Familial Cancer Risk Assessment:

1
Genetics and Primary Care

• Familial Cancer Risk Assessment
• Breast and Ovarian Cancer

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
• Cancer family history a primary tool
• Screening for hereditary breast/ovarian CA in the
  primary care setting
• Genetic counseling and testing for hereditary
  breast and/or ovarian cancer
• 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
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
7
Hereditary Breast/Ovarian CA

• Occurs in multiple generations
• Younger ages of onset (often lt50)
• 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
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

9
Average risk

• No family history of breast cancer and no other
  known risk factors
• Others who may be at average risk (?)
• One 1st degree relative diagnosed gt60 yrs
• One or two 2nd degree relatives diagnosed gt60 yrs
• Current screening recommendations
• Monthly SBE
• Annual CBE
• Annual mammography starting 40-50 yrs

10
(No Transcript)
11
Hereditary Breast and Ovarian CA (HBOC)

• About 70 to 85 of HBOC cases are caused by
  mutations in either the BRCA1 or BRCA2 gene
• Dominant deleterious mutations in either gene
  increase cancer risk dramatically
• Genetic testing for BRCA1 and BRCA2 gene
  mutations is available to women with family
  history meeting hereditary breast cancer
  criteria

12
BRCA1 and BRCA2 genes
BRCA2
BRCA1
13
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.

14
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 lt50 and one close
  relative with breast CA lt50
• 2 of all women of Ashkenazi Jewish ancestry
• 25 of all Ashkenazi Jewish women with ovarian
  cancer

15
Other Hereditary Breast Cancer Syndromes

• Cowden Syndrome lt1 of all BrCA
• Facial/buccal lesions, GI hamartomas
• Thyroid, endometrial lesions or CA, macrocephaly
• Li-Fraumeni lt1 of all BrCA
• Early-onset sarcoma, leukemia, brain CA
• Adrenocortical CA, others
• Peutz-Jeghers - lt1 of all BrCA
• Childhood GI hamartomas, GI CA
• Pigmentation of lips, buccal mucosa, hands/feet

16
Hereditary Ovarian Cancer syndromes

• Hereditary Breast/Ovarian Cancer (HBOC)
• 75 of families have mutations in BRCA1 or BRCA2
• Hereditary Site Specific Ovarian Cancer (HSSOC)
• 3 or more close relatives with ovarian cancer
• 40-60 due to BRCA1 or 2 mutations
• Remainder due to unknown gene or genes
• Hereditary Non-Polyposis Colorectal Cancer
  (HNPCC)
• Early-onset colorectal, endometrial cancer, other
  GI cancers
• 12 lifetime risk for ovarian cancer

17
(No Transcript)
18
What can YOU do?
19
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.

20
(No Transcript)
21
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
22
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.

23
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)

24
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 cancergt50 yrs not included
  clinical data not validated
• www.myriad.com
• Genetics referral appropriate for women with
  significant risk of mutation

25
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

26
Consider cancer genetic counseling referral if

• Myriad table indicates significant risk for
  BRCA1/2 mutation
• Patient and/or family history meet criteria
  listed in Who to Refer handout
• 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

27
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

28
Risk Based ManagementModerate/Familial

• Moderate Risk of Breast Cancer Gail or Claus
  lifetime risk of 15-40 with low Myriad risk of
  BRCA1 or 2 mutations and no indication of other
  cancer syndromes
• Screening recommendations
• 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 modifications

29
Preventive lifestyle measures

• Good for all risk categories!
• 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, fiber
• Alcohol less than 1-2 drinks/day
• Breast feeding

30
(No Transcript)
31
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

32
Ethical Issues Genetic Counseling/Testing

• Confidentiality/Privacy
• Preserve other family members confidentiality
  when documenting family history
• Potential insurance, employment, social
  discrimination
• Sharing information with at-risk relatives
• Positive results on one family member suggest
  risk in others without their consent
• Clients duty to warn at-risk relatives?

33
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

34
Advised Screening Plan for BRCA1/2 carriers

• BSE monthly starting at age 18
• CBE once or twice a year starting age 25
• Mammogram once a year starting at age 25
• Other screening modalities such as MRI may be
  helpful
• Ovarian surveillance
• Pelvic exam, trans-vaginal ultrasound, /- CA-125
  once or twice a year age 25-35
• Newer Proteomic-based serum screening may be
  available in near future for high-risk women

35
Treatment Options BRCA1/2 Carriers

• Chemoprevention
• Tamoxifen reduces risk in BRCA2 carriers,
  (probably also 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

36
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.

37
Case 1 Pedigree
Russian Jewish
Polish Jewish
Dx 42 82 yrs
60
58
Dx 55 d. 56
Key
-Breast CA
Ruth 35
28
37
-Ovarian CA
38
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

39
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

40
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

41
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
42
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

43
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

44
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
45
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

46
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)

47
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

48
Resource Materials

• Who to Refer? guideline
• Myriad and Claus risk tables
• 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