genetics and primary care

1. Familial Cancer Risk Assessment:
Breast and Ovarian Cancer
Genetics and Primary Care

2. Case 1: Ruth
Ruth, a 35 year old Jewish woman, comes for a family
planning visit. 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
Ruth has no other risk factors or pertinent family history

3. Case 2: Alison
Alison is a 40 year old Caucasian (non-Jewish) patient
who asks you for information about the “breast cancer
gene test”. She states she wants this test.
You ask about her family history:
– Mother with breast cancer - age 58
– Maternal aunt with breast cancer – age 65
– Paternal grandmother with breast cancer – age 79
Alison has no other risk factors for breast cancer
She feels that with her family history, breast cancer is
inevitable

4. Outline
• Hereditary breast and ovarian cancer
• Genetic counseling and testing for hereditary
breast and/or ovarian cancer
• Cancer family history – a primary tool
• Screening for hereditary breast/ovarian CA in
the primary care setting
• When and how to refer patients for genetic
services

5. Cancer Etiology:
• ~5-10% of cases have a strong
hereditary component
• ~15-20% are “familial”/multifactorial
• ~70-75% are thought to be sporadic

6. Hereditary Breast/Ovarian CA
• Occurs in multiple generations
• Younger ages of onset (often <50)
• Bilateral cancer or multiple primaries common
• Family history of unique tumor combinations
– e.g. sarcoma, breast, brain in same family
– e.g. male breast cancer, ovarian/breast
– e.g. breast, thyroid, uterine cancer

8. Hereditary Breast and Ovarian CA
(HBOC)
• 5-10% of all cases of breast and ovarian cancer
• About 70 to 85% of HBOC cases are caused by
mutations in either the BRCA1 or BRCA2 gene
• Genetic testing for BRCA1 and BRCA2 gene
mutations is available to women with family
history meeting “hereditary breast cancer”
criteria

9. Each cell has two copies of
BRCA1 and BRCA2
BRCA2
BRCA1

10. BRCA1/2 Mutation Incidence
• 1 in 800 women in the general population
• 5-10% of all women with breast CA
• ~18% of women with breast CA <50 and
one close relative with breast CA <50
• 2% of all women of Ashkenazi Jewish
ancestry

11. BRCA1/2 Mutations: Cancer Risks
BRCA1 BRCA2
• Breast cancer to age 80 50-85% 50-85%
• Ovarian cancer to age 80 20-60% up to 27%
• Male breast cancer Slight incr. ~6%
• Prostate cancer Slight incr. Slight incr.
• Pancreatic cancer No incr. 1.5-5%
• Melanoma No incr. Slight incr.
Daly MD: NCCN 2002 genetic/familial high-risk assessment clinical practice guidelines in oncology.

12. Risk-Based Management
High/Genetic Risk:
• BSE monthly starting at age 18
• CBE once or twice a year starting age 25
• Mammogram once a year starting at age 25
• Ovarian surveillance if BRCA1 or 2 mutation positive or
family history of ovarian cancer
– Pelvic exam, trans-vaginal ultrasound, +/- CA-125 once or twice
a year; age 25-35
• Options: Chemoprevention or prophylactic surgery

13. Treatment Options:
BRCA1/2 Carriers
• Chemoprevention
– Tamoxifen reduces risk in BRCA2 carriers, (still
questionable in BRCA1 carriers)
• Prophylactic bilateral mastectomy
– ~90% reduction in breast CA risk
• Prophylactic bilateral oophorectomy
– ~up to 95% reduction in ovarian CA risk
– ~50% reduction in breast CA risk

14. Other Hereditary Breast
Cancer Syndromes
• Cowden Syndrome – <1% of all BrCA
– Facial/buccal lesions, GI hamartomas
– Thyroid, endometrial lesions or CA, macrocephaly
• Li-Fraumeni – <1% of all BrCA
– Early-onset sarcoma, leukemia, brain CA
– Adrenocortical CA, others
• Peutz-Jeghers - <1% of all BrCA
– Childhood GI hamartomas, GI CA
– Pigmentation of lips, buccal mucosa, hands/feet

