Breast Cancer Genetics Dr. Ellen Warner Division of Medical Oncology MOTP Academic Half Day October 11, 2011.

Breast Cancer Genetics

Dr. Ellen Warner

Division of Medical Oncology

MOTP Academic Half Day

October 11, 2011

All cancers are caused by genetic mutations!

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

Pierre Paul Broca 1824-1880

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

TRAM flap reconstruction

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

Should I remove my uterus too?

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?

Pre-implantations Genetic Diagnosis

Thank-you for your attention.