Presentation from Peter Hulick, MD, MMSc, to help nurses and nurse practitioners: 1) Understand the genetic consultation process 2) Examine genetic contribution to breast cancer 3) Identify suggestive family history patterns and risk estimation 4) Influence of genetic testing on management Taken from a CNE-granting presentation given on 2/17/12 in Highland Park, IL, put together by the Chicago Center for Jewish Genetic Disorders and NorthShore University HealthSystem.

1. All in the Family: Using Family Health
History to Identify and Support Women at Risk
for Hereditary Cancer
2/15/12
Peter Hulick, MD MMSc
Center for Medical Genetics
NorthShore University HeathSystem

2. Objectives
1. Understand the genetic consultation process
2. Examine genetic contribution to breast
cancer
3. Identify suggestive family history patterns
and risk estimation
4. Influence of genetic testing on management

3. Reasons for a Genetics Consultation
1. Family history of a medical condition
• Cancer, heart disease, Huntington disease, connective
tissue disease, hearing/visual disorder
2. At risk for a hereditary disorder
• Thalassemia, Tay-Sachs disease
3. Unusual presentation or history
• Unexplained/early cardiomyopathy, early onset of cancer
4. Exploring recurrence risks for future pregnancies
5. Diagnostic evaluation for known syndromes
• Klinefelter, Down syndrome

4. NorthShore Clinical Genetics Practice
• Busiest adult genetic clinic in Midwest
– Vying for busiest in US
• Patient visits FY2011
– 658 New
– 1134 Total
• Focus
– Hereditary cancer
– Breadth of adult genetics diagnoses
– Expanding to pediatrics and more non-cancer

5. The Consultation Appointment
What occurs at an initial genetics consultation?
– Meet with a genetic counselor and a geneticist
– Personal and family medical history reviewed
– Targeted physical exam when appropriate
– Discussion of genetic concepts, risks, and testing
options
– Patient has option to decline or proceed with genetics
testing if indicated
– Disclosure appointment scheduled if decision to test
– Typical initial appointment lasts 1.5 hours

6. Genetic Counseling Process
• Using a questionnaire as a guide, the patient gathers
detailed information on their personal/family history
– Current ages
– Ages at death
– Causes of death
– Site that cancer originated? (i.e. uterine vs ovarian cancer?)
– Other questions, depending on reason for referral
» Who has had colonoscopies?
» Number and type of polyps on colonoscopy?
» Have the women had hysterectomies?
» Skin biopsies –what was found?

7. Genetic Counseling Process – Information Gathering

8. Costs of genetic testing
• Genetic counseling and genetic testing fees are separate
– Both are usually covered
• About 95% of patients use their insurance for
consultation and genetic testing
– Coverage is typically 70-100%
– Medicare often covers consultation and genetic testing fees

9. Genetic Information Non-discrimination Act (GINA)
• Federal law signed into law May 21st, 2008
– Went into effect in May/Nov of 2009
• Prohibits genetic discrimination by health insurance
companies and employers
• Defines genetic information as predictive genetic
tests, family members‟ genetic tests, and family
history information
• Applies to both group and individual health insurance
markets
• Prohibits the use of genetic information in
underwriting
• Prohibits insurers and employers from requiring
genetic testing

10. Facilitate Decision-making
Not a simple decision …
– Should I have testing?
– What would I do differently if I
were to test positive?
– Will it help my family
members?
– Now that I have tested
positive, should I do high risk
screening or do I go onto
preventative surgery?
– Is a negative test a true
negative?

11. Genetic Counseling Process – Disclosing Results
The disclosure appointment:
– Scheduled based on anticipated time of results
» BRCA1/2 testing 2-3 weeks
» LQT syndrome 2-3 months
– Everyone scheduled for a return disclosure appt.
» Patient not “positive” just because they are returning
» Risk implications/adjustments in setting of negative test
» Recommendations for treatment/screening
» Emotional support
» Assistance with appropriate referrals
» Implications for family members – duty to warn

12. About 5-10% of breast and ovarian cancer is hereditary—
caused by single, strong, dominant genes

13. BRCA1/2 contribution to breast cancer …
• Woman with breast cancer - ~5%
– Of Ashkenazi Jewish ancestry - ~10%
• Diagnosed w/ breast cancer <45 yrs - ~ 10%
– >45 yrs - ~2%
– < 45 yrs and AJ - ~26%
• Woman and FHx Br Ca <45 - ~20%
– Of AJ ancestry – ~30%
Cancer Res 2006; 66(16): 8297-308

14. Frequency of BRCA1 & BRCA2 mutations
General population Ashkenazi Jewish
3 Founder
Mutations
BRCA1
187delAG
5382insC
BRCA2
1 in 300 1 in 40 6174delT

