breast cancer genetics dr. ellen warner division of medical oncology motp academic half day october...
TRANSCRIPT
Breast Cancer Genetics
Dr. Ellen Warner
Division of Medical Oncology
MOTP Academic Half Day
October 11, 2011
Genetic Mutations Causing Breast Cancer
• Acquired (90%-95%) External causes Internal causes
• Inherited + Acquired (5%-10%)
Inherited Mutations that Increase Breast Cancer Risk
Penetrance Relative Risk
Genes Frequency
High 5 to 25 BRCA1BRCA2TP53PTENSTK11CDH1
.001
.001rarerarerarerare
Moderate 2 to 4 ATMCHEK2BRIP1PALB2
.003
.004
.003rare
Low 1.1-1.3 19 + 0.25-0.40
HEREDITARY BREAST CANCER: Clinical Presentation
• Autosomal dominant with high penetrance • Young age - often
• Bilateral breast cancer - often
• Epithelial ovarian cancer - often
• Male breast cancer - occasionally
• Jewish ethnicity - raises level of suspicion
HEREDITARY BREAST CANCER: Genes
BRCA1
BRCA2p53
other
PTEN
~ AllBreast-OvaryFamilies
- both highly expressed in breast, ovary, thymus and testis
- levels of both rise during epithelial cell proliferation
- hundreds of inherited mutations in each reported to date
BRCA1 BRCA2
Discovery 1994 1995
Chromosome 17q 13q
Amino acids 1863 3418
Known functions DNA repair Cell cycle arrest
DNA repair ‘
BRCA1 BRCA2
Breast cancer
risk to age 70
55-65% 45%
Males < 1% 7%
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
melanoma - probably
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%
Case : Anna age 38
• R. breast lump• Sister had ca breast age 33
(No other known family history of cancer)• Mammogram normal, very dense breasts• US: suspicious 1.5cm mass• Core biopsy: invasive ca breast• Referred to you for a pre-op consultation
Questions
1) Does Anna qualify for genetic 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
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
Question
2) What does a consultation at a
‘familial cancer / cancer genetics clinic’ involve?
Genetic Assessment
1. Detailed family history (pedigree)2. Risk assessment (familial + non-familial)3. Education (risk factors + genetics 101)4. Pre-test counseling
• Motivation for testing / mental status• Limitations, benefits, risks,• Test procedure and wait time for results• Alternatives to testing• Management options if +ve
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
Question
3) Would there be any point testing Anna if her affected sister had tested negative in 2001?
Genetic Testing
• Predictive testing– Known family mutation– Any result is meaningful
• Genetic screening– No known family mutation– Affected member tested– If no mutation found result is ‘indeterminate’ (~
50% of breast-only high risk families)
Causes of Indeterminate Test
• No BRCA mutation but some other (not testable) gene mutation(s)
• Cancers cluster in family by chance or shared environmental cause
• Phenocopy (sporadic cancer in BRCA family)
• False negative BRCA test
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 / DHPLC
PTT Sequencing / DHPLC
Sensitivity 60-70% (misses: ends, missense, large)
80-90%
(misses large deletions)
Specificity 100% 85 – 90% (benign polymorphisms)
Genetic Testing in Ontario Today
Known family mutation or Ashkenazi JewishSequence appropriate segment of DNA
No known mutation: 1) MLPA – screens for large mutations 2) Direct sequencing or DHPLC Sensitivity – 95% Specificity – 85-90%
Variants of Uncertain 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
Question
4) Is there any rationale for referring Anna for ‘urgent’ genetic testing?
Would finding a mutation change Anna’s treatment:- Local?- Systemic?
BRCA-related Breast Cancer: Local Management
• With breast conservation risk of ipsilateral recurrence low for first 5-10 years
• No evidence for radiation toxicity• Higher risk of contralateral breast cancer• No rationale for ‘prophylactic’ ipsilateral
mastectomy• TRAM flap is ‘once in a lifetime’• Radiation may preclude implants• Breast conservation or bilateral mastectomy are
both reasonable options
10 Year CBC Risk by Age of Diagnosis of 1st Cancer
Age at 1st Breast Cancer
Verhoog 2000
Malone2010
Greaser2009
BRCA1 BRCA1 BRCA2 BRCA1 BRCA2
<40 27% 30% 27% 31% 21%
41-50 52% 16% 15% 11% 13%
51-60 15% 10% 9% 8% 9%
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 ?
