BRCA ONCOLOGY.ppt

The Genetics Education Project
BRCA Genes
Prepared by : ibrahim issac
GENERAL and laparoscopic surgery
resident

Outline
 Sporadic versus familial cancer
 Hereditary breast cancer syndrome
 What are BRCA GENES
 Referral guidelines
 Benefits, risks and limitations of genetic
testing
 Management

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

Sporadic Cancer
 All cancerS arises from changes in genes….
– But NOT all cancerS are 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

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’ 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)

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

Genes involved in hereditary
breast/ovarian cancer
 > 2,600 mutations in:
–BRCA1- chromosome 17
[1994]
–BRCA2 - chromosome 13
(1995)
Autosomal dominant transmission

 The gene names come from BReast CAncer
genes 1 & 2. The official names of these genes
is breast cancer1, early onset and breast
cancer2, early onset.
 Everyone, male and female, has these genes
which normally work to repair DNA and are
involved in cell growth and cell division.

bb Bb
Bb bb Bb bb
Breast Cancer
Affected with
breast cancer
Autosomal Dominant Inheritance
Population
Risk
Population
Risk
Susceptible
BRCA gene
Unaffected
Legend
B: BRCA gene
with mutation
b: normal
BRCA gene

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

Consequences of having a BRCA mutation
Estimated Risk in
BRCA Mutation
Carriers
– by Age 70
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% <1%

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

…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

Genetic Testing
 Available at regional genetic centres
– Familial cancer clinics
 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

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

Risks/Benefits/Limitations
of genetic testing
Positive 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
 Confidentiality issues
 Intervention carries risk

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

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
 Uncertainty
 Continued anxiety
 Higher insurance premiums
may not be reduced

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

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

 Recommendations for BRCA1/2 mutation carriers:
– Ovarian surveillance
Consider…
– PV exam
– transvaginal ultrasound
– serum CA-125
» q6 months starting age 30-35
Symptom recognition

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

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

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

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)

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

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”

Thank you

BRCA ONCOLOGY.ppt

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