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
10-15% familial
5-10% hereditary
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
After review of records
Stomach Ca
Ovarian Ca
dx 43, d. 49
Bone Ca
d. 48
Prostate
problems
Breast Ca
dx 45
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
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 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)

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 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

18. Causes of Hereditary Breast Cancer
Contribution to Hereditary Breast Cancer
20%–40%
10%–30%
<1%
30%–70%
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
This syndrome is characterized by multiple cases of early onset breast cancer, ovarian cancer (particularly with a family history of breast or ovarian cancer), breast and ovarian cancer occurring in the same individual, bilateral bilateral breast, and male breast cancer. It is seen with increased frequency in individuals with 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%)
This figure depicts the cancer risks in carriers of a mutation in BRCA2. There is a 50-85% risk of breast cancer, a 10-20% risk of ovarian cancer Again, population-based studies not selecting for strong family history show lower risk estimates: 45% for breast and 11% for ovarian. In addition, carriers of BRCA2 mutations are at increased risk for developing cancers of the prostate, larynx and pancreas.
Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)

22. BRCA-mutation positive family
Breast, dx 40
d. 43
d. 83
Ovary, dx 45
d. 47
Here is a typical BRCA2 family. Review.
Unaffected
Prostate, dx 58
Mutation carrier
Affected with cancer
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
What is the relevance of Ashkenazi Jewish background?
1/40 AJ carries a mutation in BRCA1 or BRCA2.
2-3% of the Jewish community may have a susceptibility for hereditary breast and ovarian cancer. This is in contrast to the 1/400 carrier rate in non-Jewish populations.

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 <50
Any relative with Ov Ca?
Any relative with Br Ca < 50?
Proband with Bilateral Br or Ov Ca?
Probability (%) 8 25 44 55 62 81
There are a number of computer models and tables that can be used to estimate an individual’s risk for carrying a mutation in BRCA1/2. This table shows the likelihood, based on family history, that a woman with breast cancer diagnosed before age 50 will carry a mutation in BRCA1 or 2. In a woman with no family history and a diagnosis of breast cancer under the age of 50, the likelihood of carrying a BRCA mutation is about 8%. If another relative has been diagnosed with breast cancer under age 50, the probability of a mutation increases to about 25%. Any relative with ovarian cancer increases the risk to 35%. If the woman with breast cancer under 50 has bilateral breast cancer or ovarian cancer herself, the probability of a mutation in BRCA1 or 2 increases to 51% when another relative has a breast cancer under age 50 and increases to 71% when another relative has an ovarian cancer.

26. Possible Results Uninformative 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

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
Breast cancer surveillance for mutation carriers consists of monthly BSE beginning at age 18, clinical exams every 6 months and annual mammograms beginning at age 25 or 5-10 years prior to the earliest breast cancer diagnosis in the family. Other breast imaging techniques, including ultrasound and MRI, are being investigated in this high-risk population, but more information needs to be obtained before these investigations can be recommended for routine screening in this population.

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 0.19–0.74)
BRCA2 odds ratio 0.63 (95% CI 0.20–1.50)
Narod Lancet 356:1876, 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
Another option available to women with BRCA1 or 2 mutations is prophylactic mastectomy. This option not frequently selected due to the effective screening modalities available. Just a few points about prophylactic mastectomy: most, but not all of the breast tissue is removed, so breast cancer risk is decreased by about 90%, but this procedure does not completely eliminate risk. A total or simple mastectomy is recommended and immediate reconstruction should also be offered. Again, there is no data specific to BRCA-mutation carriers; this data is extrapolated from other high-risk groups.
Hartman NEJM 340:77, 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 (or 5-10 years prior to the earliest dx in the family)
Concurrent serum CA-125
Screening for ovarian cancer consists of annual transvaginal ultrasound with color Doppler and serum CA-125 every 6-12 months. Unfortunately, this screening is not very effective in detecting early disease or improving survival. The NIH consensus conference stated “read”
“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

