1. Hereditary Breast/Ovarian Cancer Prepared by: June C Carroll MD, CCFP, FCFP Sydney G. Frankfort Chair in Family Medicine Mount Sinai Hospital, University of Toronto Andrea Rideout MS, CGC, CCGC Certified Genetic Counsellor Project Manager – The Genetics Education Project Funded by:Ontario Women’s Health Council Version: March 2009

2. Acknowledgments Reviewed by:  Members of The Genetics Education Project Funded by:The Ontario Women’s Health Council as part of its funding to The Genetics Education Project * Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.

3. Outline Sporadic versus familial cancer Hereditary breast cancer syndromes Referral guidelines Benefits, risks and limitations of genetic testing Management Cases

4. Cancer All cancer involves changes in genes…. Threshold effect: During mitosis & DNA replication  mutations occur in the cell’s genetic code Mutations are normally corrected by DNA repair mechanisms If repair mechanism or cell cycle regulation damaged  Cell accumulates too many mutations → reaches ‘threshold’ → tumor development

5. Sporadic Cancer All cancer arises from changes in genes….  But NOT all cancer is inherited Most breast cancer is sporadic ~ 80%  Due to mutations acquired over a person’s lifetime: Cause unknown – multifactorial  Interaction of: age environment, lifestyle (obesity, alcohol), chance, unknown factors  Sporadic cancer generally has a later onset

6. Clustering of Cancer in Families 11% lifetime risk of developing breast cancer ~20% of women with breast cancer have a family history: 10 -15% of breast cancer is familial:  Due to some factor in the family Environmental Undiscovered gene mutation Chance Generally not eligible for genetic testing 5-10% of breast cancer is hereditary:  Caused by an inherited gene mutation which causes increased risk for cancer Variety of cancer syndromes About 2/3 of these - BRCA 1 or BRCA 2 mutations May be eligible for genetic testing

7. Proportion of Hereditary Breast Cancer Sporadic 80% Familial 10-15% Hereditary 5-10%

8. Knudson ‘two-hit’ Model Sporadic Cancer Birth: Two non-mutated copies of the gene One mutation in one gene; Second gene non-mutated ONE HIT ( hit=mutation) SECOND HIT Two mutations - one in each gene CANCER

9. Knudson ‘two-hit’ Model Hereditary Cancer Birth: Two non-mutated copies of the gene One mutation in one gene; Second gene non-mutated ONE HIT ( hit=mutation) SECOND HIT Two mutations - one in each gene CANCER

10. Compared to sporadic cancer, people with hereditary cancer have… A higher risk of developing cancer A younger age of onset of cancer  Generally < 50 years of age Multiple primary cancers Hereditary cancer is less common in the general population than sporadic cancer

11. Genes involved in hereditary breast/ovarian cancer > 2,600 mutations in:  BRCA1- chromosome 17  BRCA2 - chromosome 13 Autosomal dominant transmission Carrier frequency of BRCA1& 2 mutations  ~1/500 – 1/1,000 in general (Caucasian) population  1/40 - 1/50 in Ashkenazi Jewish people 3 common mutations in Ashkenazi Jews  Unique French Canadian mutations

12. bb BbBb BbBb BbBb BRCA mutation Autosomal Dominant Inheritance Population Risk Population Risk Susceptible BRCA gene Normal BRCA genes Legend B: BRCA gene with mutation b: normal BRCA gene Susceptible BRCA gene

13. BRCA1 and BRCA2 What happens when their function is compromised ? Both genes are tumor suppressors:  Regulation of cell growth  Maintenance of cell cycle Mutation leads to:  Inability to regulate cell death  Uncontrolled growth, cancer

14. Consequences of having a BRCA mutation: Estimated cancer risk by age 70 BRCA Mutation Carriers In General Population Breast Cancer ♀ BRCA1 & BRCA2 50-85%11% Ovarian Cancer BRCA1 40-60%1-2% Ovarian Cancer BRCA2 10-20%1-2% Breast Cancer ♂ BRCA2 ≤6%Rare

15. Who should be offered referral for genetic counselling and/or genetic testing?.... Multiple cases of breast or ovarian cancer on same side of family, especially  in closely related relatives  in more than one generation  when breast cancer is diagnosed before age 50 A family member with breast cancer diagnosed before age 35 A family member with both breast and ovarian cancers An Ashkenazi Jewish heritage, particularly with relatives with breast or ovarian cancer

16. … Who should be offered referral for genetic counselling and/or genetic testing? A family member with primary cancer in both breasts (especially if before age 50) A family member with ovarian cancer A family member with male breast cancer A family member with an identified BRCA1 or BRCA2 mutation  USPSTF 2005 recommends referral for genetic counselling and evaluation for BRCA testing to women with family history indicating increased risk of BRCA mutations

