1. What Percentage of Cancer is Considered to be Hereditary?
60-85% of cancer is thought to be sporadic
10-30% of cancer is thought to be familial
5-10% of cancer is thought to be hereditary

2. ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing
Most Cancer Susceptibility Genes Are Dominant With Incomplete Penetrance
ASCO
Penetrance is often incomplete
May appear to “skip” generations
Individuals inherit altered cancer susceptibility gene, not cancer
Normal
Carrier, affected with cancer
Susceptible Carrier
Sporadic cancer
Basic Genetics 31

3. Factors that Influence the Cancer Pattern within a Family
Penetrance
Gender
Environment
Genotype
Risk-Reduction
Early death
Modifier genes

4. Causes of Hereditary Susceptibility to Breast Cancer
ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing
Causes of Hereditary Susceptibility to Breast Cancer
Contribution to Hereditary Breast Cancer
20%–40%
10%–30%
<1%
30%–70%
Gene
BRCA1
BRCA2
TP53
PTEN
Undiscovered genes
ASCO
Breast and Ovarian Cancer 4

5. Hereditary Breast and Ovarian Cancer: BRCA1
Breast cancer 50%-85%
Second primary breast cancer 40%-60%
Ovarian cancer 20%-60%
Autosomal Dominant Transmission
Precise Risk for Male Breast Cancer Unclear
Increased Risk for Prostate Cancer?
Adapted from ASCO

6. Hereditary Breast and Ovarian Cancer: BRCA2
breast cancer
(50%-85%)
male breast cancer
(6%)
ovarian cancer
(10%-20%)
Autosomal Dominant Transmission
Increased risk of prostate, laryngeal, melanoma and pancreas cancers
Adapted from ASCO

7. Features Suggestive of BRCA1 or BRCA2 Mutations
Multiple cases of early onset breast cancer
Ovarian cancer (with family history of breast or ovarian cancer)
Breast and ovarian cancer in the same woman
Bilateral breast cancer
Ashkenazi Jewish heritage
Male breast cancer
ASCO

8. BRCA 1 or 2-Linked Hereditary Breast and Ovarian Cancer?92
Breast, dx 45
d. 89
Prostate
dx.75
Non-carrier
Ovary, dx 59
d. 62
Breast, dx 59
Breast,
dx 73 68 71
BRCA1 or 2-mutation carrier
Affected with cancer
Breast, dx 36 36
Adapted from ASCO

9. BRCA1 and BRCA2 in the Ashkenazi Jewish Population
1 in 40 Individuals of Ashkenazi Jewish descent has a BRCA1 or BRCA2 Mutation
BRCA1
185delAG
Prevalence = ~1%
5382insC
Prevalence = ~0.15%
BRCA2
6174delT
Prevalence = ~1.5%
Adapted from ASCO

10. Detecting Mutations in BRCA1 and BRCA2
Test
Comments
Cost
Full gene sequencing
Detects coding region mutations
$2,975
3-mutation panel
Targets three mutations most common in Ashkenazi Jews
$415
Single site
Targets family mutation
$350

11. Ideally, Begin Testing With an Affected Person
Breast Ca, 42
Test first, if possible
Ovarian Ca, 38
d.45
Breast Ca, 65
Person seeking counseling (proband)
If a mutation is found in an affected person, testing will be more informative for other family members
ASCO 15

12. Interpreting a Negative Result
No identified mutation in family
Family with known mutation
Breast Ca, 52
Breast Ca, 52
Ovarian Ca, 45
Breast Ca, 47
Ovarian Ca, 45
Breast Ca, 47
BRCA1 + 37
BRCA1 - 37
BRCA1 -
Inconclusive
True negative
ASCO 20

13. Clinical Management of BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2 test result
Possible testing for other adult relatives
Increased
surveillance
Lifestyle changes
Chemo-
prevention
Prophylactic
surgery
ASCO

14. Clinical Management of BRCA Mutation-Negative Patient
Negative BRCA1 and BRCA2 test result
Member of family w/ known BRCA1 or BRCA2 mutation? NO
YES
Emphasize risk of unidentified familial mutation
Emphasize risk of sporadic cancer
Encourage adherence to population screening guidelines
Provide individualized risk-management plan
ASCO

