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Genetic Testing for Hereditary Cancer Susceptibility

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Title: Genetic Testing for Hereditary Cancer Susceptibility


1
Genetic Testing for Hereditary Cancer
Susceptibility
  • The Ohio State University
  • Clinical Cancer Genetics Program
  • Comprehensive Cancer Center

2
Learning Objectives
  • The presentation will enable the participant to
  • 1. Explain the difference between hereditary and
    non-hereditary 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

3
Most cancers are not inherited
5-10 hereditary
10-15 familial
75-85 sporadic
4
Who is at high risk for cancer? History is the
key
5
CLUES
  • 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

6
CAUTION
7
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.

8
After review of records
Initial pedigree
Stomach Ca
Ovarian Ca dx 43, d. 49
Breast Ca dx 45 d. 48
Prostate problems
Bone Ca d. 48
Prostate Ca dx 50
9
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.

10
Initial History
2 years later
Colon Ca, 50
Colon Ca, 50
Endometrial Ca, 44
Colon polyps, 48
11
Autosomal Dominant - Incomplete Penetrance
Normal
Susceptible Carrier
Carrier, affected with cancer
Sporadic cancer
  • Penetrance is often incomplete
  • May appear to skip generations
  • Individuals inherit altered cancer susceptibility
    gene, not cancer

12
Genetic Counseling
13
Genetic Counseling Purpose
  • Appreciate the way heredity contributes to cancer
  • Understand an individuals 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)

14
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

15
Breast Cancer
16
Breast cancer is common
1 in every 8 American women will be diagnosed
with breast cancer in her lifetime
17
Misconceptions
  • Cancer on the fathers side of the family doesnt
    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

18
Causes of Hereditary Breast Cancer
Contribution to Hereditary Breast
Cancer 2040 1030 lt1 lt1 3070
Gene BRCA1 BRCA2 TP53 (Li Fraumeni) PTEN
(Cowden) Undiscovered genes
19
The Hereditary Breast and Ovarian Cancer Syndrome
(HBOC)
  • Multiple cases of early onset breast cancer
  • Ovarian cancer
  • Breast and ovarian cancer in the same woman
  • Bilateral breast cancer
  • Male breast cancer
  • Ashkenazi Jewish heritage

20
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)
21
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)
22
BRCA-mutation positive family
Breast, dx 40 d. 43
Ovary, dx 45 d. 47
d. 83
Prostate, dx 58
Breast, dx 33 42
38
35
23
Relevance of Ashkenazi Jewish descent
  • 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

24
Breast/Ovarian Cancer Risk Assessment
  • Likelihood of developing breast cancer
  • Gail model
  • Claus model
  • 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

25
BRCA1/2 Mutation Prob in a Woman with Breast Ca
lt50
Any relative with Ov Ca?
Proband with Bilateral Br or Ov Ca?
Any relative with Br Ca lt 50?
Probability () 8 25 44 55 62 81
26
Possible Results
  • Positive
  • Negative
  • True negative
  • Negative result when family mutation known
  • Negative result in affected person
  • Different gene? Cant find mutation?
  • Uninformative
  • Negative in unaffected individual
  • Variant of uncertain significance
  • Additional information/testing needed

27
Important considerations when ordering test
  • Mutation detection rate?
  • Methods used
  • Frequency of variants of uncertain significance
  • 10-12 in Caucasians and 40 in AA!
  • Testing technology always improving
  • Importance of ability to re-contact patients

28
Breast Cancer Surveillance
  • 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

29
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
  • Tamoxifen protected against contralateral breast
    cancer
  • BRCA1 odds ratio 0.38 (95 CI 0.190.74)
  • BRCA2 odds ratio 0.63 (95 CI 0.201.50)

Narod Lancet 3561876, 2000
30
Prophylactic Mastectomy
  • 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 34077, 1999 Meijers-Heijboer NEJM
345 1499, 2001
31
Ovarian Cancer Surveillance
  • 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 273491, 1995
32
Ovarian Cancer Chemoprevention
Oral Contraceptives
40 to 50 risk reduction in general
population after 3 years cumulative use
  • 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 316650, 1987 Ursin Cancer Res
573678, 1997 Narod NEJM 339424, 1998
33
Prophylactic Oophorectomy
  • 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
34
Benefits and Limitations of BRCA Testing
  • Benefits
  • Identifies high-risk individuals
  • Identifies noncarriers in families with a known
    mutation
  • Allows early detection and prevention strategies
  • May relieve anxiety
  • Risks and Limitations
  • Does not detect all mutations
  • Continued risk of sporadic cancer (those who test
    neg may have false sense of assurance)
  • Efficacy of interventions unproven
  • May result in psychosocial or economic harm

35
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
  • Paternal aunt with ovarian cancer age at 55
  • Paternal grandmother with breast cancer age 42