17. Case: Rachel Rachel - healthy 40 year old  Concerned about her risk for cancer  Family history of both breast & ovarian cancer

18. Case: Rachel’s family history LEGEND Breast cancer Ovarian cancer Br Ca Dx 30 Br Ca Dx 38 Ov Ca Dx 40 Ov Ca Died 48 RACHEL age 40

19. Rachel was referred to genetics… A genetics consultation involves: Detailed family history information Pedigree documentation  Confirmation of cancer history: pathology reports/death certificates Medical & exposure history Empiric risk assessment Hereditary cancer / genetic risk assessment Psychosocial assessment

20. Psychological Aspects to Consider Motivation for genetic testing:  Reduce uncertainty  Learn about risk for children  Childbearing/marital decisions  Explore further surveillance/treatment options Perceived risk Expectations of genetic testing Psychological well-being – current & past  prior experiences with cancer  prior loss/ disruptions associated with cancer  approaching age of parent’s diagnosis or death from cancer

21. A genetics consultation involves: Assessment of eligibility for genetic testing  Estimated risk of a mutation must be ≥10% for most provincial programs  Most appropriate family member to test first Discussion of risks, benefits & limitations of test Testing and disclosure of genetic test results  Will be months before results are available Discussion of types of results and what they mean Screening/management recommendations

22. Genetic Testing Available at regional genetic centres and familial cancer clinics Covered by provincial insurance plans (i.e. OHIP) if criteria are met: OntarioUS Privative Lab Full gene testing$1,400CDN$3,120 USD Ashkenazi Panel$350$535 Familial mutation$250$440 Testing is only offered if the risk of mutation is ≥10% Test highest risk affected individual first Only in exceptional circumstances will testing be offered to unaffected individuals February 2009

23. Results from Genetic Testing Positive  Deleterious mutation identified Negative  Interpretation differs if a mutation has previously been identified in the family Mutation known – true negative Mutation unknown – uninformative Variant of unknown significance  Significance will depend on how variant tracks through family - i.e. is variant present in people with disease?  Can use software to predict functional significance  Check with lab to see if reported previously

24. Risks/Benefits/Limitations of genetic testing Positive test result Potential Benefits: Clinical intervention may improve outcome Family members at risk can be identified Positive health behaviour can be reinforced Reduction of uncertainty Potential Risks: Adverse psychological reaction Family issues/distress Uncertainty -incomplete penetrance Insurance/job discrimination Confidentiality issues Intervention carries risk

25. Risks/Benefits/Limitations of genetic testing? Negative test result Potential Benefits: Avoidance of unnecessary clinical interventions Emotional - relief Children can be reassured Avoidance of higher insurance premiums Potential Risks: Adverse psychological reaction (i.e. survivor guilt) Dysfunctional family dynamics Complacent attitude to health

26. Risks/Benefits/Limitations of genetic testing? Uninformative test result Potential Benefits: Future research may clarify test results Positive health behaviour can be reinforced Some relief Higher insurance premiums may be avoided Potential Risks: Continue clinical interventions which may carry risks Complacent attitude to health Uncertainty Continued anxiety Higher insurance premiums may not be reduced

27. Normal Mutation Case: Rachel’s test results…. Rachel BRCA1 185delAG Legend Breast cancer Ovarian cancer

28. What is the benefit of having genetic testing? Can anything be done to change risk/outcome? Recommendations for BRCA1 and BRCA2 mutation carriers:  Lifestyle Reduce dietary fat Avoid obesity Reduce alcohol consumption Regular exercise Weak Evidence

29. Recommendations for BRCA1 and BRCA2 mutation carriers Breast cancer surveillance - Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007  BSE – not recommended  CBE – part of surveillance program including imaging  Mammography & MRI (if available) q12 months age ≥30  MRI (possibly + U/S) if surveillance required before age 30  MRI may have higher sensitivity for surveillance of breast cancer among BRCA1/2 carriers 2008 Meta-analysis: combined mammography and MRI screening had a 94% sensitivity, 77% specificity (95% CI; p=0.01)

30. Recommendations for BRCA1 and BRCA2 mutation carriers Ovarian cancer surveillance - Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007  Surveillance not routinely recommended  Women should be counselled on the limitations of current screening for ovarian cancer  If woman chooses surveillance, then consider the following q6 months starting at age 30-35: pelvic exam transvaginal ultrasound serum CA-125  Symptom recognition

31. Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007 Potential benefits should be raised with all women with a known mutation. Multidisciplinary team that includes at least: genetics professional, breast surgeon, plastic surgeon. Women should have access to:  Written and oral information  Support services  Adequate time for reflection Breast reconstruction options should be discussed in advance Management of Mutation Carriers – Surgical options: Risk reduction mastectomy

32. Hartmann et al. NEJM 1999  Retrospective study of 639 women with FH of breast cancer who had bilateral mastectomy (mutation status unknown)  Expected 37 br ca in 425 women at mod risk (Gail model)  Observed 4 (90% risk reduction)  3 br ca in 214 high risk women with mastectomy (1.4%)  156 br ca in 403 sisters without mastectomy – 38.7% (90% risk reduction) Meijers-Heijboer et al. NEJM 2001  139 BRCA1 and BRCA2 mutation carriers ♀  No br ca after 3 years in 76 ♀ with risk-reducing mastectomy compared with 8 cases of br ca in 63 who chose surveillance

33. Management of Mutation Carriers – Surgical options: risk reduction salpingo- oophorectomy (SO) Recommendations from Canadian Hereditary Cancer Task Force, JOGC 2007 The potential benefits of risk reduction SO should be discussed with women. Management by multidisciplinary team that includes a genetics professional 2009 meta-analysis Rebbeck et al.  80% reduction in risk of BRCA 1/2 -associated ovarian/fallopian tube cancer Hazard ratio 0.21 (95% CI = 0.12-0.39)  50% reduction in risk of breast cancer in BRCA 1/2 mutation carriers Hazard ratio 0.49 (95% CI = 0.37-0.65)  Optimal age of SO – more study needed

34. Management of Mutation Carriers - Chemoprevention Tamoxifen Prevention Trial 2005  Invasive breast ca reduced from 42.5/1000 in placebo group to 24.8/1000 in Tamoxifen group in women at increased risk of breast cancer  Preliminary data suggest benefit for BRCA2 but not BRCA1 carriers Raloxifene  Shows promise  No data for mutation carriers Aromatase inhibitors – ExCel trial  Exemestane vs. placebo (Ca Info Service – 1-888-939-3333)  No data for mutation carriers 2007 Canadian Hereditary Cancer Task Force Recommendations: women choosing chemoprevention should be enrolled in a clinical trial

35. Management of Mutation Carriers Consider… Psychosocial support to assist with:  Adjusting to new information most adjust within 3-6 months subset remain psychologically distressed (16-25% anxiety and/or depression)  Making decisions regarding management “to inflict surgery is a hard decision to make… when I don’t have the disease and feel healthy”  Addressing family issues, self concept, body image  Dealing with future concerns i.e. child bearing, surgical menopause after oophorectomy Referral to support groups

36. Management of Mutation Carriers Consider… Additional psychosocial support may be needed for high risk individuals such as those with:  History of depression/anxiety  Poor coping skills  Inadequate social support / conflict in the family  Multiple losses in the family  Loss of parent at a young age  Recent loss  Multiple surgical procedures

37. Testing children for BRCA1 and BRCA2 mutations Benefits and non-harm  No medical benefit from genetic testing for children < 18  Potential harm from this information – psychological, insurability, etc. Autonomy  Consider the child’s autonomy and ability to provide informed consent  Parents are not always the decision maker for a child Privacy/confidentiality  Results are available to the parent who may or may not share these with the child Equity & justice  Access to resources if the genetic status is known vs unknown

38. Despite focus on hereditary cancers… Most women will not develop breast cancer  Of those who do, most will not have a known family history Increasing age is the greatest risk factor Most women with family history of breast ca:  do not fall into a high-risk category  do not develop breast cancer  are not eligible for genetic testing All women should be “breast aware” and contact their health care providers if any lumps or breast changes are noted.

39. Cases

40. Assessing the Risk of Hereditary Breast Cancer Using the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?

41. Case 1 Alz -75 A&W ↑CholBrCa Dx 61 Colon Ca Dx 76 died 85Aneurysm A&W AsthmaA&W Your Patient AccidentMI 80 BrCa Dx 68 Colon Breast Legend

42. Case 1 Colon Breast Legend

43. Case 1 Answer: Moderate risk for hereditary breast cancer Two 1 st /2 nd degree relatives on the same side of the family with breast cancer < age 70 Management:  CBE and mammogram q1 years starting at 40  Discuss lifestyle changes  Consider enrollment in chemoprevention clinical trial

44. Case 2 Alz -75 A&W ↑Chol Migraines Stroke -83 A&W Asthma A&W Your Patient AccidentMI 85 IDDM Br Ca Dx 41 Breast Legend

