Hereditary Breast/Ovarian
Cancer
Prepared by:
June C Carroll MD, CCFP, FCFP
Sydney G. Frankfort Chair in Family Medicine
Mount Sinai Hospital, University of Toronto
Andrea Rideout MS, CGC, CCGC
Certified Genetic Counsellor
Project Manager – The Genetics Education Project
Funded by:
Ontario Women’s Health Council
Version: March 2006
The Genetics Education Project
Acknowledgments
 Reviewed by:
– Members of The Genetics Education Project
– Clinical subcommittee of the Ontario Cancer
Genetics Steering Committee
 Funded by:
The Ontario Women’s Health Council
as part of its funding to
The Genetics Education Project
* Health care providers must use their own clinical judgment in
addition to the information presented herein. The authors
assume no responsibility or liability resulting from the use of
information in this presentation.
The Genetics Education Project
Outline

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Sporadic versus familial cancer
Hereditary breast cancer syndromes
Referral guidelines
Benefits, risks and limitations of genetic
testing
 Management
 Cases
The Genetics Education Project
Cancer
All cancer involves changes in genes….
Threshold effect:
 During mitosis & DNA replication
– mutations occur in the cell’s genetic code
 Mutations are normally corrected by DNA repair
mechanisms
 If repair mechanism or cell cycle regulation damaged
– Cell accumulates too many mutations
→ reaches ‘threshold’
→ tumor development
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Sporadic Cancer
 All cancer arises from changes in genes….
– But NOT all cancer is inherited
 Most breast cancer is sporadic ~ 80%
– Due to mutations acquired over a person’s lifetime:
Cause unknown – multifactorial
– Interaction of many factors: age, environment,
lifestyle (obesity, alcohol), chance, unknown factors
– Sporadic cancer generally has a later onset
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Clustering of Cancer in Families
 11% lifetime risk of developing breast cancer
 ~20% of women with breast cancer have a family history:
 10 -15% of breast cancer is familial:
– Due to some factor in the family
Environmental
Undiscovered gene mutation
Chance
Generally not eligible for genetic testing
 5-10% of breast cancer is hereditary:
– Caused by an inherited gene mutation which causes increased risk for
cancer
Variety of cancer syndromes
About 2/3 of these - BRCA 1 or BRCA 2 mutations
May be eligible for genetic testing
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Proportion of Hereditary Breast Cancer
Familial 10-15%
Hereditary 5-10%
Sporadic 80%
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Knudson ‘two-hit’ Model
Sporadic Cancer
ONE HIT
(hit=mutation)
Birth: Two non-mutated
copies of the gene
SECOND
HIT
One mutation in one gene;
Second gene non-mutated
CANCER
Two mutations - one in
each gene
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Knudson ‘two-hit’ Model
Inherited Cancer
Born with one hit
(hit = mutation)
Birth: Two 2 nonmutated copies of the
BRCA1 gene
SECOND
HIT
One mutation in one BRCA1
gene; One non-mutated copy
CANCER
Two mutations - one in
each BRCA1 gene
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Compared to sporadic cancer,
people with hereditary cancer have…
 A higher risk of developing cancer
 A younger age of onset of cancer
– Generally < 50 years of age
 Multiple primary cancers
Hereditary cancer is less common in the
general population than sporadic cancer
The Genetics Education Project
Genes involved in hereditary
breast/ovarian cancer
 > 2,600 mutations in:
– BRCA1- chromosome 17
– BRCA2 - chromosome 13
 Autosomal dominant transmission
 Carrier frequency of BRCA1& 2 mutations
– ~1/800 in general (Caucasian) population
– 1/40 - 1/50 in Ashkenazi Jewish people
3 common mutations in Ashkenazi Jews
– Unique French Canadian mutations
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Autosomal Dominant Inheritance
Legend
Unaffected
Breast Cancer
bb
Bb
Bb
Affected with
breast cancer
bb
Population
Risk
Bb
B: BRCA gene
with mutation
b: normal
BRCA gene
bb
Susceptible
Population
BRCA gene
Risk
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BRCA1 and BRCA2
What happens when their function is
compromised ?
