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Hereditary Breast/Ovarian Cancer

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

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Hereditary Breast/Ovarian Cancer

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  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 2006

  2. Acknowledgments • Reviewed by: • Members of The Genetics Education Project • Clinical subcommitteeof the Ontario Cancer Genetics Steering Committee • 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 many factors: 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. ONE HIT (hit=mutation) Knudson ‘two-hit’ Model Sporadic Cancer 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 Inherited Cancer Born with one hit (hit = mutation) Birth: Two2 non-mutated copies of the BRCA1 gene SECOND HIT One mutation in oneBRCA1 gene; One non-mutated copy Two mutations - one in eachBRCA1 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 • ~1/800 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 Unaffected Breast Cancer bb Bb bb Bb Bb bb Affected with breast cancer Population Risk 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

  15. Who should be offered referral for genetic counselling and/or genetic testing?.... • Multiple cases of breast and/or ovarian cancer in family • closely related relatives • more than one generation • Breast cancer diagnosed at < age 50 • Breast cancer diagnosed at age < 35 • Family member with both breast and ovarian cancers • Ashkenazi Jewish + relatives with breast or ovarian cancer

  16. …Who should be offered referral for genetic counselling and/or genetic testing? • Family member with primary cancer in both breasts • Family member with invasive serous ovarian cancer • Male breast cancer • Family member with an identified with a 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 • Psychological assessment

  20. …A genetics consultation involves: • Assessment of eligibility for genetic testing • Estimated risk of a mutation must be ≥10% • Availability of living affected relative to be tested first • Discussion of risks, benefits & limitations of test • Testing and disclosure of genetic test results • May be months before results are available • Determining patient’s thoughts about breast cancer • Motivations for testing • Screening/management recommendations

  21. Genetic Testing • Available at regional genetic centres • Familial cancer clinics • Covered by OHIP if criteria are met: October 2005 • 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

  22. 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: ? reported previously

  23. 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

  24. 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

  25. 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 inventions 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

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

  27. 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

  28. What is the benefit of having genetic testing?Can anything be done to change risk/outcome? • Recommendations for BRCA1/2 mutation carriers: • Breast surveillance – “I” recommendation USPSTF 2005 • Monthly BSE – unproven • CBE q6 months starting when carrier status identified • Annual mammography starting at age 30 • MRI and U/S if surveillance required before age 30 • MRI may have higher sensitivity for surveillance of breast cancer among BRCA mutation carriers • Studies ongoing

  29. What is the benefit of having genetic testing?Can anything be done to change risk/outcome? • Recommendations for BRCA1/2 mutation carriers: • Ovarian surveillance • Consider… • PV exam • transvaginal ultrasound • serum CA-125 • q6 months starting age 30-35 • Symptom recognition

  30. 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 breast cancer after 3 years in 76 with risk-reducing mastectomy compared with 8 cases of breast cancer in 63 who chose surveillance

  31. Management of Mutation Carriers –Surgical options: risk reduction salpingo-oophorectomy (SO) • Kauff et al. NEJM 2002 • 170 women with BRCA1 or BRCA2 mutations • Proportion free from br ca or ovarian ca at 5 years • 94% (SO group) vs 69% p=0.006 • Hazard ratio for either cancer after SO: 0.25 (95% CI 0.08-0.74) • Rebbeck et al. NEJM 2002 • Breast cancer in 21% of SO group / 42% of control (hazard ratio 0.47) • Hazard ratio for cancer of the coelomic epithelium after SO was 0.04

  32. Management of Mutation Carriers –Surgical options: risk reduction salpingo-oophorectomy (SO) • Eisen et al. J Clin Oncol 2005 • Study of BRCA carriers who had SO and developed breast cancer within 15 years • Breast cancer in 51/1388 (3.5%) SO group / 115/1751 (6.2%) control group • BRCA1: 56% reduction in breast cancer (OR 0.43, p = 0.00006) • BRCA2: 46% reduction in breast cancer (OR 0.57, p = 0.11) • Summary: Consider for mutation carriers before age 40

  33. Management of Mutation Carriers - Chemoprevention • Tamoxifen • 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 • Tamoxifen Prevention Trial 2005 • May show promise in estrogen +ve tumours associated with BRCA2 • Raloxifene • Shows promise - conflicting data • Aromatase inhibitors – ExCel trial • Exemestane vs. placebo (Ca Info Service – 1-888-939-3333)

  34. Management of Mutation Carriers Consider… • Psychological support to assist with: • Adjusting to new information • Making decisions regarding management • Addressing family issues, self concept • Dealing with future concerns i.e. child bearing, surgical menopause after oophorectomy • Stress management • Support groups

  35. Management of Mutation Carriers Consider… • Additional psychosocial support for those with: • History of depression/anxiety • Poor coping skills • Multiple losses in the family • Loss of parent at a young age • Recent loss • Multiple surgical procedures

  36. Important messages to share with women • Most women will not develop breast cancer • Of those who do – most will not have a known FH • For most women – increasing age is the greatest risk factor • Great majority of women with FH of breast cancer do not fall into a high-risk category and do not develop breast cancer and are not eligible for genetic testing • Women at increased risk of breast cancer should be “breast aware”

  37. Cases

  38. 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?

  39. 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

  40. Legend Colon Breast Case 1

  41. 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 or ovarian cancer at any age • Management: • CBE and mammogram q1 years starting at 40 • Discuss lifestyle changes • Consider enrollment in chemoprevention clinical trials

  42. 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

  43. Legend Breast Case 2

  44. 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 trials

  45. 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

  46. Legend Prostate Breast Ovarian Case 3

  47. Case 3 Answer: • Highrisk for hereditary breast/ovarian cancer • Two relatives on the same side of the family with breast cancer <50 or ovarian cancer (any age) • One 1st/2nd degree relative with breast cancer: • <35 years • Bilateral, first before age 50 • Breast and ovarian cancer (any age) • Male breast cancer

  48. 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 • Consider chemoprevention, i.e. Tamoxifen • Referral to psychologist and/or support group • Discuss: lifestyle changes, enrollment in chemoprevention clinical trials

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

  50. Legend Colon Breast Case 4

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