Familial Cancer Risk Assessment:

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Genetics and Primary Care

• Familial Cancer Risk Assessment
• Breast and Ovarian Cancer

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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

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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

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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

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Cancer Etiology

• 5-10 of cases have a strong hereditary
  component
• 15-20 are familial/multifactorial
• 70-75 are thought to be sporadic

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Hereditary Breast/Ovarian CA

• Occurs in multiple generations
• Younger ages of onset (often
• 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

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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

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Each cell has two copies of BRCA1 and BRCA2
BRCA2
BRCA1
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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 relative with breast CA
• 2 of all women of Ashkenazi Jewish ancestry

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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.

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Risk-Based ManagementHigh/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

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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

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Other Hereditary Breast Cancer Syndromes

• Cowden Syndrome
• Facial/buccal lesions, GI hamartomas
• Thyroid, endometrial lesions or CA, macrocephaly
• Li-Fraumeni
• Early-onset sarcoma, leukemia, brain CA
• Adrenocortical CA, others
• Peutz-Jeghers -
• Childhood GI hamartomas, GI CA
• Pigmentation of lips, buccal mucosa, hands/feet

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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

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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

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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

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What can YOU do?
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Goal ClassificationWho needs what?
Assessment
Intervention
Risk Classification
Standard prevention recommendations
Average
Personalized prevention recommendations
Moderate (Familial)
Family Hx
Referral for genetic evaluation with personalized
prevention recommendations
High/Genetic
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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.

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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.

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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 73643-651 (1994)

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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 cancer50 yrs not included
  clinical data not validated
• www.myriad.com
• Genetics referral appropriate for women with
  significant risk of mutation

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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

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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.

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

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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

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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

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High/Genetic Risk Indications for referral

• Two 1st degree, or one 1st and one 2nd degree
  relative in the same lineage with breast cancer
  
• 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

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High/Genetic Risk Indications for referral
(cont.)

• Patient or 1st degree relative with breast CA yrs, with or without family history
• Two or more cases of ovarian CA, same lineage
• Ashkenazi Jewish ancestry and any family history
  of breast
• Both breast and ovarian CA, same lineage

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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

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

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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

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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
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Risk Based ManagementModerate/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

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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

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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

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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)

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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

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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.oregongenetics.org
• Genetics tutorials on www.modimes.org