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 2009
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 Presentation
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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 2009
Acknowledgments Reviewed by:
Members of The Genetics Education Project
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.
Outline
Sporadic versus familial cancer Hereditary breast cancer syndromes Referral guidelines Benefits, risks and limitations of genetic
testing Management Cases
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
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: age environment, lifestyle (obesity,
alcohol), chance, unknown factors
Sporadic cancer generally has a later onset
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
Proportion of Hereditary Breast Cancer
Sporadic 80%
Familial 10-15%
Hereditary 5-10%
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
Knudson ‘two-hit’ ModelHereditary 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
Compared to sporadic cancer, people with hereditary cancer have…A higher risk of developing cancerA younger age of onset of cancer
Generally < 50 years of ageMultiple primary cancers
Hereditary cancer is less common in the general population than sporadic cancer
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
~1/500 – 1/1,000 in general (Caucasian) population 1/40 - 1/50 in Ashkenazi Jewish people
3 common mutations in Ashkenazi Jews
Unique French Canadian mutations
bb Bb
Bb bb Bb bb
BRCA mutation
Autosomal Dominant Inheritance
Population Risk
Population Risk
SusceptibleBRCA gene
Normal BRCA genes
Legend
B: BRCA gene with mutation
b: normal BRCA gene
SusceptibleBRCA gene
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 deathUncontrolled growth, cancer
Consequences of having a BRCA mutation:
Estimated cancer risk by age 70
BRCA Mutation Carriers
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% Rare
Who should be offered referral for genetic counselling and/or genetic testing?.... Multiple cases of breast or ovarian cancer on same side
of family, especially in closely related relatives in more than one generation when breast cancer is diagnosed
before age 50 A family member with breast cancer
diagnosed before age 35 A family member with both breast and ovarian cancers An Ashkenazi Jewish heritage, particularly with relatives
with breast or ovarian cancer
…Who should be offered referral for genetic counselling and/or genetic testing?
A family member with primary cancer in both breasts(especially if before age 50)
A family member with ovarian cancer A family member with male breast cancer A family member with an identified
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
Case: Rachel
Rachel - healthy 40 year oldConcerned about her risk for cancerFamily history of both breast & ovarian
cancer
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
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 Psychosocial assessment
Psychological Aspects to Consider Motivation for genetic testing:
Reduce uncertainty
Learn about risk for children
Childbearing/marital decisions
Explore further surveillance/treatment options
Perceived risk
Expectations of genetic testing
Psychological well-being – current & past prior experiences with cancer
prior loss/ disruptions associated with cancer approaching age of parent’s diagnosis or
death from cancer
A genetics consultation involves: Assessment of eligibility for genetic testing
Estimated risk of a mutation must be ≥10%
for most provincial programs Most appropriate family member to test first
Discussion of risks, benefits & limitations of test Testing and disclosure of genetic test results
Will be months before results are available
Discussion of types of results and what they mean
Screening/management recommendations
Genetic Testing Available at regional genetic centres and familial cancer
clinics Covered by provincial insurance plans (i.e. OHIP) if criteria
are met: Ontario US Privative Lab
Full gene testing $1,400CDN $3,120 USD
Ashkenazi Panel $350 $535
Familial mutation $250 $440
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
February 2009
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 to see if reported previously
Risks/Benefits/Limitations of genetic testingPositive test resultPotential 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
Recommendations for BRCA1 and BRCA2 mutation carriers
Breast cancer surveillance- Recommendations from Canadian Hereditary
Cancer Task Force, JOGC 2007BSE – not recommendedCBE – part of surveillance program including imaging Mammography & MRI (if available) q12 months age ≥30MRI (possibly + U/S) if surveillance required before age 30MRI may have higher sensitivity for surveillance of breast
cancer among BRCA1/2 carriers 2008 Meta-analysis: combined mammography and MRI screening
had a 94% sensitivity, 77% specificity (95% CI; p=0.01)
Recommendations for BRCA1 and BRCA2 mutation carriers Ovarian cancer surveillance
- Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007 Surveillance not routinely recommended Women should be counselled on the limitations of
current screening for ovarian cancer If woman chooses surveillance, then consider the
following q6 months starting at age 30-35: pelvic exam transvaginal ultrasound serum CA-125
Symptom recognition
Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007
Potential benefits should be raised with all women with a known mutation.
Multidisciplinary team that includes at least: genetics professional, breast surgeon, plastic surgeon.