16. Cancer Genetic Counseling
• Full pedigree analysis and risk assessment
• Discussion of:
– Personal risks of cancer based on family history
– Risks of genetic syndrome in the family
– Appropriate genetic testing and chances of mutation
– Full informed consent prior to genetic testing
– Personalized, risk-based screening and prevention
options
– Support resources

17. Ethical Issues: Genetic Testing
• Confidentiality/Privacy
– Preserve other family members’ confidentiality when
documenting family history
• Potential insurance, employment, social
discrimination
• Sharing information with at-risk relatives
– What if client refuses?
– Positive results on one family member suggest risk in
others without their consent

18. BRCA1/2 and Other
Genetic Testing
• Affected family member should be tested
first, when possible
– If no mutation found (or “uncertain variant”): testing
others not warranted
– If mutation identified, unaffected relatives can be
offered testing for that specific mutation - after
genetic counseling and informed consent

19. What can YOU do?

20. Goal: Classification
Who needs what?
Family Hx
Assessment
Personalized prevention
recommendations
Referral for genetic evaluation
with personalized prevention
recommendations
Standard prevention
recommendations
Intervention
Average
Moderate
(“Familial”)
High/Genetic
Risk Classification

21. Screening for “Familial Cancer”
• Help your clients collect appropriate Family
History Details:
– Type of primary cancer(s) in each relative
– Age of disease onset in each relative
– Cancer status in 1st and 2nd degree relatives
– Cancer status in both sides of the family
– Ethnic background on both sides
– Other medical findings – benign tumors, etc.

23. Gail Model
• Calculates 5 yr and lifetime risk (to 90 yrs) of
breast cancer based on multiple criteria
• Limitations: age of onset, 2nd degree relatives,
paternal history, ovarian cancer, ethnicity not
included in risk analysis
http://bcra.nci.nih.gov/brc/start.htm
Gail MH: J Natl Cancer Inst (1989); 81; 24; 1979-1886.

24. Claus Model
• Calculates risk of breast CA to age 80 based on:
– Age of onset of breast cancer in 1st and 2nd degree
relatives, including paternal
• Limitations:
– May underestimate risk in families with 3 or more
affected members; ethnicity not included
Claus EB et al. Cancer 73:643-651 (1994)

25. Myriad Risk Tables
• Identifies the chance of detecting a BRCA1 or BRCA2
mutation in women with a family history of early-onset
breast and/or breast and ovarian cancer
– Limitations: breast cancer>50 yrs not included; clinical
data not validated
– www.myriad.com
• Genetics referral appropriate for women with significant
risk of mutation

26. 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, CAGene
• Likelihood of other breast cancer syndrome
– Pedigree analysis

27. Case 1: Ruth
Ruth, a 35 year old Jewish woman, comes for a family
planning visit. 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
Ruth has no other risk factors or pertinent family
history. Her first menses was at age 12.

28. Case 1: Pedigree
Key
-Breast CA
-Ovarian CA
Dx 55
d. 56
Dx 42
82 yrs
Ruth
35
Russian Jewish Polish Jewish
37 28
60
58

29. Case 1: Risk Assessment
• Gail Model:
– 0.3% five year risk. 11.3% lifetime risk
• Claus Model:
– No category for 1 breast CA, 1 ovarian CA in
second degree relatives
– Lifetime risk of 10.4% based on affected
paternal grandmother
• Limitations in each model

30. Case 1: BRCA1/2 Risks
• Myriad Table:
– 28.6% risk of mutation in patient
– 41.3% risk of mutation in grandmother
• Referral for Cancer Genetic Counseling is
appropriate
– For cancer risk assessment and discussion of
genetic testing for BRCA1/2

