Breast Cancer Genetics and Prevention

1. Breast Cancer Genetics and Prevention January 13, 2009

2. Case: Anna age 38 • Recent core biopsy for clinical stage I ca breast • Sister had ca breast age 33 • BRCA testing done 2001 was normal • Referred to you for pre-op consultation

3. Questions • Is there any rationale for referring Anna for genetic testing? • If yes, would finding a mutation: • Alter treatment of Anna’s cancer? • Local? • Systemic? • Alter her post-treatment management? 3) If neither Anna nor her sister have a BRCA mutation what is their 3rd sister’s risk of breast cancer and how should she be managed?

4. BREAST CANCER

5. ‘FAMILIAL’ BREAST CANCER • less striking family history • no ovarian cancer • often older onset • no BRCA1 or BRCA2 mutation found • likely causes: • chance • common environmental factors • lower penetrance genes

6. Lower Penetrance Genes • CHEK2 1100 delC • ATM carriers • BRIP1 (Nature Genetics, Oct. 2006) • PALB2(Nature Genetics Feb. 2007) • Other ‘cancer genes’? (CDKN2A, HNPCC?) • Not yet isolated: • breast density gene (s) • carcinogen metabolism genes? • estrogen receptor and metabolism genes? • CDH –1 (familial gastric cancer)

7. HEREDITARY BREAST CANCER: Clinical Presentation • Autosomal dominant with high penetrance • Young age • Bilateral breast cancer • Epithelial ovarian cancer • Male breast cancer • (certain ethnic groups)

8. Hereditary Breast Cancer:History • 1866 Broca: 1st description • 1970’s: Lynch: 3 breast /breast-ovary families • 1990: linkage to chromosome 17 • 1994: BRCA1 localized on chromosome 17 • 1995: BRCA2 localized on chromosome 13

9. PREVALENCE • ~5% of all breast cancer • ~10% of all ovarian cancer • ~ 1/250 of general population

10. ~ All Breast- Ovary Families

11. - both highly expressed in breast, ovary, thymus and testis - both involved in repair of double-stranded DNA breaks- levels of both rise during epithelial cell proliferation

12. Pathogenesis of ‘BRCA Cancer’ Cell proliferation in breast/ovary, etc. Loss / inactivation of normal BRCA gene in a cell (chance)= LOH Use of less accurate DNA repair pathways Progressive accumulation of mutations Cancer

14. Genetic Counseling • Risk assessment (familial + non-familial) • Education (risk factors + genetics 101) • Pre-test counseling • Motivation for testing / mental status • Limitations, benefits, risks, • Test procedure • Alternatives to testing • Management options

15. Genetic Counseling (contd.) 4. Post-test counseling • Meaning of result reviewed • Patient response assessed • Patient’s plans for sharing results with family reviewed • Management plan formulated 5. Longitudinal follow-up? • Promote compliance with management plan • Psychological support • Update new developments

16. Genetic Testing • Predictive testing • Known family mutation • Any result is meaningful • Genetic screening • No known family mutation • If no mutation found result is ‘indeterminate’

17. Main Challenges of Genetic Testing • Cost (genetic screening) • Availability • > 50% of screening results ‘indeterminate’ • Variable ‘natural history’ of mutation carriers • Limitations of current management strategies • Unkown risk with ‘negative’ predictive testing

18. GENETIC TESTING CRITERIA:Affected Individuals • Breast cancer < age 35 • Jewish and breast cancer < age 50 • Bilateral breast ca, first < age 50 • Male breast cancer • Epithelial ovarian cancer any age • 2+ close relatives (including self) & any combination of • Breast cancer < age 50 • Ovarian cancer • Male breast cancer • Jewish and breast / ovarian cancer any age • 3+ close relatives with breast / ovarian cancer

19. METHODS OF GENETIC TESTING • Protein Truncation Test (PTT) • Gene Sequencing • Denaturing High Performance Liquid Chromatography (DHPLC) • Multiplex Ligation Dependent Probe Amplification (MLPA) • other

20. Normal DNA: CTAGCATGTATAGGG  RNA: CUAGCAUGUAUAGGG  Polypeptide: Leu-Ala-Tyr-Ile-Gl  Mutant CTAGCATGAATAGGG  CUAGCAUGCAUAGGG  Leu-Ala-(stop)  Protein Truncation Test Normal protein Truncated protein Protein gel:

21. ATCTTAGAGTGTCCC ATCTTAGTGTCCC DNA Sequencing A T C G A T C G Mutant (185delAG) Normal Start Start

22. PTT vs. Sequencing

23. Genetic Testing in Ontario Today Known mutation or Ashkenazi Jewish Sequence appropriate segment of DNA Unknown mutation Fresh blood  mRNA  cDNA: 1) MLPA – screens for large mutations 2) DHPLC – equivalent to ‘sequencing’ Sensitivity – 95% Specificity – 85-90%

24. POPULATION vs. FAMILY ASCERTAINMENT

25. MANAGEMENTOPTIONS FOR MUTATION CARRIERS X

26. Prevention

27. Risk-Reducing Mastectomy • ‘official’ risk reduction 90% in literature • Likely closer to 100% if total mastectomy • ~ 25% of women with mutations opt for it but wide variations (counseling, culture, etc.) • Revival of subcutaneous mastectomy? • Reconstruction gives better cosmetic result than after breast cancer surgery

28. Salpingo-oophorectomy • Prevents ovarian & fallopian tube cancer • Lowers breast cancer risk by ~ 50 -80% - risk reduction greater if surgery earlier - risk reduction not affected by HRT - works at least as well for BRCA1 as BRCA2 • Peritoneal cancer risk likely over-stated • Ideally by age 40 for BRCA1 and age 45 for BRCA2 • TAH is optional

29. Tamoxifen Benefits • Invasive cancer & DCIS reduced by 50% in all high risk subgroups including BRCA2 • Effect sustained after tamoxifen stopped • Non-signficant reduction in fractures BUT • Reduction in ER+ tumours only • No survival benefit to date • No apparent effect on BRCA1 carriers

30. Tamoxifen Risks

31. Raloxifene • Not an agonist in the uterus • Shorter half-life than tamoxifen • Not appropriate for pre-menopausal women

32. NSABP P-2 (STAR) 20,000 women 5 yr. Gail risk 1.66% postmenopausal randomized 5 years tamoxifen raloxifene

34. Oral Contraceptives • Reduce risk of ovarian cancer by 50% • Optimal duration is 5 years • No significant effect on breast cancer risk if taken ages 25 to 40.

35. Breast Screening

36. The Ideal 100% sensitivity DCIS invasive  1cm, node -ve The Reality 50% sensitivity DCIS rarely found 50% > 1 cm 40% node +ve Mammography Screening for Women with BRCA Mutations

37. Limitations of Mammographyfor High Risk Screening • young age = dense breasts

39. Limitations of Mammographyfor High Risk Screening • young age = dense breasts • Faster tumour growth • Earlier invasion • Less time for DCIS to calcify • BRCA1 pathology?

40. Why should MRI be more sensitive than mammography? • Contrast agent (Gad –DTPA) • Tomographic slices (3-D)

42. Disadvantages of MRI • $$$ • Lower specificity • Biopsies more difficult • Logistics • Claustrophobia

43. Breast MRI Screening Studiesfor ‘High Familial Risk’ Women • Interval cancer rate < 10% • Sensitivity • MRI 71% - 91% • Mammography 23% - 40% • Ultrasound 32% - 40% • CBE 6% - 18% • Stage distribution more favourable

44. False Positive Rates

45. Does MRI screening improve survival?

46. Evidence for effect of MRI screening on survival • Cohort studies • Comparison with historical controls • Randomized studies

47. Prospective Cohort Study (CBCRA 2004) • Women with BRCA mutations • Screened for breast cancer • ‘MRI group’ (n=466) • ‘Control group’ (n=903) • Median follow-up = 3.3 yrs.

48. Stage Distribution of Breast Cancer Cases

49. Indications for Screening Breast MRI • Known BRCA mutation • Untested 1st degree relative of BRCA mutation carrier • Untested/ no family mutation but > 20% lifetime risk (BRACPRO, BOADICEA) • Chest irradiation < age 30, at least 8 yrs. Post treatment

50. MRI Screening Protocol • Annually with mammography (or staggered q 6months) • Start age 30 • Reasonable to stop age 65-69