32. Ovarian Cancer: Chemoprevention
Oral Contraceptives
40% to 50% risk reduction in general population
after 3 years cumulative use
Chemoprevention with oral contraceptives is an effective strategy in high-risk women. Oral contraceptive use reduces the risk of ovarian cancer 40-50% after 3 years of continuous use. Although limited data is available in BRCA mutation carriers, there appears to be about a 60% reduction in risk in this population. One of the concerns is the potential for an increased risk of breast cancer with oral contraceptive 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 fold
CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997;
Narod NEJM 339:424, 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
In families with hereditary breast ovarian cancer syndrome, prophylactic oophorectomy is strongly recommended for all female carriers of the mutation over the age of 35 or who have completed their child-bearing. In addition to lowering the ovarian cancer risk by 95-99%, there is about 50% reduction in breast cancer risk when performed before age 40. One problem, of course, is the sudden onset of a surgically induced menopause. Some advocate removing the uterus as well and using unopposed estrogen for hormone replacement, as this has a lower breast cancer risk than combination therapy necessary with an intact uterus. The procedure can be performed laparoscopically with decreased morbidity. No data specific to the BRCA mutation population is available.
* 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
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
Mutation testing is generally recommended when the estimated risk of finding a mutation is > 10%, but is always the choice of the at-risk individual. Genetic counseling should be a component of this process, because the risks, benefits and limitations of testing can be discussed and emotional support provided. This table lists the benefits, risks and limitations of genetic testing.

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 Key -Breast CA -Ovarian CA Dx 42
82 yrs 58 60
Dx 55
d. 56
Key
-Breast CA
Ruth 45 28 37
-Ovarian CA 22 18

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 50% risk to daughters English/Irish German Key
Dx 42
82 yrs 58 60
Dx 55
d. 56
Key
BRCA1 2800delAA
-Breast CA
Ruth 45
BRCA1 +ive
s/p TAH/BSO 42 35
-Ovarian CA
BRCA1 +ive
Both negative for
specific mutation
50% risk to daughters 22 18

39. Case 1: Impact of results – medical management
Ruth
may want to consider oophorectomy
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 child-bearing, ~40)
Ruth’s 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
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

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 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

43. Case 2: Pedigree Swedish / Finnish Caucasian mix Key: -Breast CA Dx 79
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: Claus Model: Myriad table:
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
Gail Model:
5 year risk of 1.1%; lifetime risk of 18.8%
Claus Model:
Lifetime risk of 18.8% based on mother, age 58 and maternal aunt, age 65
Myriad table – risk of BRCA1/2 mutation:
2.9% risk of mutation based on family history (no one with breast <50 or ovarian cancer)
Pedigree analysis: no indications of other breast cancer syndromes

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 Swedish / Finnish Caucasian mix Key: -Breast CA Dx 79
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 ] [ 64 58 62
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 = % (1.25-7%)
a priori risk of mutation in Vera’s aunt = 15-64% (5-28%)
Recommended genetic testing for Vera’s 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 ] [ + BRCA2 N517S Variant of uncertain
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
dx 55 colon
or ovarian ca
d. 56
dx 55 ] [ 65 58 62
+ 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 ] [ + BRCA2 N517S + BRCA2 N517S
Italian
dx 31 R brca
dx 50 L brca
d. 75 CVA
dx 55 colon
or ovarian ca
d. 56
dx 55 ] [
+ BRCA2 N517S 65 58 62
+ 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 ] [ + BRCA1 C61G + BRCA2 N517S Decides to
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 65 58 62
Decides to
have comprehensive
BRCA1/2 testing
+ BRCA2 N517S
True Negative!
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
Don’t assume other family members won’t 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: Cons:
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
Just to review the pros and cons of testing:

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

63. Implications for the Entire Family
Consider the impact of testing on all family members.
Ultimately, testing is the individual’s choice.
The implications for the entire family need to be considered, since knowledge that a cancer susceptibility syndrome exists in the family impacts ALL of the members of that family. Ultimately, however, each individual must choose whether testing is right for him or her.

64. Thank you.