Hereditary Breast/Ovarian Cancer

1
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 Womens Health Council
• Version March 2009

2
Acknowledgments

• Reviewed by
• Members of The Genetics Education Project
• Funded by The Ontario Womens 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.

3
Outline

• Sporadic versus familial cancer
• Hereditary breast cancer syndromes
• Referral guidelines
• Benefits, risks and limitations of genetic
  testing
• Management
• Cases

4
Cancer

• All cancer involves changes in genes.
• Threshold effect
• During mitosis DNA replication
• mutations occur in the cells 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

5
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 persons
  lifetime
• Cause unknown multifactorial
• Interaction of age environment, lifestyle
  (obesity, alcohol), chance, unknown factors
• Sporadic cancer generally has a later onset

6
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

7
Proportion of Hereditary Breast Cancer
Familial 10-15 Hereditary 5-10
Sporadic 80
8
Knudson two-hit Model Sporadic Cancer
ONE HIT (hitmutation)
Birth Two non-mutated copies of the gene
SECOND HIT
One mutation in one gene Second gene non-mutated
Two mutations - one in each gene
CANCER
9
Knudson two-hit Model Hereditary Cancer
ONE HIT (hitmutation)
Birth Two non-mutated copies of the gene
SECOND HIT
One mutation in one gene Second gene non-mutated
Two mutations - one in each gene
CANCER
10
Compared to sporadic cancer, people with
hereditary cancer have

• A higher risk of developing cancer
• A younger age of onset of cancer
• Generally lt 50 years of age
• Multiple primary cancers
• Hereditary cancer is less common in the general
  population than sporadic cancer

11
Genes involved in hereditary breast/ovarian cancer

• gt 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

12
Autosomal Dominant Inheritance

• Legend
• B BRCA gene with mutation
• b normal BRCA gene

BRCA mutation
Normal BRCA genes
bb
Bb
bb
Bb
Bb
bb
Population Risk
Population Risk
Susceptible BRCA gene
Susceptible BRCA gene
13
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

14
Consequences of having a BRCA mutationEstimated
cancer risk by age 70
BRCA Mutation Carriers In General Population
Breast Cancer ? BRCA1 BRCA2 50-85 11
Ovarian Cancer BRCA1 40-60 1-2
Ovarian Cancer BRCA2 10-20 1-2
Breast Cancer ? BRCA2 6 Rare
15
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

16
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

17
Case Rachel

• Rachel - healthy 40 year old
• Concerned about her risk for cancer
• Family history of both breast ovarian cancer

18
Case Rachels family history
Ov Ca Died 48
Br Ca Dx 38
Ov Ca Dx 40
RACHEL age 40
Br Ca Dx 30
19
Rachel was referred to geneticsA 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

20
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 parents diagnosis or
• death from cancer

21
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

22
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
February 2009

• 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

23
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

24
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

25
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

26
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 interventions which may carry
  risks
• Complacent attitude to health
• Uncertainty
• Continued anxiety
• Higher insurance premiums may not be reduced

27
Case Rachels test results.
Rachel BRCA1 185delAG
Normal
Mutation
28
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
29
Recommendations for BRCA1 and BRCA2 mutation
carriers

• Breast cancer surveillance
• - Recommendations from Canadian Hereditary
  Cancer Task Force, JOGC 2007
• BSE not recommended
• CBE part of surveillance program including
  imaging
• Mammography MRI (if available) q12 months age
  30
• MRI (possibly U/S) if surveillance required
  before age 30
• MRI 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 p0.01)

30
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

31
Management of Mutation Carriers Surgical
options Risk reduction mastectomy

• 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

32
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

33
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

34
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

35
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 dont 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

36
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

37
Testing children for BRCA1 and BRCA2 mutations

• Benefits and non-harm
• No medical benefit from genetic testing for
  children lt 18
• Potential harm from this information
  psychological, insurability, etc.
• Autonomy
• Consider the childs 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

38
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.

39
Cases
40
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?
41
Case 1
Colon Ca Dx 76 died 85Aneurysm
Accident
MI 80
Alz -75
?Chol
BrCa Dx 61
AW
BrCa Dx 68
AW
AW
Asthma
AW
Your Patient
42
Case 1
43
Case 1 Answer

• Moderate risk for hereditary breast cancer
• Two 1st/2nd degree relatives on the
• same side of the family with breast cancer lt age
  70
• Management
• CBE and mammogram q1 years starting at 40
• Discuss lifestyle changes
• Consider enrollment in chemoprevention clinical
  trial

44
Case 2
Accident
MI 85
Alz -75
Stroke -83
?Chol
AW
IDDM
AW
AW
Migraines
Br Ca Dx 41
Asthma
AW
Your Patient
45
Case 2
46
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

47
Case 3
Bilateral Breast Ca Dx 49 died 53 Aneurysm
Accident
BrCa Dx 75
Alz -75
Prost Ca 65
AW
IDDM
AW
OvCa Dx 52
? Chol
Asthma
AW
Your Patient
48
Case 3
49
Case 3 Answer

• High risk for hereditary breast/ovarian cancer
• One 1st/2nd degree relative with
• bilateral breast cancer, first one before age 50
• ovarian cancer (any age)

50
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
• Referral to psychologist and/or support group
• Discuss lifestyle changes, enrollment in
  chemoprevention clinical trials

51
Case 4
Colon Ca Dx 76 died 85Aneurysm
Accident
Breast Ca 85
Alz -75
?Chol
MI 69
AW
AW
BrCa Dx 71
AW
?Chol
AW
Your Patient
52
Case 4
53
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

54
Case 5
Eastern Europe Ashkenazi Jewish
Irish / German Christian
Prost Ca Dx 80 Died 81
BrCa Dx 55
Nt Causes -75
Died 81 stroke
MI 65
IDDM
IDDM
AW
Schizophrenic
? Chol
BrCa Dx 45
Asthma
AW
Your Patient OvCa Dx 52
55
Case 5
56
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

57
Case 6
Neck CA Dx 70
Bladder CA Dx 58 died 62
Accident
MI-84
Head CA Dx 65
BrCa Dx 61
AW
Diabetes
Bladder CA Dx55
AW
Asthma
AW
Your Patient
58
Case 6
59
Case 6 Answer

• Low risk for hereditary breast cancer
• Meets none of the high or moderate criteria
• Patients 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.

60
Resources

• The National Cancer Institute http//cancernet.nc
  i.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

61
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

62
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