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

http://www.stern.de/_content/50/44/504448/dna_500.jpg

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)

http://www.stern.de/_content/50/44/504448/dna_500.jpg

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%

Does MRI screening improve survival?

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?