Transcript Clinical Cancer Genetics - Scioto County Medical Society

Genetic Testing for
Hereditary Cancer
Susceptibility
The Ohio State University
Clinical Cancer Genetics Program
Comprehensive Cancer Center
Learning Objectives
The presentation will enable the participant to:
1. Explain the difference between hereditary and nonhereditary cancers.
2. Point out the clinical characteristics of hereditary
cancer.
3. Summarize the importance of counseling prior to
genetic testing for hereditary cancer.
4. Identify the current benefits and limitations of
genetic testing for hereditary cancer
Most cancers are not inherited
10-15% familial
5-10% hereditary
75-85% sporadic
Who is at high risk for cancer?
History is the key…
CLUES:
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Cancer in 2 or more close relatives
(on same side of family)
Early age at diagnosis
Bilateral/multiple cancers
Multiple rare cancers
Multiple primary tumors (breast and ovary;
colon and uterus)
Evidence of autosomal dominant
transmission
CAUTION
Family History is Unreliable

Many patients do not know the details
of their family history.
– Specific sites of tumors unknown
– Ages of onset unknown

Historical information needs to be
verified in order to accurately assess
risk.
Initial pedigree
Stomach
Ca
Bone Ca Prostate
d. 48 problems
After review of records
Ovarian Ca
dx 43, d. 49
Breast Ca
dx 45 Prostate Ca
dx 50
d. 48
Histories are dynamic


With the passage of time, additional
diagnoses may have been made.
These changes may affect the
likelihood of a hereditary cancer
syndrome.
Initial History
2 years later
Colon Ca, 50
Colon Ca, 50
Endometrial
Ca, 44
Colon polyps, 48
Autosomal Dominant - Incomplete Penetrance
Normal
Susceptible Carri
Carrier, affected
with cancer
Sporadic cancer



Penetrance is often incomplete
May appear to “skip” generations
Individuals inherit altered cancer susceptibility gene,
not cancer
Genetic
Counseling
Genetic Counseling:
Purpose


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Appreciate the way heredity contributes to
cancer
Understand an individual’s risk of developing
cancer
Understand the options for dealing with an
increased risk for cancer
Choose a course of action for managing
cancer risk that seems personally
appropriate (genetic testing, screening or
long-term follow up)
Genetic Counseling:
What happens



Collection of personal and family history
(3 generation pedigree)
Education and risk assessment
Options for genetic testing and medical
management
– Discussion of risks, benefits and limitations
– Screening/Chemoprevention/Prophylaxis

Follow-up
– Provide psychosocial support
– Family members
Breast Cancer
Breast cancer is common
1 in every 8 American women will
be diagnosed with breast cancer in
her lifetime
Misconceptions

Cancer on the father’s side of the family
doesn’t count
– Half of all women with hereditary risk inherited it
from their father

Ovarian cancer is not a factor in breast
cancer risk
– Ovarian cancer is an important indicator of
hereditary risk, although it is not always present

The most important thing in the family
history is the number of women with breast
cancer
– Age of onset of breast cancer is more important
than the number of women with the disease
Causes of Hereditary
Breast Cancer
Gene
Contribution to Hereditary
Breast Cancer
BRCA1
20%–40%
BRCA2
10%–30%
TP53 (Li Fraumeni)
<1%
PTEN (Cowden)
<1%
Undiscovered genes
30%–70%
The Hereditary Breast and
Ovarian Cancer Syndrome (HBOC)
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Multiple cases of early onset breast
cancer
Ovarian cancer
Breast and ovarian cancer in the same
woman
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Bilateral breast cancer
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Male breast cancer
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Ashkenazi Jewish heritage
BRCA1-Associated
Cancers: Risk by age 70
Breast cancer 50-85% (often early age at onset)
Second primary breast cancer 20%-60%
Ovarian cancer 15-45%
Possible increased risk of other
cancers (e.g., prostate)
BRCA2-Associated
Cancers: Risk by age 70
breast cancer
(50-85%) male breast cancer
(6%)
ovarian cancer
(10-20%)
Increased risk of prostate,
laryngeal, and pancreatic
cancers (magnitude unknown)
BRCA-mutation positive
family
Breast, dx 40
d. 43
d. 83
Ovary, dx 45
d. 47
Unaffected
Prostate, dx 58
Mutation carrier
38
Breast, dx 33
42
35
Affected
with cancer
Relevance of Ashkenazi
Jewish descent
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1 in 40 (2.5%) Ashkenazi Jews (males
and females) carry a BRCA1 or BRCA2
mutation
The carrier rate in non-Jewish
populations is 1/400 (0.25%)
3 mutations (2 in BRCA1 and 1 in
BRCA2) account for 95% of HBOC
Breast/Ovarian Cancer Risk
Assessment