 Both genes are tumor suppressors:
–Regulation of cell growth
–Maintenance of cell cycle
 Mutation leads to:
–Inability to regulate cell death
–Uncontrolled growth, cancer
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Consequences of having a BRCA mutation
Estimated Risk in
BRCA Mutation
Carriers
In General
Population
– by Age 70
Breast Cancer ♀
50 - 85%
11%
40-60%
1-2%
10-20%
1-2%
6%
<1%
BRCA1 & BRCA2
Ovarian Cancer
BRCA1
Ovarian Cancer
BRCA2
Breast Cancer ♂
BRCA2
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Who should be offered referral for genetic
counselling and/or genetic testing?....
 Multiple cases of breast and/or ovarian cancer in
family
– closely related relatives
– more than one generation
– Breast cancer diagnosed at < age 50
 Breast cancer diagnosed at age < 35
 Family member with both breast and ovarian cancers
 Ashkenazi Jewish + relatives with breast or ovarian
cancer
The Genetics Education Project
…Who should be offered referral for
genetic counselling and/or genetic testing?
 Family member with primary cancer in both breasts
 Family member with invasive
serous ovarian cancer
 Male breast cancer
 Family member with an identified with
a BRCA1 or BRCA2 mutation
USPSTF 2005 recommends referral for genetic
counselling and evaluation for BRCA testing to women
with family history indicating increased risk of BRCA
mutations
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Case: Rachel
 Rachel - healthy 40 year old
– Concerned about her risk for cancer
– Family history of both breast & ovarian
cancer
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Case: Rachel’s family history
LEGEND
Breast cancer
Ov Ca
Died 48
Ovarian cancer
Br Ca
Dx 38
Br Ca
Dx 30
Ov Ca
Dx 40
RACHEL,
age 40
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Rachel was referred to genetics…
A genetics consultation involves:
 Detailed family history information
 Pedigree documentation
– Confirmation of cancer history: pathology
reports/death certificates

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
Medical & exposure history
Empiric risk assessment
Hereditary cancer / genetic risk assessment
Psychological assessment
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…A genetics consultation involves:
 Assessment of eligibility for genetic testing
– Estimated risk of a mutation must be ≥10%
– Availability of living affected relative to be tested first
 Discussion of risks, benefits & limitations of test
 Testing and disclosure of genetic test results
– May be months before results are available
 Determining patient’s thoughts about breast cancer
– Motivations for testing
 Screening/management recommendations
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Genetic Testing
 Available at regional genetic centres
– Familial cancer clinics
 Covered by OHIP if criteria are met:
Ontario
US Privative Lab
Full gene testing
$1,200CDN $2,975US
Ashkenazi Panel
$325
$415
Familial mutation
$250
$350
October 2005
 Testing is only offered if the risk of mutation is ≥10%
 Test highest risk affected individual first
 Only in exceptional circumstances will testing be offered to
unaffected individuals
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Results from Genetic Testing
 Positive
– Deleterious mutation identified
 Negative
– Interpretation differs if a mutation has previously been
identified in the family
Mutation known – true negative
Mutation unknown – uninformative
 Variant of unknown significance
– Significance will depend on how variant tracks through
family - i.e. is variant present in people with disease?
– Can use software to predict functional significance
– Check with lab: ? reported previously
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Risks/Benefits/Limitations
of genetic testing
Positive test result
Potential Benefits:
Potential Risks:
 Clinical intervention may
improve outcome
 Family members at risk can
be identified
 Positive health behaviour
can be reinforced
 Reduction of uncertainty
 Adverse psychological reaction
 Family issues/distress
 Uncertainty -incomplete
penetrance
 Insurance/job discrimination
 Confidentiality issues
 Intervention carries risk
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Risks/Benefits/Limitations
of genetic testing?
