Breast Cancer Genetics

1. Breast Cancer Genetics Dr. Ellen Warner Division of Medical Oncology MOTP Academic Half Day October 11, 2011

2. All cancers are caused by genetic mutations!

3. Genetic Mutations Causing Breast Cancer Acquired (90%-95%) External causes Internal causes Inherited + Acquired (5%-10%)

4. Inherited Mutations that Increase Breast Cancer Risk

5. ‘Hereditary’ Breast Cancer

6. Pierre Paul Broca 1824-1880

8. HEREDITARY BREAST CANCER: Clinical Presentation • Autosomal dominant with high penetrance • Young age - often • Bilateral breast cancer - often • Epithelial ovarian cancer - often • Male breast cancer - occasionally • Jewish ethnicity - raises level of suspicion

9. ~ All Breast- Ovary Families

10. - both highly expressed in breast, ovary, thymus and testis - levels of both rise during epithelial cell proliferation- hundreds of inherited mutations in each reported to date

12. POPULATION vs. FAMILY ASCERTAINMENT

13. Case : Anna age 38 • R. breast lump • Sister had ca breast age 33 (No other known family history of cancer) • Mammogram normal, very dense breasts • US: suspicious 1.5cm mass • Core biopsy: invasive ca breast • Referred to you for a pre-op consultation

14. Questions 1) Does Anna qualify for genetic testing?

15. 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

16. 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

17. Question • What does a consultation at a ‘familial cancer / cancer genetics clinic’ involve?

18. Genetic Assessment • Detailed family history (pedigree) • Risk assessment (familial + non-familial) • Education (risk factors + genetics 101) • Pre-test counseling • Motivation for testing / mental status • Limitations, benefits, risks, • Test procedure and wait time for results • Alternatives to testing • Management options if +ve

19. 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

20. Question 3) Would there be any point testing Anna if her affected sister had tested negative in 2001?

21. Genetic Testing • Predictive testing • Known family mutation • Any result is meaningful • Genetic screening • No known family mutation • Affected member tested • If no mutation found result is ‘indeterminate’ (~ 50% of breast-only high risk families)

22. Causes of Indeterminate Test • No BRCA mutation but some other (not testable) gene mutation(s) • Cancers cluster in family by chance or shared environmental cause • Phenocopy (sporadic cancer in BRCA family) • False negative BRCA test

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

24. 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:

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

26. PTT vs. Sequencing / DHPLC

27. Genetic Testing in Ontario Today Known family mutation or Ashkenazi Jewish Sequence appropriate segment of DNA No known mutation : 1) MLPA – screens for large mutations 2) Direct sequencing or DHPLC Sensitivity – 95% Specificity – 85-90%

28. Variants of Uncertain Significance (VUS) • 10-15% of all testing today • Huge problem for all • Need to check database regularly • Some upgraded to detrimental • Some downgraded to benign • Manage as ‘indeterminate’ test

29. Question 4) Is there any rationale for referring Anna for ‘urgent’ genetic testing? Would finding a mutation change Anna’s treatment: • Local? • Systemic?

30. BRCA-related Breast Cancer: Local Management • With breast conservation risk of ipsilateral recurrence low for first 5-10 years • No evidence for  radiation toxicity • Higher risk of contralateral breast cancer • No rationale for ‘prophylactic’ ipsilateral mastectomy • TRAM flap is ‘once in a lifetime’ • Radiation may preclude implants • Breast conservation or bilateral mastectomy are both reasonable options

31. 10 Year CBC Risk by Age of Diagnosis of 1st Cancer

32. BRCA-related Breast Cancer: Systemic Management • Prognosis similar to non-BRCA with similar age, stage, grade • Faster doubling time • May be more responsive to DNA x-linking chemotherapy (cisplatin, carboplatin,etc.) • Taxane resistant? • Adriamycin resistant? • PARP inhibitors ?

33. PARP Inhibitors Double-stranded DNA break (chemo) normal cells tumour cells X BRCA PARP Homologous repair Base excision repair Cell Death

34. BRCA Status should not be used to guide systemic therapy outside a clinical trial

35. Expedited Genetic Testing • 8 weeks (vs. 10 months) Criteria • Patient considering bilateral mastectomy instead of radiotherapy • Patient needs semi-urgent pelvic surgery eg. hysterectomy for bleeding

36. Questions 5) Would finding a mutation alter Anna’s post-treatment management?

37. MANAGEMENTOPTIONS FOR MUTATION CARRIERS X

38. MANAGEMENTOPTIONS FOR MUTATION CARRIERS X

39. Risk-Reducing Mastectomy • Reduces risk by ~98% if nipple removed • Eliminates need for screening • ~ 25% of unaffected, 50% affected opt for it but wide variations • Patient satisfaction high if no coercion • No evidence that survival superior to MRI screening + BSO • Cosmetic result better if done before breast cancer diagnosis

40. TRAM flap reconstruction

41. Risk- Reducing BSO • Single most important management strategy for BRCA mutation carriers • ↓ breast cancer risk by 50% to 80% if prior to natural menopausal • More effective if: • Younger age • BRCA2 vs. BRCA1 ?? • HRT doesn’t lower effectiveness

42. Does Tamoxifen Prevent Cancer in Unaffected BRCA1 Mutations Carriers? Evidence for • Adjuvant studies • Effectiveness of BSO for BRCA1 Evidence Against • NSABP P-1 study • Bilateral cancers tend to be concordant for ER

43. ER Concordance of Bilateral BRCA1-Related Breast Cancers Odds ratio 6.4 p<0.0001 Weitzel J et al. CEBP 2005

44. Ongoing Prevention Studies Post-menopausal women • Letrozole vs. placebo (phase 3, BRCA) • Anastrozole vs. placebo ± BP (phase 3, high risk) Pre-menopausl women • LHRH agonist + estradiol + testosterone (phase 2, BRCA) • Arzoxifene vs. tam vs. placebo ( phase 2, high risk) • Vitamin D3 vs. placebo (phase 2, high risk) Any menopausl status • Contralateral radiation (phase 2, BRCA)

45. MANAGEMENTOPTIONS FOR MUTATION CARRIERS X

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

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

49. Limitations of Mammographyfor High Risk Screening • young age = dense breasts • Faster tumour growth

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