Likelihood of developing breast cancer:
– Gail model
– Claus model
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Likelihood of having a BRCA1 or 2 mutation
– Myriad risk tables
– BRCAPRO, Couch, Shattuck-Eidens

Likelihood of other breast cancer syndrome
(Cowden, Li Fraumeni)
– Pedigree analysis
BRCA1/2 Mutation Prob in a
Woman with Breast Ca <50
Any relative
with
Br Ca < 50?
Any
relative
with Ov
Ca?
Proband with
Bilateral Br or
Ov Ca?
Probability
(%)
8
25
44
55
62
81
Possible Results

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Positive
Negative
– True negative
Negative result when family mutation known
 Negative result in affected person

– Different gene? Can’t find mutation?

Uninformative
– Negative in unaffected individual
– Variant of uncertain significance

Additional information/testing needed
Important considerations
when ordering test
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Mutation detection rate?
Methods used
Frequency of variants of uncertain
significance
– 10-12% in Caucasians and 40% in AA!
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Testing technology always improving
– Importance of ability to re-contact
patients
Breast Cancer: Surveillance
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Monthly BSE beginning at age 18
CBE every 6 months starting at age 25 (or
5-10y before the earliest dx in family)
Annual mammography starting at age 25 (or
5-10y before the earliest dx in family)
MRI now being used in conjunction with
mammogram; increased sensitivity but
decreased specificity
Breast Cancer:
Chemoprevention

Matched case-control study
– 209 women with bilateral breast ca and BRCA1
or BRCA2 mutation
– 384 women with unilateral breast ca and BRCA1
or BRCA2 mutation
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Tamoxifen protected against
contralateral breast cancer
– BRCA1 odds ratio 0.38 (95% CI 0.19–0.74)
– BRCA2 odds ratio 0.63 (95% CI 0.20–1.50)
Narod Lancet 356:1876, 2000
Prophylactic Mastectomy
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Total mastectomy is recommended
method, if mastectomy is done.
Significantly reduces breast cancer risk in
women with a family history (90%)
In women with a BRCA1 or BRCA2
mutation, prophylactic bilateral total
mastectomy reduces the incidence of
breast cancer at 3 years follow-up
Hartman NEJM 340:77, 1999; Meijers-Heijboer NEJM 345: 1499, 2001
Ovarian Cancer:
Surveillance
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Pelvic examination and transvaginal ultrasound
with color Doppler imaging every 6 months
beginning at age 30-35 (or 5-10 years prior to
the earliest dx in the family)
Concurrent serum CA-125
“There are no data demonstrating that screening
these high-risk women reduces their mortality from ovarian
cancer. Nonetheless, [these measures] are
recommended.”*
*NIH Consensus Conference, JAMA 273:491, 1995
Ovarian Cancer:
Chemoprevention
Oral Contraceptives
40% to 50% risk reduction in general population
after 3 years cumulative use
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Limited data available for BRCA-mutation carriers;
preliminary study showed a 60% risk reduction with
≥6 years use
Increases breast cancer risk in carriers by 1.2-1.4 fold
CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997;
Narod NEJM 339:424, 1998
Prophylactic Oophorectomy
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Decreases risk of ovarian cancer by 95% (primary
peritoneal carcinoma may still occur)*
Reduces risk of breast cancer by 63% if done prior
to age 40 and by 50% if done prior to age 50
Induces surgical menopause
Laparoscopic procedure reduces postsurgical
morbidity
Consider complete hysterectomy for management
of menopause – unopposed, low-dose estrogen
* 5-10% of carriers will have occult malignancy at time of PO many in the fallopian tube
Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002
Benefits and Limitations of
BRCA Testing
Benefits
Risks and Limitations
• Identifies high-risk
individuals
• Does not detect all mutations
• Identifies noncarriers in
families with a known
mutation
• Continued risk of sporadic cancer
(those who test neg may have
false sense of assurance)
• Allows early detection and • Efficacy of interventions unproven
prevention strategies
• May relieve anxiety
• May result in psychosocial
or economic harm
Case 1: Ruth
Ruth is a 45 year old woman recently diagnosed
with breast cancer and is concerned about the risk
to her daughters, ages 18 and 22. You inquire
about family health history and find out the
following information:
– Maternal family history is negative for cancer
– Paternal family history is significant for:
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Paternal aunt with ovarian cancer age at 55
Paternal grandmother with breast cancer
age 42
Case 1: Pedigree
English/Irish
German
Dx 42
82 yrs
60
58
Dx 55
d. 56
Key
Ruth
45
22
18
37
28
-Breast CA
-Ovarian CA
Case 1: BRCA1/2 Risks
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Risk of BRCA1/2 mutation:
– 36-44% risk of mutation in patient