15. Clinical Case
• 53 year old woman diagnosed with breast cancer
• Underwent bilateral mastectomy with
reconstruction, chemotherapy, hormonal therapy
• Eager to get back to work so that she could focus on
matters other than her health
• Significant family history of breast cancer
• Surgeon told her about the link between breast and
ovarian cancer and referred her for genetics
consultation

16. Significant family history of breast cancer:
• Mother BC age 40
• 4 paternal relatives with BC
• Young-onset BC (35) in cousin, linked through father w/ colon & prostate CA

17. Risk assessment and genetic testing
• Her motivations for genetic testing:
– determine her risk of ovarian cancer
– „put all this behind her‟
– clarify her sister‟s risk of breast cancer
• Calculated 43% chance of having a
positive gene test (i.e. a mutation)

18. Use the right model to get the right answer
Modified From: Rubinstein WS, O‟Neill SM: Quantitative Risk Assessment. In: Singletary SE, Robb GL, Hortobagyi GN (eds):
Advanced Therapy of Breast Disease, Second Edition. BC Decker, Inc., 2nd Edition, pp. 97-112, 2004.

19. Levels of BRCA1 and BRCA2 testing
• Multi-site analysis
– AJ Founder mutations – 80-90%
– BRCA1 187delAG and 5385insC
– BRCA2 6174delT
• Comprehensive
– “spell-check” of the genes – sequencing
– 5-site rearrangement panel of BRCA1
• BART
– Rearrangements in BRCA1 and 2
– Adds 1-3% detection in high risk families

20. Costs of genetic consultation and testing
• Genetic counseling and genetic testing fees are separate
– Both are usually covered
• Genetic testing
– ~$400 to ~$3000
» Lower costs apply when familial mutation is known
– We help patients obtain preauthorization and write letters of
medical necessity
• ~95% of patients use their insurance for consultation and
genetic testing
» Coverage is typically 70-100%
» Medicare often covers consultation and genetic testing fees

21. Risk assessment and genetic testing
• Her motivations for genetic testing:
– determine her risk of ovarian cancer
– „put all this behind her‟
– clarify her sister‟s risk of breast cancer
• Calculated 43% chance of having a positive gene test
(i.e. a mutation)
• Testing covered by insurance
– she said she would get testing regardless of coverage
• Results: BRCA2 886delGT mutation

22. BRCA1 and BRCA2 lifetime cancer risks
Breast cancer (+ early age at onset)
(50-85%)
Second primary breast cancer
(40-60%)
Male breast cancer
(5-6%)
Prostate cancer
Ovarian cancer (30-40%)
(20%-40%)
Increased risk of pancreatic,
fallopian tube, other cancers

23. Cancer screening and prevention:
the patient
• Evidence-based medicine
– ovarian cancer lifetime risk 20-40%
– preventive removal of ovaries and fallopian tubes reduces ovarian
cancer risk by 96%
• Patient referred by geneticist to gynecologic oncologist
• Laparoscopic removal of ovaries and fallopian tubes shortly after
finishing chemotherapy for breast cancer
• Pathology revealed ovarian cancer
– stage 1-C: caught very early, 90% cure rate
– underwent 6 cycles of chemotherapy
• Patient remains free of evident disease and is probably cured
– “natural presentation” is late-stage with poor survival rates

24. In genetics, the family is the patient

25. In genetics, the family is the patient

26. Genetic testing, cancer screening
and prevention: the sister
• Sister underwent genetic testing,
also a BRCA2 886delGT mutation carrier
• Breast and ovarian cancer screening was negative
• Underwent preventive removal of ovaries and
fallopian tubes and prophylactic mastectomy
• Stage 1 breast cancer diagnosed

27. “I’d have been here sooner if it hadn’t been for early detection.”

28. BRCA1 and BRCA2 lifetime cancer risks
Breast cancer (+ early age at onset)
(50-85%)
Second primary breast cancer
(40-60%)
Male breast cancer
(5-6%)
Prostate cancer
Ovarian cancer (30-40%)
(20%-40%)
Increased risk of pancreatic,
fallopian tube, other cancers

29. Cancer Risk Management in BRCA1/2 carriers
Breast cancer – Screening
• Annual mammography/MRI start age 20-25
• Clinical breast exam every 6 months
• Monthly self breast exam
Breast cancer – Prevention
• Tamoxifen chemoprevention (50% effective)
• Prophylactic mastectomy (90-95% effective)
• Prophylactic oophorectomy (40% effective against breast cancer)
Ovarian cancer – Screening
• Transvaginal ultrasound + Ca-125 every 6-12 months limited efficacy
Ovarian cancer – Prevention
• PBSO after childbearing complete (80-96% effective) strongly recommended
• Consider oral contraceptives

