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Familial Cancer Risk Assessment: Breast and Ovarian Cancer

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  • ~5-10% of all cancer cases have a strong hereditary component with significant increased risk for close relatives ~15-20% of cancer cases are “familial” with clustering of cases and probable multifactorial causation ~75% of all cancers are sporadic with minimal inherited component and slight to negligible increased risk for relatives
  • Accounts for about 5-10% of all cases of breast and ovarian cancer ~50-70% of HBOC cases associated with mutations in the tumor suppressor genes BRCA1 or BRCA2 Genetic testing for BRCA1 and BRCA2 mutations is available to women whose family history meet “hereditary breast cancer” criteria. Important to test affected family member first.
  • 13% of Ashkenazi Jewish women with “sporadic” breast CA <50 24% of Ashkenazi Jewish women with ovarian CA
  • Chemoprevention Tamoxifen - up to 45% reduction in BrCA risk in BRCA2 carriers (?in BRCA1 carriers) Oral Contraceptives – 50% reduction in ovarian CA Prophylactic bilateral mastectomy May reduce breast CA risk up to 90% Prophylactic bilateral oophorectomy May reduce risk for ovarian CA by 50-90% studies need validation May reduce risk for breast CA by 50% - studies also need validation
  • Cowden Syndrome– <1% of all BrCA Multiple lesions of the skin and mucosa (acral keratoses, papillomas, trichilemmomas), breast, thyroid and endometrial lesions/cancer, GI hamartomas, truncal lipomas, macrocephaly Li-Fraumeni – <1% of all BrCA Very early onset cancers: sarcoma, breast, leukemia, osteosarcoma, melanoma, colon, pancreas, brain, adrenal cortex Peutz-Jeghers - <1% of all BrCA Multiple early-onset GI hamartomas, mucocutaneous hyperpigmentation, cancers: breast, testes, ovaries, GI-tract
  • Type of primary cancer(s) in each affected relative Age of disease onset in each affected relative earlier onset generally confers higher risk for close relatives Cancer status in 1 st and 2 nd degree relatives (often discounted) Other medical findings associated with hereditary cancer syndromes: i.e. thyroid findings, benign breast disease, lipomas, uterine fibroids, skin findings, etc. Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers)
  • 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 Based on the age of diagnosis, total number of affected 1 st and 2 nd degree relatives Separate risk tables for persons of Ashkenazi Jewish ancestry Limitations: Based on non-validated clinical data sent in with samples Does not include relatives with breast cancer >50 years Does not capture other breast cancer syndromes www.myriad.com
  • 2 or more 1 st degree, or one 1 st and one 2 nd degree relative in the same lineage with breast cancer <50 yrs or two or more 1 st degree relatives of the patient’s father Insurance coverage: Some insurers and some plans will cover cancer genetic risk assessment/cancer genetic counseling. Others will not. More difficult to obtain coverage for unaffected person with a family history than an affected person. Pre-authorization recommended. Pre-authorization for cancer genetic testing is important as tests are expensive. The genetic counselor will facilitate the pre-auth for testing if indicated and if patient decides to have testing. Insurance discrimination – needs to be discussed before insurer is contacted regarding coverage.
  • 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
  • Again, it is important for patient to check own insurance policy to see if genetics referral is covered. Some patients will not want their insurance notified of a genetics referral because of concerns about insurance discrimination.
  • Transcript

    • 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
    • 7.  
    • 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
    • 15.  
    • 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 1 st and 2 nd degree relatives
        • Cancer status in both sides of the family
        • Ethnic background on both sides
        • Other medical findings – benign tumors, etc.
    • 22.  
    • 23. Gail Model
      • Calculates 5 yr and lifetime risk (to 90 yrs) of breast cancer based on multiple criteria
      • Limitations: age of onset, 2 nd 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 1 st and 2 nd 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 1 st degree, or one 1 st and one 2 nd degree relative in the same lineage with breast cancer <50 yrs
      • 3 or more family members (1 st or 2 nd 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 1 st 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. 1 st 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.oregongenetics.org
      • Genetics tutorials on www.modimes.org

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