Referral for Cancer Genetic Counseling is
appropriate
– For cancer risk assessment and discussion of
genetic testing for BRCA1/2
Case 1: Pedigree
English/Irish
German
Dx 42
82 yrs
Dx 55
d. 56
60
58
Key
BRCA1 2800delAA
s/p TAH/BSO
BRCA1 +ive
Both negative for
specific mutation 22
Ruth
45
18
42
35 BRCA1 +ive
-Breast CA
-Ovarian CA
50% risk to daughters
Case 1: Impact of results –
medical management

Ruth
– may want to consider oophorectomy
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Ruth’s daughters
– General pop’n risk for breast and ovarian cancer –
follow ACS guidelines
– Cannot pass this on to their children

Ruth’s sister
– Consider increased breast cancer screening +/chemoprevention OR mastectomy/MRI and ovarian
cancer screening and oophorectomy (after childbearing, ~40)

Ruth’s 1st cousin
– Consider increased breast cancer screening +/chemoprevention or mastectomy/MRI
Case 1: Impact of results psychosocial

Ruth feels relieved about daughters
but overwhelmed about risk of ovarian
cancer
– timing
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Ruth’s daughters are happy
Ruth’s sister feels empowered by
information
Ruth’s other sister wants nothing to do
with this and won’t go to the doctor
Case 1: Take Home
Messages

Risk assessment and genetic testing gives
information to patient AND family members
– Some family members may want this information
and some may not
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Genetic testing, when informative, can help
individuals make decisions about early
detection and risk-reduction
Can also relieve anxiety about cancer risk (if
negative)
Informed decision-making imperative
Follow-up support and/or counseling
sometimes necessary
Case 2: Alison
Alison is a 40 year old daughter of one of your patients.
While attending her mother’s appointment, she asks you
for information about the “breast cancer gene test”.
She states she wants this test.
You ask her about her family history:
– Mother with breast cancer - age 58
– Maternal aunt with breast cancer – age 65
– Paternal grandmother with breast cancer – age 79
She feels that with her family history, breast cancer is
inevitable
Case 2: Pedigree
Swedish / Finnish
Caucasian mix
Dx 79
d.81
Dx 58
65 yr
Menses began at age 11
1st child at age 25
No other risk factors
Dx 65
71 yr
Key:
Alison
40 yr
15 yr
-Breast CA
Case 2: Risk Assessment

Gail Model:

Claus Model:
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Myriad table:
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Pedigree analysis:
– 5 year risk of breast cancer 1.2%; Lifetime risk of
20.4%
– Lifetime risk for breast cancer of 18.8%
– 3.4% risk of BRCA1/2 mutation using family history
– no indications of other breast cancer syndromes
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Patient concerns
“Moderate/Familial” Risk
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Clustering of cancer cases seen in the family
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Ages of onset not strikingly young
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Risks for first degree relatives increased
– Risk depends on number of family members
affected, how closely related, ages of onset
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Multiple low-penetrance genes may play a
role and interact with environmental triggers
Case 2: Pedigree
Swedish / Finnish
Caucasian mix
Dx 79
d.81
Dx 58
65 yr
Dx 65
71 yr
Key:
Alison
40 yr
15 yr
-Breast CA
Case 2: Assessment
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Patient is in “Moderate/Familial” risk category
Can begin breast cancer screening by age 35
Ovarian cancer risk not increased
Counseling issues:
–
–
–
–
Low risk for BRCA1 or BRCA2 mutation
Screening and preventive strategies
Psychosocial – perceived risk, fears
Future research?
Case 2: Take Home
Messages