PARP Inhibitors
Double-stranded DNA break (chemo)
normal cells
Homologous repair
tumour cellsBRCA
Base excision repair
PARP
XCell Death
BRCA Status should not be used to guide systemic
therapy outside a clinical trial
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
5) Would finding a mutation alter Anna’s post-treatment management?
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
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
Risk-Reducing Mastectomy
• Reduces risk by ~98% if nipple removed• Eliminates need for screening• ~ 25% of unaffected, 50% affected opt for it but
wide variations• Patient satisfaction high if no coercion• No evidence that survival superior to MRI
screening + BSO• Cosmetic result better if done before breast
cancer diagnosis
Risk- Reducing BSO
• Single most important management strategy for BRCA mutation carriers
• ↓ breast cancer risk by 50% to 80% if prior to natural menopausal
• More effective if:– Younger age– BRCA2 vs. BRCA1 ??
• HRT doesn’t lower effectiveness
Does Tamoxifen Prevent Cancer in
Unaffected BRCA1 Mutations Carriers?
Evidence for• Adjuvant studies• Effectiveness of
BSO for BRCA1
Evidence Against• NSABP P-1 study• Bilateral cancers
tend to be concordant for ER
ER Concordance of Bilateral BRCA1-Related Breast Cancers
First ER-ve First ER+ve
Second ER -ve 99 (88%) 13 (54%)
Second ER +ve 13 (12%) 11 (46%)
Weitzel J et al. CEBP 2005
Odds ratio 6.4 p<0.0001
Ongoing Prevention Studies
Post-menopausal women•Letrozole vs. placebo (phase 3, BRCA)•Anastrozole vs. placebo ± BP (phase 3, high risk)
Pre-menopausl women•LHRH agonist + estradiol + testosterone (phase 2, BRCA)•Arzoxifene vs. tam vs. placebo ( phase 2, high risk)•Vitamin D3 vs. placebo (phase 2, high risk)
Any menopausl status
•Contralateral radiation (phase 2, BRCA)
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
Screening for Women with BRCA Mutations
The Ideal• 100% sensitivity• DCIS • invasive 1cm,
node -ve
Mammography• 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
Why should MRI be more sensitive than mammography?
• Contrast agent (Gad –DTPA)
• Tomographic slices (3-D)
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%
False Positive Rates
MRI Mammography
Recalls
- round 1 19% 2%
- round 2+ 9% 2%
Biopsies
- round 1 8% <1%
- round 2+ 3% <1%
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 70
Does MRI screening (+BSO) offer same
survival as mastectomy?
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
Risk- Reducing BSO
• Removing fallopian tubes critical• Ideally by age 40 for BRCA1, 45 for BRCA2• Should be done by gyne oncologist• Can usually be done laparoscopically• HRT afterwards safe• ~ 1% residual risk of primary peritoneal
carcinoma• No indication for post-op screening
Hysterectomy
Advantages
• No need for progesterone if goes on HRT
• No endometrial ca risk if goes on tamoxifen
Disadvantages
• ↑ surgical risk somewhat
• ? Higher risk of bladder problems later
• Psychologcial: Removes yet another female body part
Oral Contraceptives
• ↓ ovarian cancer risk by 50%
• No advantage beyond 5 years
• No ↑ breast cancer risk if taken between ages 25 and 40
Question
6) If neither Anna nor her sister have a BRCA mutation, what is the lifetime cancer risk for their 30 year old sister (never had cancer)?
Lifetime breast cancer risk?
a) Population risk (~ 11%)
b) 15% - 20%
c) 25% - 35%
d) 55% - 65%
e) 70% - 80%
Lifetime ovarian cancer risk?
a) Population risk (1-2%)
b) 5% - 10%
c) 15% - 25%
d) 25% - 40%
e) 40% to 60%
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• Can they avoid transmitting a BRCA
mutation to their children?