Negative test result
Potential Benefits:
Potential Risks:
 Avoidance of unnecessary
clinical interventions
 Emotional - relief
 Children can be reassured
 Avoidance of higher
insurance premiums
 Adverse psychological
reaction (i.e. survivor guilt)
 Dysfunctional family
dynamics
 Complacent attitude to
health
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Risks/Benefits/Limitations
of genetic testing?
Uninformative test result
Potential Benefits:
Potential Risks:
 Future research may clarify
test results
 Positive health behaviour
can be reinforced
 Some relief
 Higher insurance premiums
may be avoided
 Continue clinical inventions
which may carry risks
 Complacent attitude to
health
 Uncertainty
 Continued anxiety
 Higher insurance premiums
may not be reduced
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Legend
Breast cancer
Ovarian cancer
Case: Rachel’s test
results….
Rachel
BRCA1 185delAG
Normal
Mutation
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What is the benefit of having genetic testing?
Can anything be done to change risk/outcome?
 Recommendations for BRCA1 and BRCA2
mutation carriers:
– Lifestyle
Reduce dietary fat
Avoid obesity
Reduce alcohol consumption
Regular exercise
Weak
Evidence
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What is the benefit of having genetic testing?
Can anything be done to change risk/outcome?
Recommendations for BRCA1/2 mutation carriers:
– Breast surveillance – “I” recommendation USPSTF 2005
Monthly BSE – unproven
CBE q6 months starting when carrier status identified
Annual mammography starting at age 30
MRI and U/S if surveillance required before age 30
MRI may have higher sensitivity for surveillance of breast
cancer among BRCA mutation carriers
– Studies ongoing
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What is the benefit of having genetic testing?
Can anything be done to change risk/outcome?
 Recommendations for BRCA1/2 mutation carriers:
– Ovarian surveillance
Consider…
– PV exam
– transvaginal ultrasound
– serum CA-125
» q6 months starting age 30-35
Symptom recognition
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Management of Mutation Carriers –
Surgical options: Risk reduction mastectomy
 Hartmann et al. NEJM 1999
– Retrospective study of 639 women with FH of breast cancer
who had bilateral mastectomy (mutation status unknown)
– Expected 37 br ca in 425 women at mod risk (Gail model)
– Observed 4 (90% risk reduction)
– 3 br ca in 214 high risk women with mastectomy (1.4%)
– 156 br ca in 403 sisters without mastectomy – 38.7% (90%
risk reduction)
Meijers-Heijboer et al. NEJM 2001
– 139 BRCA1 and BRCA2 mutation carriers
– No breast cancer after 3 years in 76 with risk-reducing
mastectomy compared with 8 cases of breast cancer in 63
who chose surveillance
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Management of Mutation Carriers –
Surgical options: risk reduction salpingo-oophorectomy
(SO)
 Kauff et al. NEJM 2002
– 170 women with BRCA1 or BRCA2 mutations
– Proportion free from br ca or ovarian ca at 5 years
94% (SO group) vs 69% p=0.006
– Hazard ratio for either cancer after SO: 0.25 (95% CI 0.08-0.74)
 Rebbeck et al. NEJM 2002
– Breast cancer in 21% of SO group / 42% of control (hazard ratio
0.47)
– Hazard ratio for cancer of the coelomic epithelium after SO was
0.04
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Management of Mutation Carriers –
Surgical options: risk reduction salpingooophorectomy (SO)
 Eisen et al. J Clin Oncol 2005
– Study of BRCA carriers who had SO and developed
breast cancer within 15 years
– Breast cancer in 51/1388 (3.5%) SO group / 115/1751
(6.2%) control group
– BRCA1: 56% reduction in breast cancer (OR 0.43, p =
0.00006)
– BRCA2: 46% reduction in breast cancer (OR 0.57, p =
0.11)
 Summary: Consider for mutation carriers
before age 40
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Management of Mutation Carriers Chemoprevention
 Tamoxifen
– Invasive breast ca reduced from 42.5/1000 in placebo group to
