Transcript Breast cancer - Medical Oncology at University of Toronto

Breast Genetics
Dr. Ellen Warner
Division of Medical Oncology
MOTP Academic Half Day
February 11, 2011
All cancers are caused by
genetic alterations!
• acquired
• Inherited + acquired
Causes of Breast Cancer
• Acquired gene abnormalities
– External causes (radiation, HRT, alcohol, etc.)
– Internal causes (reproductive, obesity,
random DNA repair errors, etc.)
• Inherited gene abnormalities (+ acquired)
Inherited Breast Cancer
Predisposition Genes
Penetrance
High
Genes
Frequency
Relative
Risk
5 to 25
BRCA1,
BRCA2
TP53
PTEN
STK11
CDH1
..001
.001
Rare
Rare
Rare
rare
Moderate
ATM
CHEK2
BRIP1
PALB2
.003
.004
.003
rare
2 to 4
Low
10 so far
0.25-040
1.1-1.3
Finding High Penetrance
Genes
• Collect very large, very high risk families
• Identify chromosome (using markers)
common to affected individuals in a
specific family (= linkage)
• Study multiple families with same
chromosome linkage to localize specific
area on chromosome until gene found
Search for Lower
Penetrance Genes
• Target probable pathways
– Hormone (synthesis, binding, metabolism,
receptor)
– DNA repair
– Cell cycle control
• Compare to unaffected women or
general population
Genome-Wide Association
Studies (GWAS)
• Screen multiple breast cancer cases for
SNPs
• Compare frequency to that of general
population
• Varies by region, race, etc.
• Difficult to localize to specific gene
HEREDITARY BREAST CANCER:
Clinical Presentation
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Autosomal dominant with high penetrance
Young age
Bilateral breast cancer
Epithelial ovarian cancer
Male breast cancer
(certain ethnic groups)
Hereditary Breast Cancer:
History
• 1866 Broca: 1st description
• 1970’s: Lynch: 3 breast /breast-ovary families
• 1990: linkage to chromosome 17
• 1994: BRCA1 localized on chromosome 17
• 1995: BRCA2 localized on chromosome 13
HEREDITARY BREAST CANCER:
Genes
BRCA1
~ All
BreastOvary
Families
other
PTEN
p53
BRCA2
BRCA1
BRCA2
Chromosome
17q
13q
Coding exons
22
27
Amino acids
1863
3418
Known functions
Caretaker
Gatekeeper
Caretaker
‘
- both highly expressed in breast, ovary, thymus and testis
- both involved in repair of double-stranded DNA breaks
- levels of both rise during epithelial cell proliferation
Pathogenesis of ‘BRCA Cancer’
Cell proliferation in breast/ovary, etc.
Loss / inactivation of normal
BRCA gene in a cell (chance)= LOH
Use of less accurate DNA
repair pathways
Progressive accumulation of mutations
Cancer
BRCA1
BRCA2
65%
45%
< 1%
6%
-Little DCIS
- 70-80% ‘basal like’
-Similar to sporadic
25-40%
15-20%
prostate
?
yes
pancreas
?
yes
cervix
?
-
H and N
-
?
melanoma
-
?
Breast cancer
risk to age 70
Males
Pathology
Ovarian cancer
risk to age 70
Other cancers
POPULATION vs. FAMILY
ASCERTAINMENT
Family studies
Population
studies
Breast cancer
risk by age 70
85%
37%-56%
Ovarian cancer
risk by age 70
40%-60% BRCA1
25%-40% BRCA2
16%
Genetic Assessment
1. Detailed family history (pedigree)
2. Risk assessment (familial + nonfamilial)
3. Education (risk factors + genetics 101)
4. Pre-test counseling
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Motivation for testing / mental status
Limitations, benefits, risks,
Test procedure
Alternatives to testing
Management options
Genetic Counseling (contd.)
4. Post-test counseling
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Meaning of result reviewed
Patient response assessed
Patient’s plans for sharing results with family
reviewed
Management plan formulated
5. Longitudinal follow-up?
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Promote compliance with management plan
Psychological support
Update new developments
Genetic Testing
• Predictive testing
– Known family mutation
– Any result is meaningful
• Genetic screening
– No known family mutation
– If no mutation found result is ‘indeterminate’
METHODS OF GENETIC
TESTING
• Protein Truncation Test (PTT)
• Gene Sequencing
• Denaturing High Performance Liquid
Chromatography (DHPLC)
• Multiplex Ligation Dependent Probe
Amplification (MLPA)
• other
Protein Truncation Test
Normal
DNA:
Mutant
CTAGCATGTATAGGG

