1. Dr. Jan-Willem Henning MBChB FRCPC Medical Oncologist Tom Baker Cancer Centre APPROACH TO BREAST CANCER

5. Halsted Radical Mastectomy

6. SURGERY CHEMORADIATION Sequential therapy

8. CHEMO SURGERYRADIATION Sequential therapy

9. EPIDEMIOLOGY

11. 2/5 Canadians will develop cancer in their lifetime 2/5 Canadians will develop cancer in their lifetime ¼ Canadians will die of cancer ¼ Canadians will die of cancer 63% of Canadians diagnosed with cancer will survive at least 5 years 63% of Canadians diagnosed with cancer will survive at least 5 years 1 in 9 lifetime risk for Canadian women to develop Breast Cancer 1 in 9 lifetime risk for Canadian women to develop Breast Cancer Average Lifetime risk of 12% Average Lifetime risk of 12% 1 in 29 women will die from breast cancer 1 in 29 women will die from breast cancer In Canada In Canada ** Lung cancer is the most common cause of cancer death in women, breast cancer is the second most common ** Lung cancer is the most common cause of cancer death in women, breast cancer is the second most common CANADIAN STATS Canadian Cancer Statistics 2014

12. CANADIAN STATS ON BREAST CANCER  It is estimated that in 2015:  25,000 women will be diagnosed with breast cancer. This represents 26% of all new cancer cases in women in 2015.  5,000 women will die from breast cancer. This represents 14% of all cancer deaths in women in 2015.  On average, 68 Canadian women will be diagnosed with breast cancer every day.  On average, 14 Canadian women will die from breast cancer every day.  220 men will be diagnosed with breast cancer and 60 will die from it. Canadian Breast Cancer Society 2015

13. Canadian Cancer Statistics 2014

14. RISK FACTORS IN BREAST CANCER

16. RISK FACTORS: CANCER SOCIETY OF CANADA Canadian Breast Cancer Society 2015

17. ANNALS OF SURGERY Vol. 237, No. 4, 474–482© 2003.

18. SYSTEMIC THERAPIES FOR BREAST CANCER

19. SYSTEMIC THERAPIES IN BREAST CANCER  Chemotherapy  Anthracylines, taxanes, platinums (TCH), and others…  Targeted therapy  Trastuzumab, Trastuzumab-Emtansine, Pertuzumab  Endocrine therapy  Tamoxifen  Aromatase Inhibitors  GnRH analogues

20. GOALS OF ADJUVANT THERAPY  To prevent Breast Cancer Recurrence  To improve overall survival

21. DOES IT WORK?  EBCTCG meta-analysis has shown a decrease in disease specific mortality  Relative risk reduction – therefore women at highest risk derive the greatest benefit  Should all Women with Breast Cancer receive Chemotherapy?

22. HOW DO DECIDE AN INDIVIDUAL’S RISK FOR RECURRENCE?  Prognostic factors  Clinicopathologic factors  Tumor size  Histologic grade  Lymph node status  Lymphovascular invasion  Patient age  ER/PR status  Her2 status  ?Ki67  Risk calculators – Adjuvant!/Cancermath.net/Finprog  Molecular profile – Oncotype Dx/Mammaprint

23. HOW DO WE DETERMINE THE BENEFIT FROM ADJUVANT THERAPY?  Predictive factors  ER/PR status  Her 2 status  Adjuvant!  Oncotype Dx

24. TWO IMPORTANT QUESTIONS ASKED BY PATIENTS 24 Will my cancer come back? Do I need chemotherapy?

25. THE ONCOTYPE DX ® BREAST CANCER ASSAY  Determines the expression of 21 specific genes from an individual patient's tumour  Prognostic: provides information about the individual risk of recurrence at 10 years  Predictive: predicts the likelihood of benefit of chemotherapy in patients who will receive endocrine therapy 25

26. THE RECURRENCE SCORE ® RESULT USES KEY GENES LINKED TO MOLECULAR PATHWAYS  16 breast cancer-related genes and 5 reference genes Paik S et al. NEJM 2004;351:2817-26 26 Proliferation Ki67 STK15 Survivin CCNB1 (cyclin B1) MYBL2 HER2 GRB7 HER2 Oestrogen ER PGR BCL2 SCUBE2 Invasion MMP11 (stromelysin 3) CTSL2 (cathepsin L2) Others GSTM1 CD68 BAG1 Reference ACTB (β-actin) GAPDH RPLPO GUS TFRC

27. THE RECURRENCE SCORE ® RESULT PROVIDES A CONTINUOUS SCORE BASED ON THE EXPRESSION LEVEL OF DIFFERENT GENES AND GENE GROUPS Paik S et al. NEJM 2004;351:2817-26 27 + 0.47 x HER2 group score – 0.34 x ER group score + 1.04 x proliferation group score + 0.10 x invasion group score + 0.05 x CD68 – 0.08 x GSTM1 – 0.07 x BAG1 Recurrence Score ® result (0–100) categories Low risk <18 Intermediate risk ≥18 and <31 High risk ≥31 Recurrence Score ® result = The score captures the continuous biology