30. Other Cancers with BRCA1/2
• Male Breast
• Prostate
• Pancreatic
• Stomach
• Melanoma of the skin and eye
• Colon cancer: inconsistently observed

31. Recognition of
Hereditary Cancer Syndromes

32. When to Suspect
Hereditary Cancer Syndrome
• Cancer in 2 or more close relatives
(on same side of family)
• Early age at diagnosis
• Multiple primary tumors
• Bilateral or multiple rare cancers
• Constellation of tumors c/w specific cancer syndrome
breast + ovary = HBOC
colon + endometrial = HNPCC
colon + adenomatous polyposis = FAP
melanoma + pancreatic = p16
• Evidence of autosomal dominant transmission

33. Most Cancer Susceptibility Genes are
Dominant with 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
• Paternal family history matters!

34. Features of hereditary breast-ovarian
cancer (BRCA1 and BRCA2)
• Early age of breast cancer onset
• Ovarian cancer at any age
• Bilateral breast cancer, or more than once
• An individual with both ovarian and breast cancer
• Many relatives affected; multiple generations
• Male breast cancer
• Other cancers in the family, e.g. pancreas
• Ashkenazi Jewish ancestry
• Medullary breast cancer (BRCA1)
• ER/PR/Her2 neg (triple negative) breast cancer (BRCA1)

36. ―Family History is Negative
for Breast Cancer‖
Need more information to pick the right gene
• Ovarian cancer, male breast cancer, pancreatic, prostate cancer:
BRCA1, BRCA2
• Sarcoma, childhood leukemia/lymphoma, others:
TP53 (Li-Fraumeni syndrome)
• Thyroid, endometrial, trichilemmomas, hamartomas:
PTEN (Cowden syndrome)
• Diffuse gastric cancer, lobular breast cancer:
CDH1 (Hereditary diffuse gastric cancer)
• Ovarian (granulosa), testicular, pancreatic, uterine, GI; intestinal
hamartomatous polyps, mucocutaneous pigmentation:
STK11 (Peutz-Jeghers)

37. Li-Fraumeni syndrome
• Young breast cancer (most common cancer)
• Adrenocortical carcinoma
• Sarcoma
• Leukemia

38. J Clin Oncol 27:1250-1256.

39. Pathognomonic mucocutaneous features of
Cowden syndrome
(a) Trichilemmomas on the
nape of the neck
(b) Palmar keratoses
(c) Perioral papillomatous
papules (arrow head) and
nasal polyposis
(d) Gastric hamartomas as
seen by endoscopy
European Journal of Human Genetics (2008) 16, 1289–1300

40. What if genetic testing in a family with significant
breast cancer history is negative?
• BRCA1/2 testing ~90%
sensitive
• Risk models for lifetime
risk calculation
– Tyrer-Cusick
– Gail
• Addition of MRIs?
• Tamoxifen?

41. Breast MRI Surveillance
• Higher sensitivity for
detection of invasive
breast cancers
• Mammography has
higher sensitivity for
ductal carcinoma in
situ (DCIS)
• Reserved for
screening high risk
patients

43. Who is considered high risk?

44. ACS Recommendations for Breast MRI
Screening as an Adjunct to Mammography
Saslow D et al. (2007) CA Cancer J Clin 2007; 57:75-89

45. Continue to follow-up …
• Family history changes
– New information
– New cancer diagnosed in family (missed 10%
families, different syndrome to consider?)
• Genetic testing
– BART relatively recent
– New gene(s) clinically available for testing
• New Screening guidelines
– MRI for women with 20-25% lifetime risk of developing
breast cancer

46. NorthShore Center for Medical Genetics
Clinical Research
PROSE Study of BRCA1 and BRCA2 Mutation Carriers
– How do lifestyles, habits, exposures, hormones, preventive
surgery and other interacting genes influence cancer risk?
Pancreatic Cancer Family Registry (PCFR)
– Database for families affected by pancreatic cancer in hopes of
learning the causes of familial pancreatic cancer
IMPACT Study
– Evaluation of usefulness of prostate cancer screening methods
for screening high risk BRCA positive men
SIFT Registry
– Families with history of breast cancer but negative genetic testing
for breast cancer susceptibility genes

47. The Center for Medical Genetics
NorthShore University HealthSystem
• Peter Hulick, MD, MMSc
Medical Geneticist
• Genetic Counselors
Scott Weissman, MS, CGC
Anna Newlin, MS, CGC
Kristen Vogel, MS, CGC
Shelly Weiss, MS, CGC
• Research Coordinator
Tina Selkirk, MS