RNA: CUAGCAUGUAUAGGG

Polypeptide: Leu-Ala-Tyr-Ile-Gl
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Protein gel:
CTAGCATGAATAGGG

CUAGCAUGCAUAGGG

Leu-Ala-(stop)

Normal protein
Truncated protein
DNA Sequencing
ATCTTAGAGTGTCCC
A
T
C
G
Start
Normal
ATCTTAGTGTCCC
A
T
C
G
Start
Mutant (185delAG)
PTT vs. Sequencing
PTT
Sensitivity
Specificity
Cost
Sequencing
60-70%
80-90%
(misses: ends,
(misses large
missense, large) deletions)
100%
90-95% (benign
polymorphisms)
Cheaper
More expensive
Genetic Testing in Ontario Today
Known mutation or Ashkenazi Jewish
Sequence appropriate segment of DNA
Unknown mutation
Fresh blood  DNA:
1) MLPA – screens for large mutations
2) Direct sequencing or DHPLC
Sensitivity – 95%
Specificity – 85-90%
Variants of Undetermined
Significance (VUS)
• 10-15% of all testing today
• Huge problem for all
• Need to check database regularly
– Some upgraded to detrimental
– Some downgraded to benign
• Manage as ‘indeterminate’ test
Other Challenges of
Genetic Testing
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Cost (genetic screening)
Delay of getting results
Availability
> 50% of screening results ‘indeterminate’
Variable ‘natural history’ of mutation carriers
Limitations of current management strategies
Unknown risk with ‘negative’ predictive
testing
Case #1: Anna age 38
• Recent core biopsy for clinical stage I
ca breast
• Sister had ca breast age 33
• Referred to you for ‘routine’ pre-op
consultation
Questions
1) Does Anna qualify for genetic testing?
GENETIC TESTING CRITERIA:
Affected Individuals
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Breast cancer < age 35
Jewish and breast cancer < age 50
Bilateral breast ca, first < age 50
Male breast cancer
Epithelial ovarian cancer any age
2+ close relatives (including self) & any combination of
– Breast cancer < age 50
– Ovarian cancer
– Male breast cancer
– Jewish and breast / ovarian cancer any age
• 3+ close relatives with breast / ovarian cancer
GENETIC TESTING CRITERIA:
Affected Individuals
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Breast cancer < age 35
Jewish and breast cancer < age 50
Bilateral breast ca, first < age 50
Male breast cancer
Epithelial ovarian cancer any age
2+ close relatives (including self) & any combination of
– Breast cancer < age 50
– Ovarian cancer
– Male breast cancer
– Jewish and breast / ovarian cancer any age
• 3+ close relatives with breast / ovarian cancer
Questions
2) Is there any rationale for referring
Anna for ‘urgent’ genetic testing?
Would finding a mutation alter Anna’s
treatment:
- Local?
- Systemic?
BRCA-related Breast Cancer:
Local Management
• With breast conservation risk of ipsilateral
recurrence low for first 5-10 years
• Higher risk of contralateral breast cancer
• No evidence for  radiation toxicity
• No rationale for ‘prophylactic’ ipsilateral
mastectomy
• TRAM flap is ‘once in a lifetime’
• Caveat: radiation may preclude implants
• Breast conservation or bilateral mastectomy are
both reasonable options
BRCA-related Breast Cancer:
Systemic Management
• Prognosis similar to non-BRCA with
similar age, stage, grade
• Faster doubling time
• May be more responsive to DNA x-linking
chemotherapy (cisplatin, carboplatin,etc.)
• Taxane resistant?
• Adriamycin resistant?
• PARP inhibitors ?
Poly (ADP Ribose) Polymerase
(PARP) Inhibitors
• To repair double-strand DNA breaks in