Number of cancers in family is not as
important as the ages at diagnosis
– Side of family matters as well (all on one
side or some on each)
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Perceived risk does not always equal
actual risk
– Genetic counseling/risk assessment can
help

Genetic counseling/risk assessment
does not always lead to genetic testing
Case 3 - Vera
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Vera is a 38 year old microbiologist
concerned about her breast cancer risk
Family history of breast and ovarian
cancer in 2nd and 3rd degree relatives
Wants gene testing
Case 3 - Pedigree
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
dx 55
64
dx 55 colon
or ovarian ca
d. 56
] [
58
62
Menses began at age 12
1st child at age 31
Vera
No other risk factors
38
7
Case 3 - Assessment
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Gail risk = 14.3%
Claus = General population
a priori risk of mutation in Vera =
3.75-16% (1.25-7%)
a priori risk of mutation in Vera’s aunt
= 15-64% (5-28%)
Recommended genetic testing for
Vera’s aunt
Case 3 – Counseling
issues


Vera did not feel comfortable contacting her
aunt
Vera wanted to be tested herself
– Genetic counseling covered risks, benefits and
limitations of testing
– Always try to start testing with an affected
individual

Inconclusive result
– Negative in Vera – not true negative
– Variant of uncertain significance
Case 3 – Test results
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
dx 55
65
dx 55 colon
or ovarian ca
d. 56
] [
58
62
+ BRCA2 N517S
Vera
38
7
Variant of uncertain
significance
Variants of uncertain
significance (VUS)


10-12% of people tested for BRCA1/2 will
have a VUS
Use lab data to determine significance
– incidence in controls
– amino acid change and position in gene
– segregation in family – free testing for VUS in
certain family members
– FUNCTIONAL STUDIES


On research basis only
Most are NOT disease causing but can take
years to determine this
Case 3 - Test results
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
dx 55
65
+ BRCA2 N517S
dx 55 colon
or ovarian ca
d. 56
] [
58
62
+ BRCA2 N517S
N517S is true mutation
N517S is not true mutation
Vera
38
Follow Vera as high risk
until proven otherwise
(1 in 4 chance of sharing by chance)
7
Case 3 - Test results
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
+ BRCA1 C61G
dx 55
65
+ BRCA2 N517S
dx 55 colon
or ovarian ca
d. 56
] [
58
Decides to
have comprehensive
BRCA1/2 testing
62
True Negative!
+ BRCA2
N517S
Vera
38
7
Follow ACS guidelines
Take Home Messages –
Case 3

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Always try to start testing with an
affected individual
Some patients have higher risk of VUS
than a true mutation
Pre-test counseling for VUS important
Don’t assume other family members
won’t be interested in testing
Summary
When Should Genetic
Testing Be Considered?




Significant family cancer history
Reasonable likelihood of carrying a
mutation (affected usually tested first)
Results will influence medical
management
Patient wants information
(empowerment)
When Should Genetic
Testing Be Considered?

Genetic testing should always be
performed in the context of genetic
counseling
– Discuss all medical and social concerns
– Provide psychosocial support

It is easier to review the implications
of testing prior to obtaining results
Pros and Cons of
Genetic Testing
Pros:
Improved cancer risk management
Information for individual and family members
Lifestyle decision making
Cons:
Limited testing is available, especially for
moderate risk families
Results indicate probability, not certainty
Insurance issues, confidentiality
Insurance issues

HIPAA protects patients with group
health insurance from genetic
discrimination
– Some gaps

GINA –Passed the House; Senate vote
pending
– Cover gaps in HIPAA

Most states have state laws in place
– Wide variability in coverage
http://www.genome.gov/10002077
http://www.cancerdiagnosis.nci.nih.gov/specimens/50_state_survey/appendix_a.htm
Implications
for the Entire Family
Consider the
impact of testing
on all family
members.
Ultimately,
testing is the
individual’s
choice.