Hereditary Breast/Ovarian Cancer

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 Familial 10-15% Hereditary 5-10% Sporadic 80%

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

9. Knudson ‘two-hit’ Model Hereditary Cancer ONE HIT (hit=mutation) Birth: Two non-mutated copies of the gene SECOND HIT One mutation in one gene; Second gene non-mutated 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. Autosomal Dominant Inheritance Legend B:BRCA gene with mutation b: normal BRCA gene Normal BRCA genes BRCA mutation bb Bb bb Bb Bb bb Population Risk Susceptible BRCA gene Susceptible BRCA gene Population Risk

13. BRCA1 and BRCA2What 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

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

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: February 2009 • 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

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. 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 Risks/Benefits/Limitations of genetic testingPositive test result

25. 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 Risks/Benefits/Limitations of genetic testing?Negative test result

26. 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 Risks/Benefits/Limitations of genetic testing?Uninformative test result

27. Legend Breast cancer Ovarian cancer Case: Rachel’s test results…. Rachel BRCA1185delAG Normal Mutation

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. Management of Mutation Carriers –Surgical options: Risk reduction mastectomy 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

32. Management of Mutation Carriers –Surgical options: Risk reduction mastectomy • 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 CancerUsing the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?

41. Legend Colon Breast Case 1 Colon Ca Dx 76 died 85Aneurysm Accident MI 80 Alz -75 ↑Chol BrCa Dx 68 A&W BrCa Dx 61 A&W A&W Your Patient A&W Asthma

42. Legend Colon Breast Case 1

43. Case 1 Answer: • Moderate risk for hereditary breast cancer • Two 1st/2nd 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. Legend Breast Case 2 Accident MI 85 Alz -75 Stroke -83 ↑Chol IDDM A&W Br Ca Dx 41 A&W A&W Migraines Asthma Your Patient A&W

45. Legend Breast Case 2

46. Case 2 Answer: • Moderaterisk for hereditary breast cancer • One 1st/2nd 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. Legend Prostate Breast Ovarian Case 3 Bilateral Breast Ca Dx 49 died 53 Aneurysm Accident BrCa Dx 75 Alz -75 Prost Ca 65 IDDM A&W A&W OvCa Dx 52 ↑ Chol Asthma Your Patient A&W

48. Legend Prostate Breast Ovarian Case 3

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

50. Case 3 Answer: Highrisk • 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