36
Case 1 Pedigree
English/Irish
German
Dx 42 82 yrs
60
58
Dx 55 d. 56
Key
-Breast CA
Ruth 45
28
37
-Ovarian CA
18
22
37
Case 1 BRCA1/2 Risks
  • 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

38
Case 1 Pedigree
English/Irish
German
Dx 42 82 yrs
60
58
Dx 55 d. 56
Key
BRCA1 2800delAA
-Breast CA
BRCA1 ive
Ruth 45
42
35
s/p TAH/BSO
-Ovarian CA
BRCA1 ive
Both negative for specific mutation
50 risk to daughters
18
22
39
Case 1 Impact of results medical management
  • Ruth
  • may want to consider oophorectomy
  • Ruths daughters
  • General popn risk for breast and ovarian cancer
    follow ACS guidelines
  • Cannot pass this on to their children
  • Ruths sister
  • Consider increased breast cancer screening /-
    chemoprevention OR mastectomy/MRI and ovarian
    cancer screening and oophorectomy (after
    child-bearing, 40)
  • Ruths 1st cousin
  • Consider increased breast cancer screening /-
    chemoprevention or mastectomy/MRI

40
Case 1 Impact of results - psychosocial
  • Ruth feels relieved about daughters but
    overwhelmed about risk of ovarian cancer
  • timing
  • Ruths daughters are happy
  • Ruths sister feels empowered by information
  • Ruths other sister wants nothing to do with this
    and wont go to the doctor

41
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
  • 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

42
Case 2 Alison
  • Alison is a 40 year old daughter of one of your
    patients. While attending her mothers
    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

43
Case 2 Pedigree
Caucasian mix
Swedish / Finnish
Dx 79 d.81
Dx 58 65 yr
Dx 65 71 yr
Menses began at age 11 1st child at age 25 No
other risk factors
Key
-Breast CA
Alison 40 yr
15 yr
44
Case 2 Risk Assessment
  • Gail Model
  • 5 year risk of breast cancer 1.2 Lifetime risk
    of 20.4
  • Claus Model
  • Lifetime risk for breast cancer of 18.8
  • Myriad table
  • 3.4 risk of BRCA1/2 mutation using family
    history
  • Pedigree analysis
  • no indications of other breast cancer syndromes
  • Patient concerns

45
Moderate/Familial Risk
  • Clustering of cancer cases seen in the family
  • Ages of onset not strikingly young
  • Risks for first degree relatives increased
  • Risk depends on number of family members
    affected, how closely related, ages of onset
  • Multiple low-penetrance genes may play a role and
    interact with environmental triggers

46
Case 2 Pedigree
Caucasian mix
Swedish / Finnish
Dx 79 d.81
Dx 58 65 yr
Dx 65 71 yr
Key
Alison 40 yr
-Breast CA
15 yr
47
Case 2 Assessment
  • 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?

48
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)
  • 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

49
Case 3 - Vera
  • 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

50
Case 3 - Pedigree
Italian
dx 31 R brca dx 50 L brca d. 75 CVA
dx 55 colon or ovarian ca d. 56
dx 55


58
62
64
Menses began at age 12 1st child at age 31 No
other risk factors
Vera 38
7
51
Case 3 - Assessment
  • 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 Veras aunt 15-64
    (5-28)
  • Recommended genetic testing for Veras aunt

52
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

53
Case 3 Test results
Italian
dx 31 R brca dx 50 L brca d. 75 CVA
dx 55 colon or ovarian ca d. 56
dx 55


58
62
65
BRCA2 N517S
Variant of uncertain significance
Vera 38
7
54
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

55
Case 3 - Test results
Italian
dx 31 R brca dx 50 L brca d. 75 CVA
dx 55 colon or ovarian ca d. 56
dx 55


BRCA2 N517S
58
62
65
BRCA2 N517S
Vera 38
N517S is true mutation N517S is not true
mutation (1 in 4 chance of sharing by chance)
Follow Vera as high risk until proven otherwise
7
56
Case 3 - Test results
Italian
dx 31 R brca dx 50 L brca d. 75 CVA
dx 55 colon or ovarian ca d. 56
BRCA1 C61G
dx 55


BRCA2 N517S
58
62
65
Decides to have comprehensive BRCA1/2 testing
True Negative!
BRCA2 N517S
Follow ACS guidelines
Vera 38
7
57
Take Home Messages Case 3
  • 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
  • Dont assume other family members wont be
    interested in testing

58
Summary
59
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)

60
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

61
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
62
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.cancerdi
agnosis.nci.nih.gov/specimens/50_state_survey/appe
ndix_a.htm
63
Implications for the Entire Family
Consider the impact of testing on all family
members. Ultimately, testing is the individuals
choice.
64
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