31. Consider cancer genetic
counseling referral if:
• Myriad table indicates significant risk for
BRCA1/2 mutation
• Family medical history is suspicious for a
hereditary cancer syndrome
• Client has extreme anxiety about the cancer
family history
• Client has questions beyond the scope of your
practice

32. “High/Genetic Risk”
Indications for referral
• Two 1st degree, or one 1st and one 2nd degree
relative in the same lineage with breast cancer
<50 yrs
• 3 or more family members (1st or 2nd degree)
with breast cancer, same lineage, any age
• Male with breast CA + breast or ovarian CA in a
relative

33. “High/Genetic Risk”
Indications for referral (cont.)
• Patient or 1st degree relative with breast CA <40
yrs, with or without family history
• Two or more cases of ovarian CA, same lineage
• Ashkenazi Jewish ancestry and any family
history of breast <50 or ovarian cancer, any age
• Both breast and ovarian CA, same lineage

34. Case 2: Alison
Alison is a 40 year old Caucasian (non-Jewish) patient
who 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
Alison has no other risk factors for breast cancer.
Menses began at age 11. 1st child at age 25.
She feels that with her family history, breast cancer is
inevitable

35. Case 2: Pedigree
Dx 58
65 yr
Dx 65
71 yr
Dx 79
d.81
Caucasian mix
Swedish / Finnish
Key:
-Breast CA
Alison
40 yr
15 yr

36. Case 2: Risk Assessment
• Gail Model:
– 5 year risk of 1.2% / lifetime risk of 20.4%
• Claus Model:
– Lifetime risk 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

37. “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-power genes may play a role and
interact with environmental triggers

38. Case 2: Pedigree
Dx 58
65 yr
Dx 65
71 yr
Dx 79
d.81
Caucasian mix
Swedish / Finnish
Key:
-Breast CA
Alison
40 yr

39. Risk Based Management
Moderate/Familial:
• BSE monthly; CBE once or twice a year
• Mammogram once a year starting at 35 or 5-10
yrs prior to earliest case of breast cancer
– Immediate biopsy of any suspicious findings
• Option: Chemoprevention
• Lifestyle changes

40. Case 2: Assessment
• Patient is in “Moderate/Familial” risk category
• Can begin breast cancer screening by age 35
• Counseling issues:
– Low risk for BRCA1 or BRCA2 mutation
– Screening and preventive strategies
– Psychosocial – perceived risk, fears
– Support resources
– Referral to genetics if patient anxiety remains high or
other questions arise

41. Preventive lifestyle measures
• Increase exercise – 30 min. or more most days
• Weight control
• Diet ?? (results inconclusive):
– Less saturated, animal and trans fat, more fish
– Less refined flour, sugar
– More fruits/vegetables, whole grains, beans, nuts
– More fiber, antioxidant supplements?? (data limited)
• Alcohol: less than 1-2 drinks/day
• Breast feeding

42. Oregon Genetics Providers
• Portland
– Oregon Health & Science University
– Legacy Health Care
– Northwest Perinatal Services
– Kaiser-Permanente
• Eugene
– Center for Genetics & Maternal Fetal Medicine
• Bend
– Genetic Counseling of Central Oregon (cancer only)

43. Genetic Services Information
• Consult “Genetic Services contact list”
• Phone consultations available:
– OHSU Genetics Consultation Line 503-494-5516
• Refer patients by phone, fax, mail, or patient self-
referral
• ‘Indications For Referral’ in resource packet
– Preconception/prenatal
– Pediatric
– Adolescent/Adult

44. Resource Materials
• Pedigree symbols and template
• Patient pamphlets:
– ‘Do You Have Cancer in Your Family?’
– ‘Genetic Testing: A Fact Sheet’
• Web-based cancer genetics resource list
• Resource materials at
www.healthoregon.org/genetics
• Genetics tutorials on www.modimes.org