24.8/1000 in Tamoxifen group in women at increased risk of
breast cancer
– Tamoxifen Prevention Trial 2005
– May show promise in estrogen +ve tumours associated with
BRCA2
 Raloxifene
– Shows promise - conflicting data
 Aromatase inhibitors – ExCel trial
– Exemestane vs. placebo (Ca Info Service – 1-888-939-3333)
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Management of Mutation Carriers
Consider…
 Psychological support to assist with:
–
–
–
–
Adjusting to new information
Making decisions regarding management
Addressing family issues, self concept
Dealing with future concerns i.e. child bearing,
surgical menopause after oophorectomy
 Stress management
 Support groups
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Management of Mutation Carriers
Consider…
 Additional psychosocial support for those with:
–
–
–
–
–
–
History of depression/anxiety
Poor coping skills
Multiple losses in the family
Loss of parent at a young age
Recent loss
Multiple surgical procedures
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Important messages to share with
women
 Most women will not develop breast cancer
– Of those who do – most will not have a known FH
 For most women – increasing age is the greatest risk
factor
 Great majority of women with FH of breast cancer do
not fall into a high-risk category and do not develop
breast cancer and are not eligible for genetic testing
 Women at increased risk of breast cancer should be
“breast aware”
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Cases
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Assessing the Risk of Hereditary Breast Cancer
Using the Canadian Cancer Society triage card (below), what
category of risk do the following family histories fit into?
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Case 1
Legend
Colon
Breast
Colon Ca Dx 76
died 85Aneurysm
Alz -75
A&W
A&W
Your Patient
↑Chol
A&W
Accident
BrCa Dx 68
A&W
MI 80
BrCa Dx 61
Asthma
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Case 1
Legend
Colon
Breast
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Case 1
Answer :
 Moderate risk for hereditary breast cancer
 Two 1st/2nd degree relatives on the same side of the
family with breast cancer <age 70 or ovarian cancer
at any age
 Management:
– CBE and mammogram q1 years starting at 40
– Discuss lifestyle changes
– Consider enrollment in chemoprevention clinical trials
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Case 2
Legend
Breast
Alz -75
Br Ca Dx 41
A&W
Accident
Stroke -83
A&W
Your Patient
↑Chol
A&W
IDDM
A&W
MI 85
Migraines
Asthma
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Case 2
Legend
Breast
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Case 2
Answer:
 Moderate risk for hereditary breast cancer
 One 1st/2nd degree relative with breast cancer at 35-49
years
 Management:
– CBE and mammogram q1 years staring at 40
– Discuss lifestyle changes
– Consider enrollment in chemoprevention clinical trials
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Legend
Case 3
Prostate
Breast
Ovarian
Alz -75
A&W
Bilateral Breast Ca Dx 49
died 53 Aneurysm
OvCa Dx 52
Prost Ca 65
Your Patient
A&W
Accident
IDDM
A&W
BrCa Dx 75
↑ Chol
Asthma
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Case 3
Legend
Prostate
Breast
Ovarian
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Case 3
Answer:
 High risk for hereditary breast/ovarian cancer
 Two relatives on the same side of the family
with breast cancer <50 or ovarian cancer (any
age)
 One 1st/2nd degree relative with breast cancer:
–
–
–
–
<35 years
Bilateral, first before age 50
Breast and ovarian cancer (any age)
Male breast cancer
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Case 3
Answer: High risk
 Management:
– Offer genetics or familial cancer clinic referral
Pt. agrees: Familial Cancer Clinic will suggest management
Pt. declines: Discuss management with familial cancer clinic
or manage as moderate risk
 Consider chemoprevention, i.e. Tamoxifen
