hereditary breast/ovarian cancer
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
The Genetics Education ProjectThe Genetics Education Project
Hereditary Breast/Ovarian Cancer
Prepared by: June C Carroll MD, CCFP, FCFPSydney G. Frankfort Chair in Family MedicineMount Sinai Hospital, University of Toronto
Andrea Rideout MS, CGC, CCGCCertified Genetic CounsellorProject Manager – The Genetics Education Project
Funded by: Ontario Women’s Health Council
Version: March 2006
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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.
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Outline
Sporadic versus familial cancer Hereditary breast cancer syndromes Referral guidelines Benefits, risks and limitations of genetic
testing Management Cases
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CancerAll 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
EnvironmentalUndiscovered gene mutation ChanceGenerally not eligible for genetic testing
5-10% of breast cancer is hereditary: – Caused by an inherited gene mutation which causes increased risk for
cancerVariety of cancer syndromesAbout 2/3 of these - BRCA 1 or BRCA 2 mutationsMay be eligible for genetic testing
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Proportion of Hereditary Breast Cancer
Sporadic 80%
Familial 10-15%
Hereditary 5-10%
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Knudson ‘two-hit’ Model
Sporadic Cancer
Birth: Two non-mutated copies of the gene
One mutation in one gene; Second gene non-mutated
ONE HIT
(hit=mutation)
SECOND HIT
Two mutations - one in each gene
CANCER
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Knudson ‘two-hit’ Model
Inherited Cancer
Birth: Two 2 non-mutated copies of the BRCA1 gene
One mutation in one BRCA1 gene; One non-mutated copy
SECOND HIT
Two mutations - one in each BRCA1 gene
CANCER
Born with one hit(hit = mutation)
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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
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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 people3 common mutations in Ashkenazi Jews
– Unique French Canadian mutations
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bb Bb
Bb bb Bb bb
Breast Cancer
Affected withbreast cancer
Autosomal Dominant Inheritance
Population Risk
Population Risk
SusceptibleBRCA gene
Unaffected
Legend
B: BRCA gene with mutation
b: normal BRCA gene
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BRCA1 and BRCA2What 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 mutationEstimated Risk in BRCA Mutation
Carriers – by Age 70
In General Population
Breast Cancer ♀BRCA1 & BRCA2
50 - 85% 11%
Ovarian CancerBRCA1
40-60% 1-2%
Ovarian CancerBRCA2
10-20% 1-2%
Breast Cancer ♂BRCA2
6% <1%
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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
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…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 historyLEGEND
Breast cancer
Ovarian cancer
Br Ca
Dx 30
Br Ca
Dx 38
Ov Ca
Dx 40
Ov Ca
Died 48
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
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
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
October 2005
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Results from Genetic Testing
Positive– Deleterious mutation identified
Negative– Interpretation differs if a mutation has previously been
identified in the familyMutation known – true negativeMutation 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 testingPositive test result
Potential Benefits: Clinical intervention may
improve outcome Family members at risk can
be identified Positive health behaviour
can be reinforced Reduction of uncertainty
Potential Risks: 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: Avoidance of unnecessary
clinical interventions Emotional - relief Children can be reassured Avoidance of higher
insurance premiums
Potential Risks: 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: Future research may clarify
test results Positive health behaviour
can be reinforced Some relief Higher insurance premiums
may be avoided
Potential Risks: 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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Normal
Mutation
Case: Rachel’s test results….
Rachel
BRCA1 185delAG
Legend
Breast cancer
Ovarian cancer
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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
WeakEvidence
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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 30-35Symptom 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 salpingo-
oophorectomy (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 CancerUsing the Canadian Cancer Society triage card (below), what
category of risk do the following family histories fit into?
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Case 1
Alz -75
A&W A&W ↑Chol BrCa Dx 61
Colon Ca Dx 76
died 85Aneurysm
A&W
AsthmaA&WYour Patient
Accident MI 80
BrCa Dx 68
Colon
Breast
Legend
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Case 1
Colon
Breast
Legend
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Case 1Answer :
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
Alz -75
A&W A&W ↑Chol Migraines
Stroke -83
A&W
AsthmaA&WYour Patient
Accident MI 85
IDDM
Breast
Legend
Br Ca Dx 41
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Case 2
Breast
Legend
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Case 2Answer:
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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Case 3
Alz -75
A&W OvCa Dx 52 Prost Ca 65 ↑ Chol
Bilateral Breast Ca Dx 49
died 53 Aneurysm
A&W
AsthmaA&WYour Patient
Accident BrCa Dx 75
IDDM
Legend
Prostate
Breast
Ovarian
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Case 3
Legend
Prostate
Breast
Ovarian
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Case 3Answer: 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 3Answer: 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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Case 4
Alz -75
A&W A&W ↑Chol BrCa Dx 71
Colon Ca Dx 76
died 85Aneurysm
A&W
↑CholA&WYour Patient
Accident Breast Ca 85
MI 69
Colon
Breast
Legend
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Case 4
Colon
Breast
Legend
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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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Case 5Legend
Prostate
Breast
Ovarian
Nt Causes -75
A&W Schizophrenic MI 65 ↑ Chol
Died 81 stroke
IDDM
AsthmaA&WYour Patient
OvCa Dx 52
Prost Ca Dx 80
Died 81
BrCa Dx 55
IDDM BrCa Dx 45
Eastern Europe
Ashkenazi JewishIrish / German
Christian
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Case 5
Legend
Prostate
Breast
Ovarian
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Case 5Answer: 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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Case 6
Neck CA
Dx 70
Bladder CA Dx55
A&WHead CA
Dx 65BrCa Dx 61
Bladder CA Dx 58
died 62
A&W
AsthmaA&WYour Patient
Accident MI-84
Diabetes
Bladder
Breast
Head & Neck
Legend
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Case 6
Bladder
Breast
Head & Neck
Legend
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Case 6Answer: 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.
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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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The Genetics Education Project 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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