BRCA-deficient cell:
– |normal cells use homologous recombination
– BRCA-related tumours use less accurate
methods of base excision repair
• PARP necessary for base excision repair
• PARP Inhibition → cell death
• Should work synergistically with platinum
agents
• Clinical trials in metastatic basal-like and/or
BRCA tumours show promising results
• Resistance still a problem
Expedited Genetic Testing
• 8 weeks (vs. 10 months)
Criteria
1) Patient considering bilateral
mastectomy instead of radiotherapy
2) Patient needs semi-urgent pelvic
surgery eg. hysterectomy for bleeding
Questions
3) Would finding a mutation alter Anna’s
post-treatment management?
Questions
4) Would there be any point testing Anna
if her affected sister had tested
negative in 2001?
Questions
5) If neither Anna nor her sister have a
BRCA mutation what is their 3rd
sister's lifetime risk of:
- breast cancer?
- ovarian cancer ?
Questions
6) If Anna and her 2 sisters all have a
BRCA mutation: what are the
management options for her
unaffected sister?
MANAGEMENT OPTIONS FOR
MUTATION CARRIERS
PREVENTION
CA BREAST
CA OVARY
 Mastectomy
 BSO
 tamoxifen
 raloxifene
 AIs?
SCREENING
 BSE
 CBE
 Mammogram
 MRI
 Transvaginal
 BSO  TAH
US
 Oral
contraceptives  CA 125
X
Breast Screening
Screening for Women with
BRCA Mutations
The Ideal
• 100% sensitivity
• DCIS
• invasive  1cm,
node -ve
Mammography
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50% sensitivity
DCIS rarely found
50% > 1 cm
40% node +ve
Limitations of Mammography
for High Risk Screening
• young age = dense breasts
Limitations of Mammography
for High Risk Screening
• young age = dense breasts
• Faster tumour growth
Why should MRI be more sensitive
than mammography?
• Contrast agent (Gad –DTPA)
• Tomographic slices (3-D)
Disadvantages of MRI
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$$$
Lower specificity
Biopsies more difficult
Logistics
Claustrophobia
Breast MRI Screening Studies
for ‘High Familial Risk’ Women
• Interval cancer rate < 10%
• Sensitivity
– MRI
– Mammography
– Ultrasound
– CBE
71% - 91%
23% - 40%
32% - 40%
6% - 18%
False Positive Rates
MRI
Mammography
19%
2%
9%
2%
8%
3%
<1%
<1%
Recalls
- round 1
- round 2+
Biopsies
- round 1
- round 2+
Indications for Screening
Breast MRI (ACS 2007)
• Known BRCA mutation
• Untested 1st degree relative of BRCA
mutation carrier
• Untested/ no family mutation but > 20%
lifetime risk (BRACPRO, BOADICEA)
• (Chest irradiation < age 30, at least 8 yrs.
post treatment)
MRI Screening Protocol
• Annually with mammography (or
staggered q 6months)
• Start age 30
• Reasonable to stop age 65-69
Does MRI screening
improve survival?
Evidence for effect of MRI
screening on survival
• Randomized studies
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Cohort studies
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Comparison with historical controls
Case #2, Jennifer
• Age 25, Jewish, obs/gyn resident
• Recently married
• Husband’s mother died age 45 of ca
ovary
• Husband tests positive for BRCA1
mutation
• Recommendations? Options?
Hereditary Breast Cancer:
History
• 1866 Broca: 1st description
• 1980’s: genetic studies
• 1990: linkage to chromosome 17
• 1994: BRCA1 localized on chromosome 17
• 1995: BRCA2 localized on chromosome 13
• 2011 ~ normal life expectancy for most
women with BRCA mutations
Thank-you for your
attention.
Familial Risk