 Referral to psychologist and/or support group
 Discuss: lifestyle changes, enrollment in
chemoprevention clinical trials
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Legend
Case 4
Colon
Breast
Colon Ca Dx 76
died 85Aneurysm
Alz -75
A&W
A&W
Your Patient
↑Chol
A&W
Accident
MI 69
A&W
Breast Ca 85
BrCa Dx 71
↑Chol
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Case 4
Legend
Colon
Breast
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Case 4
 Answer:
 Low risk for hereditary breast cancer
 Meets none of the high or moderate risk
criteria
 Management:
– Clinical breast exam & mammogram q 1-2 years
beginning at age 50
– Discuss lifestyle changes
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Legend
Case 5
Prostate
Breast
Nt Causes -75
A&W
Eastern Europe
Ashkenazi Jewish
Irish / German
Christian
Ovarian
Prost Ca Dx 80
Died 81
Died 81 stroke
Schizophrenic
Your Patient
OvCa Dx 52
MI 65
A&W
IDDM
IDDM
BrCa Dx 55
↑ Chol
BrCa Dx 45
Asthma
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Case 5
Legend
Prostate
Breast
Ovarian
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Case 5
Answer:
 High risk for hereditary breast/ovarian cancer
 3 relatives on the same side of the family breast or
ovarian cancer any age
Management:
 Offer genetics or familial cancer clinic referral
– Agrees: Familial Cancer Clinic will suggest management
– Declines: Discuss management with familial cancer clinic
or manage as moderate risk
 Consider chemoprevention i.e.Tamoxifen
 Discuss: lifestyle changes, enrollment in
chemoprevention clinical trials
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Legend
Case 6
Bladder
Breast
Head & Neck
Neck CA
Dx 70
Bladder CA
Dx55
Bladder CA Dx 58
died 62
A&W
Your Patient
Head CA
Dx 65
A&W
Accident
Diabetes
A&W
MI-84
BrCa Dx 61
Asthma
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Case 6
Legend
Bladder
Breast
Head & Neck
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Case 6
Answer:
 Low risk for hereditary breast cancer
– Meets none of the high or moderate criteria
 Patient’s family worked in a tannery and shoe
factory.
– Aromatic amines (dyes) increase the risk of
bladder cancers
– Shoe manufacturers have an increase risk of nasal
cavity cancers
– The high incidence of cancer is due to common
environment exposures.
The Genetics Education Project
Resources
 The National Cancer Institute: http://cancernet.nci.nih.gov/
– Detailed information on cancer for patients and physicians
including causes, treatments, clinical trials & more
 Canadian Cancer Society: www.cancer.ca
 FORCE: www.facingourrisk.org
 www.hereditarybreastcancer.cancer.ca
– Patient information aid
 Gene Clinics: www.Genetests.org
– See Gene Reviews for clinical summaries
 Where to find a genetics centre:
– www.cagc-accg.ca/centre1.html
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Committee
 June Carroll MD CCFP
 Judith Allanson MD FRCP
FRCP(C) FCCMG FABMG
 Sean Blaine MD CCFP
 Mary Jane Esplen PhD RN
 Sandra Farrell MD FRCPC
FCCMG
 Judy Fiddes
 Gail Graham MD FRCPC
FCCMG
 Jennifer MacKenzie MD
FRCPC FAAP FCCMG
 Wendy Meschino MD FRCPC
FCCMG
 Joanne Miyazaki
 Andrea Rideout MS CGC
CCGC
 Cheryl Shuman MS CGC
 Anne Summers MD FCCMG
FRCPC
 Sherry Taylor PhD FCCMG
 Brenda Wilson BSc MB ChB
MSc MRCP(UK) FFPH
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4. Lightning bolt photo credit:
http://www.ghouli.com/articles/sp/mainstream_4b.htm
The Genetics Education Project
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The Genetics Education Project
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The Genetics Education Project
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The Genetics Education Project
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The Genetics Education Project
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The Genetics Education Project
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The Genetics Education Project
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