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 BRCA1BRCA2 Breast cancer to age 8050-85%50-85% Ovarian cancer to age 8020-60%up to 27% Male breast cancerSlight incr.~6% Prostate cancerSlight incr. Slight incr. Pancreatic cancerNo incr.1.5-5% MelanomaNo 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 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.

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.comwww.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 mixSwedish / 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 mixSwedish / 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 www.healthoregon.org/genetics Genetics tutorials on www.modimes.orgwww.modimes.org