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Breast Cancer Genetics and Prevention. January 13, 2009. Case: Anna age 38. Recent core biopsy for clinical stage I ca breast Sister had ca breast age 33 BRCA testing done 2001 was normal Referred to you for pre-op consultation. Questions. - PowerPoint PPT Presentation
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Breast Cancer Genetics and Prevention
January 13, 2009
Case: Anna age 38
• Recent core biopsy for clinical stage I ca breast
• Sister had ca breast age 33 – BRCA testing done 2001 was normal
• Referred to you for pre-op consultation
Questions
1) Is there any rationale for referring Anna for genetic testing?
2) If yes, would finding a mutation:- Alter treatment of Anna’s cancer?
- Local?- Systemic?
- Alter her post-treatment management?3) If neither Anna nor her sister have a BRCA
mutation what is their 3rd sister’s risk of breast cancer and how should she be managed?
BREAST CANCER
Familial15%
Sporadic80%
Hereditary5%
‘FAMILIAL’ BREAST CANCER
• less striking family history• no ovarian cancer• often older onset• no BRCA1 or BRCA2 mutation found• likely causes:
– chance– common environmental factors– lower penetrance genes
Lower Penetrance Genes
• CHEK2 1100 delC• ATM carriers• BRIP1 (Nature Genetics, Oct. 2006)
• PALB2 (Nature Genetics Feb. 2007)
• Other ‘cancer genes’? (CDKN2A, HNPCC?)• Not yet isolated:
– breast density gene (s)– carcinogen metabolism genes? – estrogen receptor and metabolism genes?
• CDH –1 (familial gastric cancer)
HEREDITARY BREAST CANCER: Clinical Presentation
• 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
PREVALENCE
• ~5% of all breast cancer
• ~10% of all ovarian cancer
• ~ 1/250 of general population
HEREDITARY BREAST CANCER: Genes
BRCA1
BRCA2p53
other
PTEN
~ AllBreast-OvaryFamilies
- 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
BRCA1 BRCA2 Chromosome 17q 13q
Coding exons 22 27
Amino acids 1863 3418
Known functions Caretaker Gatekeeper
Caretaker ‘
Cell proliferation in breast/ovary, etc.
Loss / inactivation of normal BRCA gene in a cell (chance)= LOH
Use of less accurate DNArepair pathways
Progressive accumulation of mutations
Cancer
Pathogenesis of ‘BRCA Cancer’
BRCA1 BRCA2
Breast cancer
risk to age 70
65% 45%
Males < 1% 6%
Pathology -Little DCIS- 70-80% ‘basal like’
-Similar to sporadic
Ovarian cancer
risk to age 70
25-40% 15-20%
Other cancers
prostate ? yes
pancreas ? yes
cervix ? -
H and N - ?
melanoma - ?
Genetic Counseling
1. Risk assessment (familial + non-familial)2. Education (risk factors + genetics 101)3. Pre-test counseling
• Motivation for testing / mental status• Limitations, benefits, risks,• Test procedure• Alternatives to testing• Management options
Genetic Counseling (contd.)
4. Post-test counseling– Meaning of result reviewed– Patient response assessed– Patient’s plans for sharing results with family
reviewed– Management plan formulated
5. Longitudinal follow-up?– 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’
Main Challenges of Genetic Testing
• Cost (genetic screening) • Availability • > 50% of screening results ‘indeterminate’• Variable ‘natural history’ of mutation carriers• Limitations of current management strategies• Unkown risk with ‘negative’ predictive testing
GENETIC TESTING CRITERIA:Affected Individuals
• 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
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
NormalDNA: CTAGCATGTATAGGG
RNA: CUAGCAUGUAUAGGG
Polypeptide: Leu-Ala-Tyr-Ile-Gl
MutantCTAGCATGAATAGGG
CUAGCAUGCAUAGGG
Leu-Ala-(stop)
Protein gel: Normal proteinTruncated protein
DNA Sequencing
ATCTTAGAGTGTCCC ATCTTAGTGTCCC
Start StartNormal Mutant (185delAG)
A T C G A T C G
PTT vs. Sequencing
PTT Sequencing
Sensitivity 60-70% (misses: ends, missense, large)
80-90%
(misses large deletions)
Specificity 100% 90-95% (benign polymorphisms)
Cost Cheaper More expensive
Genetic Testing in Ontario Today
Known mutation or Ashkenazi JewishSequence appropriate segment of DNA
Unknown mutationFresh blood mRNA cDNA: 1) MLPA – screens for large mutations 2) DHPLC – equivalent to ‘sequencing’ Sensitivity – 95% Specificity – 85-90%
POPULATION vs. FAMILY ASCERTAINMENT
Family studies Populationstudies
Breast cancerrisk by age 70 85% 37%-56%
Ovarian cancerrisk by age 70
40%-60% BRCA125%-40% BRCA2
16%
MANAGEMENT OPTIONS FOR MUTATION CARRIERS
PREVENTION
SCREENING
CA BREAST Mastectomy BSO tamoxifen raloxifene AIs?
