age, FHx, no of biopsies, age at
menarche, first live birth, menopause
– most useful for women with no family history and
regular screening

• Claus
– 3400 women with breast cancer and 3600 controls
– Most valuable for women whose major risk is their
family history

Risk Assessment

• Computer models

• BRCAPRO
– Also calculates likelihood of being a mutation carrier.

• Tyrer-Cuzick
– Based on IBIS studies

• Boadicea
– Estimates the likelihood of detecting BRCA1/2 mutation

Cancers in Cohort

Observed Expected E/O 95%
(O) (E) confidence
intervals
Gail 64 44.3
0.69 0.54-0.90
Claus 64 48.56
0.76 0.59-0.99
Ford 64 42.28
0.66 0.52-0.86
Tyrer-Cusack 64 69.56
1.09 0.85-1.41
Manual 64 77.92
1.22 0.95-1.58









Mutation testing

• NICE guidelines allow NHS mutation screening if
likelihood of mutation 20% or over.

• Use Manchester scoring system for working out if
eligible for mutation screening.

Manchester scoring system

BRCA1 BRCA2
5
FBC<30 6 4
3
FBC 30-39 4 2
1
FBC 40-49 3 8
5
FBC 50-59 2 5
5
FBC>59 1 1
2
MBC <60 5
1
MBC>59 5

Ovarian cancer <60 8

Ovarian cancer >59 5

Pancreatic cancer 0

Prostate cancer 0
<60

Prostate cancer 0

> 59

Pathology BRCA1 adj BRCA2 adj

Her2+ -4 0
0
Lobular -2 0
0
DCIS only -1 0
0
LCIS only -4 0
0
Grade 1 IDC -2 0
0
Grade 2 IDC 0

Grade 3 IDC +2

ER pos -1

ER neg +1

Grade 3 triple neg +4

Mutation testing

• Computer models

– BOADICEA, BRCAPRO, Tyrer-Cusisck, Myriad II

– Antoniou et al
– BOADICEA only model accurately predicting overall

numbers of mutations detected

Antoniou et al, J Med Genet, 2008;44;425-431

Management of high risk women

• Screening

– Mammography
– MRI

• Chemoprevention

– Tamoxifen
– Razor

• Surgery

– Bilateral Risk Reducing mastectomy
– Risk Reducing Bilateral salpingo-oophorectomy

Summary

• Possible to undertake individual risk assessment
• Possible to stratify likelihood of detecting mutation

within a family

• Management options include screening and
preventive surgery