45. Case 2 Breast Legend

46. Case 2 Answer: Moderate risk for hereditary breast cancer One 1 st /2 nd degree relative with breast cancer at 35-49 years Management:  CBE and mammogram q1 years staring at 40  Discuss lifestyle changes  Consider enrollment in chemoprevention clinical trial

47. Case 3 Alz -75 A&WOvCa Dx 52 Prost Ca 65 ↑ Chol Bilateral Breast Ca Dx 49 died 53 Aneurysm A&W Asthma A&W Your Patient AccidentBrCa Dx 75 IDDM Legend Prostate Breast Ovarian

48. Case 3 Legend Prostate Breast Ovarian

49. Case 3 Answer: High risk for hereditary breast/ovarian cancer One 1 st /2 nd degree relative with:  bilateral breast cancer, first one before age 50  ovarian cancer (any age)

50. Case 3 Answer: High risk Management:  Offer genetics or familial cancer clinic referral Pt. agrees: Familial Cancer Clinic will suggest management Pt. declines: Discuss management with familial cancer clinic or manage as moderate risk Referral to psychologist and/or support group Discuss: lifestyle changes, enrollment in chemoprevention clinical trials

51. Case 4 Alz -75 A&W ↑Chol BrCa Dx 71 Colon Ca Dx 76 died 85Aneurysm A&W ↑CholA&W Your Patient AccidentBreast Ca 85 MI 69 Colon Breast Legend

52. Case 4 Colon Breast Legend

53. Case 4 Answer: Low risk for hereditary breast cancer Meets none of the high or moderate risk criteria Management:  Clinical breast exam & mammogram q 1-2 years beginning at age 50  Discuss lifestyle changes

54. Case 5 Nt Causes -75 A&WSchizophrenic MI 65 ↑ Chol Died 81 stroke IDDM Asthma A&W Your Patient OvCa Dx 52 Prost Ca Dx 80 Died 81 BrCa Dx 55 IDDM BrCa Dx 45 Eastern Europe Ashkenazi Jewish Irish / German Christian Legend Prostate Breast Ovarian

55. Case 5 Legend Prostate Breast Ovarian

56. Case 5 Answer: High risk for hereditary breast/ovarian cancer 3 relatives on the same side of the family with breast or ovarian cancer at any age Management: Offer genetics or familial cancer clinic referral  Agrees: Familial Cancer Clinic will suggest management  Declines: Discuss management with familial cancer clinic or manage as moderate risk Referral to psychologist and/or support group Discuss: lifestyle changes, enrollment in chemoprevention clinical trials

57. Case 6 Neck CA Dx 70 Bladder CA Dx55 A&W Head CA Dx 65 BrCa Dx 61 Bladder CA Dx 58 died 62 A&W AsthmaA&W Your Patient AccidentMI-84 Diabetes Bladder Breast Head & Neck Legend

58. Case 6 Bladder Breast Head & Neck Legend

59. Case 6 Answer: Low risk for hereditary breast cancer  Meets none of the high or moderate criteria Patient’s family worked in a tannery and shoe factory.  Aromatic amines (dyes) increase the risk of bladder cancers  Shoe manufacturers have an increase risk of nasal cavity cancers  The high incidence of cancer is due to common environment exposures.

60. Resources The National Cancer Institute: http://cancernet.nci.nih.gov/ http://cancernet.nci.nih.gov/  Detailed information on cancer for patients and physicians including causes, treatments, clinical trials & more Canadian Cancer Society: www.cancer.cawww.cancer.ca FORCE: www.facingourrisk.orgwww.facingourrisk.org www.hereditarybreastcancer.cancer.ca  Patient information aid Gene Clinics: www.Genetests.orgwww.Genetests.org  See Gene Reviews for clinical summaries Where to find a genetics centre:  www.cagc-accg.ca/centre1.html www.cagc-accg.ca/centre1.html

61. The Genetics Education Project Committee June Carroll MD CCFP Judith Allanson MD FRCP FRCP(C) FCCMG FABMG Sean Blaine MD CCFP Mary Jane Esplen PhD RN Sandra Farrell MD FRCPC FCCMG Judy Fiddes Gail Graham MD FRCPC FCCMG Jennifer MacKenzie MD FRCPC FAAP FCCMG Wendy Meschino MD FRCPC FCCMG Joanne Miyazaki Andrea Rideout MS CGC CCGC Cheryl Shuman MS CGC Anne Summers MD FCCMG FRCPC Sherry Taylor PhD FCCMG Brenda Wilson BSc MB ChB MSc MRCP(UK) FFPH

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