15. Benefits, Risks, and Limitations of BRCA Testing
Identifies high-risk individuals
Identifies non-carriers in families with a known mutation
Allows early detection and prevention strategies
May relieve anxiety (positive or negative)
Risks and Limitations
Does not detect all mutations
Continued risk of sporadic cancer
Efficacy of interventions unproven
Variant of uncertain significance
May result in psychosocial or economic harm
Adapted from ASCO

16. Genetic Predisposition Testing Is a Multi-Step Process
Provide post-test counseling and
follow-up
Disclose results
Select and offer test
Provide informed consent
Provide pretest counseling
Identify at-risk patients
ASCO 2

17. Case Discussions What are the ethical issues?
Beneficence
Nonmaleficence
Autonomy
Right to know
Right not to know
Justice
What are the counselor’s duties?
Duty to warn
Duty to recontact
How might the issues be resolved?

18. [ Ashkenazi Jewish ] 93 Breast dx. 61 40 39
Proband is 61 AJ with breast cancer. She is overwhelmed by her diagnosis when she comes for genetic counseling. She decides not to pursue genetic testing because she can’t cope with too much new information at one time.
Some time later the daughter independently presents seeking counseling. The daughter’s results will be relevant to mom.
Jennifer said that ethically, since she was no longer caring for the mothr, she regarded the daughter as her patient of obligation. (In Baltimore she could refer the daughter to another caregiver; but not in many areas).
In the end, the daughter tested negative for the three most common Ashkenazic mutations.
Breast dx. 61 40 39

19. [ Ashkenazi Jewish ] 93 Breast dx. 61 Breast dx. 40 40 39
Two months later, her daughter calls with a new diagnosis of breast cancer. She wants to undergo genetic testing to guide her treatment (a positive result will dictate a full mastectomy). If she tests positive, she will “inform on” her mother. What do you do? Which family member is your patient?
Breast dx. 61
Breast dx. 40 40 39

20. Breast dx. 43 BRCA1/2 NMF NMF - no mutation found
Patient has genetic testing and is BRCA1/2 NMF. She cancels two appoints for disclosure. You are concerned that she is afraid to receive positive results. Do you call her with the NMF results?

21. 3
= Pancreas Cancer
The proband is concerned about her family history of pancreas cancer. You look at the history and realize that you recognize this family.

22. 3 3 3 BRCA2 + 3 = Pancreas Cancer
An affected family member was found to have a BRCA2 mutation, but the next of kin refuses to receive the results. What responsibility do you have to maintain confidentiality? 3
= Pancreas Cancer

23. 3 Breast dx. 51 Breast dx. 42 “BRCA1 +”
Two sisters come to your clinic seeking genetic testing because a third sister apparently has a BRCA1 mutation. After further investigation, you believe that the sister lied about her genetic testing in order to get insurance to pay for a prophylactic mastectomy. How do you provide appropriate information to her sisters without calling her sister a liar? How do you keep them from viewing a NMF result as a “true negative”?
“BRCA1 +”

24. Ovarian dx. ? Breast dx. 63 Breast dx. 59 Breast dx. 57 Breast dx. 47
The proband’s mother was found to have a BRCA2 mutation. The proband elects to have genetic testing and is a “true negative”. 29 30

25. Ovarian dx. ? Breast dx. 63 Breast dx. 59 Breast dx. 57
Breast dx. 47 BRCA2 +
Her sister accompanies her to the disclosure visit and wants genetic testing. You are concerned that the sister is not emotionally stable enough to receive positive results. Do you “let” her get testing? 29 30
BRCA2 -

26. P Breast dx. 30s Ovary dx. 40s Breast dx. 20s Ovary dx. 60s 39 68
[ Polish Jewish ]
The proband is pregnant and has found a breast lump. She wants genetic testing, and says she’ll test her fetus is she is positive.

27. [ Polish Jewish ] Breast dx. 30s 68 Breast dx. 20s Ovary dx. 60s
She is found to have a BRCA1 mutation, and still wants to test the fetus. How do you handle the case?
39 BRCA1 + P