BSE CBE Mammogram
MRI
CA OVARY BSO TAH Oral
contraceptives
Transvaginal US
CA 125
X
Prevention
Risk-Reducing Mastectomy
• ‘official’ risk reduction 90% in literature• Likely closer to 100% if total mastectomy• ~ 25% of women with mutations opt for it but
wide variations (counseling, culture, etc.)• Revival of subcutaneous mastectomy?• Reconstruction gives better cosmetic result
than after breast cancer surgery
Salpingo-oophorectomy
• Prevents ovarian & fallopian tube cancer• Lowers breast cancer risk by ~ 50 -80%
- risk reduction greater if surgery earlier- risk reduction not affected by HRT
- works at least as well for BRCA1 as BRCA2• Peritoneal cancer risk likely over-stated• Ideally by age 40 for BRCA1 and age 45 for
BRCA2• TAH is optional
Tamoxifen Benefits
• Invasive cancer & DCIS reduced by 50% in all high risk subgroups including BRCA2
• Effect sustained after tamoxifen stopped• Non-signficant reduction in fractures
BUT• Reduction in ER+ tumours only• No survival benefit to date• No apparent effect on BRCA1 carriers
Tamoxifen Risks
Tamoxifen Placebo
Hot flashes 65% 50%
Vaginal d/c 30% 13%
stroke 0.15% 0.10%
PE 0.7% 0.2%
Endometrial
cancer
1.3% 0.5%
Raloxifene
• Not an agonist in the uterus
• Shorter half-life than tamoxifen
• Not appropriate for pre-menopausal women
NSABP P-2 (STAR)
20,000 women
5 yr. Gail risk 1.66%
postmenopausal
randomized
raloxifenetamoxifen
5 years
Tamoxifen Raloxifene
Invasive cancer
163 167
DCIS 57 81
Uterine cancer 36 23
DVT/PE fewer
fractures same
Oral Contraceptives
• Reduce risk of ovarian cancer by 50%
• Optimal duration is 5 years
• No significant effect on breast cancer risk if taken ages 25 to 40.
Breast Screening
Mammography Screening for Women with BRCA
Mutations
The Ideal• 100% sensitivity• DCIS • invasive 1cm,
node -ve
The Reality• 50% sensitivity• DCIS rarely found• 50% > 1 cm• 40% node +ve
Limitations of Mammographyfor High Risk Screening
• young age = dense breasts
Limitations of Mammographyfor High Risk Screening
• young age = dense breasts
• Faster tumour growth
– Earlier invasion
– Less time for DCIS to calcify
• BRCA1 pathology?
Why should MRI be more sensitive than mammography?
• Contrast agent (Gad –DTPA)
• Tomographic slices (3-D)
Disadvantages of MRI
• $$$• Lower specificity
• Biopsies more difficult
• Logistics
• Claustrophobia
Breast MRI Screening Studiesfor ‘High Familial Risk’ Women
• Interval cancer rate < 10%
• Sensitivity– MRI 71% - 91%– Mammography 23% - 40%– Ultrasound 32% - 40%– CBE 6% - 18%
• Stage distribution more favourable
False Positive Rates
MRI Mammography
Recalls
- round 1 19% 2%
- round 2+ 9% 2%
Biopsies
- round 1 8% <1%
- round 2+ 3% <1%
Evidence for effect of MRI screening on survival
• Cohort studies
• Comparison with historical controls
• Randomized studies
Prospective Cohort Study (CBCRA 2004)
• Women with BRCA mutations
• Screened for breast cancer
• ‘MRI group’ (n=466)
• ‘Control group’ (n=903)
• Median follow-up = 3.3 yrs.
MRI cohort
(n=41)
Controls
(n=69)
Mean age 48 48
DCIS 24% 12%
Invasive
<1cm 58% 33%
≥ 2cm 10% 35%
Node +ve 13% 45%
Stage Distribution of Breast Cancer Cases
Indications for Screening Breast MRI
• 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
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 (alkylators, cisplatin, etc.)
• Taxane resistant?
• PARP inhibitors ?
PARP Inhibitors
• Poly (ADP Ribose) Polymerase • PARP repairs single strand DNA breaks• Inhibition
– leads to more double strand breaks– Non-toxic to normal cells– Works synergistically with cells lacking BRCA1 or
BRCA2 to promote cell death
• Clinical trials in basal-like and/or BRCA tumours are ongoing
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
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
• 2009 ~ normal life expectancy for most women with BRCA mutations
Questions
1) Is there any rationale for referring Anna for genetic testiing?
2) If yes, would finding a mutation:- Alter treatment of Anna’s cancer?
- Local:?- Systemic?
- Alter her post-treatment management?
3) If neither Anna nor her sister have a BRCA mutation what is their 3rd sister’s risk of breast cancer?