Women should have access to: Written and oral information Support services Adequate time for reflection
Breast reconstruction options should be discussed in advance
Management of Mutation Carriers – Surgical options: Risk reduction mastectomy
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 br ca after 3 years in 76 ♀♀ with risk-reducing mastectomy
compared with 8 cases of br ca in 63 who chose surveillance
Management of Mutation Carriers –Surgical options: risk reduction salpingo-oophorectomy (SO)Recommendations from Canadian Hereditary Cancer
Task Force, JOGC 2007 The potential benefits of risk reduction SO should be
discussed with women. Management by multidisciplinary team that includes a
genetics professional 2009 meta-analysis Rebbeck et al.
80% reduction in risk of BRCA 1/2 -associated ovarian/fallopian tube cancer
Hazard ratio 0.21 (95% CI = 0.12-0.39) 50% reduction in risk of breast cancer in BRCA 1/2 mutation
carriers Hazard ratio 0.49 (95% CI = 0.37-0.65)
Optimal age of SO – more study needed
Management of Mutation Carriers - Chemoprevention Tamoxifen Prevention Trial 2005
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
Preliminary data suggest benefit for BRCA2 but not BRCA1 carriers
Raloxifene Shows promise No data for mutation carriers
Aromatase inhibitors – ExCel trial Exemestane vs. placebo (Ca Info Service – 1-888-939-3333) No data for mutation carriers
2007 Canadian Hereditary Cancer Task Force Recommendations: women choosing chemoprevention should be enrolled in a clinical trial
Management of Mutation Carriers Consider… Psychosocial support to assist with:
Adjusting to new information most adjust within 3-6 months subset remain psychologically distressed (16-25% anxiety
and/or depression)
Making decisions regarding management“to inflict surgery is a hard decision to make… when I don’t have the disease and feel healthy”
Addressing family issues, self concept, body image Dealing with future concerns i.e. child bearing,
surgical menopause after oophorectomy
Referral to support groups
Management of Mutation Carriers Consider…
Additional psychosocial support may be needed for high risk individuals such as those with: History of depression/anxiety
Poor coping skills
Inadequate social support / conflict in the family
Multiple losses in the family
Loss of parent at a young age
Recent loss
Multiple surgical procedures
Testing children for BRCA1 and BRCA2 mutations
Benefits and non-harm No medical benefit from genetic testing for children < 18 Potential harm from this information – psychological, insurability, etc.
Autonomy Consider the child’s autonomy and ability to provide informed
consent Parents are not always the decision maker for a child
Privacy/confidentiality Results are available to the parent who may or may not share these
with the child Equity & justice
Access to resources if the genetic status is known vs unknown
Despite focus on hereditary cancers… Most women will not develop breast cancer
Of those who do, most will not have a known family history
Increasing age is the greatest risk factor
Most women with family history of breast ca: do not fall into a high-risk category do not develop breast cancer are not eligible for genetic testing
All women should be “breast aware” and contact their health care providers if any lumps or breast changes are noted.
Cases
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?
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
Case 1
Colon
Breast
Legend
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
Management:CBE and mammogram q1 years starting at 40Discuss lifestyle changes Consider enrollment in chemoprevention
clinical trial
Case 2
Alz -75
A&W A&W ↑Chol Migraines
Stroke -83
A&W
AsthmaA&WYour Patient
Accident MI 85
IDDMBr Ca Dx 41
Breast
Legend
Case 2
Breast
Legend
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 trial
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
Case 3
Legend
Prostate
Breast
Ovarian
Case 3 Answer:
High risk for hereditary breast/ovarian cancer
One 1st/2nd degree relative with:bilateral breast cancer, first one before
age 50ovarian cancer (any age)
Case 3 Answer: High risk Management:
Offer genetics or familial cancer clinic referralPt. agrees: Familial Cancer Clinic will suggest
managementPt. declines: Discuss management with familial
cancer clinic or manage as moderate risk Referral to psychologist and/or support
group Discuss: lifestyle changes, enrollment in
chemoprevention clinical trials
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
Case 4
Colon
Breast
Legend
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 50Discuss lifestyle changes
Case 5
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
Legend
Prostate
Breast
Ovarian
Case 5
Legend
Prostate
Breast
Ovarian
Case 5 Answer: High risk for hereditary breast/ovarian cancer 3 relatives on the same side of the family with
breast or ovarian cancer at 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
Referral to psychologist and/or support group Discuss: lifestyle changes, enrollment in
chemoprevention clinical trials
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
Case 6
Bladder
Breast
Head & Neck
Legend
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 cancersShoe manufacturers have an increase risk of
nasal cavity cancersThe high incidence of cancer is due to
common environment exposures.
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
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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