28. RECURRENCE RATES IMPLICATED WITH NODAL+ (STAGE II AND III)  Nodes 1-3: 20-30% risk of recurrence (T>3cm)  Nodes 4-9: 50-70% risk of recurrence  Nodes >9: >80% risk of recurrence  Benefit:risk ratio very favorable for systemic chemotherapy  The greater the risk, the more benefit: -Reduction of Recurrence -Improving Survival (OS)

29. ADJUVANT CHEMOTHERAPY

30. PRINCIPLES OF CHEMOTHERAPY  Oxford Overview (2005-2011): EBCTCG Lancet  Meta-analysis 100,000 randomly selected patients treated in different RCT’s  Non-taxanes vs. Taxanes 44,000  Different Anthracyclines 6,000  Anthracyclines compared to CMF 18,000  No chemo vs. poly-chemotherapy 32, 000

31. PRINCIPLES OF CHEMOTHERAPY  Oxford Overview (EBCTCG) Lancet 2011update  Benefit for Anthracycline and Taxane-based chemotherapy (Poly-chemotherapy).  Regardless of nodal, ER, or PR status  Molecular Diagnostic Assays may identify ER+ tumors that may not warrant Chemotherapy

33.  FEC-D (3 cycles of 5-FU, Epirubicin and Cyclophosphamide, followed by 3 cycles of Docetaxel) given IV for 18 weeks  Risk of Breast CA Recurrence 35-40%  Risk reduction (benefit) 10-12% with chemo  Risk of Breast CA Mortality 15-25%  Absolute Survival Benefit of 8-10% with chemo FOR OUR CASE:

34.  Additional Benefit with Adjuvant Endocrine Therapy  Sum total of Benefit for both chemo and endocrine therapy  In Breast Oncology: 1+1 is not 2 BUT THE TUMOR ER+

35. EXTENDED TAMOXIFEN: ASCO GUIDELINES 2014

36. ADJUVANT ENDOCRINE THERAPY IN 2014  Tamoxifen (5+5)10y  Menopausal status unknown: tamoxifen 10y  Ovarian Function Suppression (OFS)  Tamoxifen alone (AI contra-indicated) 10y  AI Upfront 5 y  Switch tamoxifen 2-3y followed AI up to 5y  Tamoxifen 5y extended AI up to 5y  Intolerance: switch Pre-or Perimenopausal Women Post-menopausal Women

37. EXTENDED TAMOXIFEN: ATLAS

38.  Reduction: Breast Cancer Recurrence and mortality, as well as reduction in overall mortality for 10y group.  Carry Over Effect  Cumulative Risk Recurrence for years 5-14: 21.4% vs 25%  Mortality (RR) years 5-14: 12.2% vs 15.0%  Absolute OS benefit 2.8%  Increase VTE and Endometrial CA  Decrease IHD  Stroke equivocal

39. TAMOXIFEN: SERM (SELECTIVE ESTROGEN RECEPTOR MODIFIER)

40. TAMOXIFEN  20 mg po daily  Reduces risk of breast cancer recurrence by 40% and breast cancer mortality by 35% (Relative Risk, Meta- analysis EBCTCG).  Antitumor effect: estrogen receptor antagonist  Partial estrogen agonist  Bone –helps prevent bone demineralization  Uterus – causes endometrial hyperplasia which leads to an increased risk of endometrial cancer  ?lowers risk of CVD – favorable effect on lipids

41. TAMOXIFEN SIDE-EFFECTS  Hot Flashes  Common  ?due to an anti-estrogenic effect on the CNS causing thermoregulatory dysfunction  Venous thromboembolic disease  Risk may be as high as 2 – 3 fold over normal  Risk factors include prior surgery, fracture and immobilization  Conflicting data on arterial thromboembolism  Endometrial cancer  Majority present with vaginal bleeding  In the NSABP P1 study – nearly all occurred in >50 age group  Risk increases with longer duration of tam  Risk decreases with discontinuation of tam  Approximate risk is 3 fold higher than normal

42. TAMOXIFEN SIDE-EFFECTS  Other uterine pathology  Fibroids, polyps  Menstrual irregularity in pre-menopausal women  Vaginal discharge  Sexual dysfunction  Cataracts  – controversial but may be slight increased risk  -recommend annual eye examination

43. AROMATASE INHIBITORS

44.  Letrozole & anastrozole  Non-steroidal inhibitors  Exemestane  Steroidal inactivator  Block aromatization of androstenedione and testosterone to estrone  Aromatase is in skeletal muscle, adipose tissue and breast tissue

45. AROMATASE INHIBITOR SIDE-EFFECTS  Lack partial agonist activity therefore do not see side-effects such as an increased risk of thromboembolic disease and endometrial hyperplasia/carcinoma  Not indicated in women with functioning ovaries  Negative effect on bone density  Ca and vit D +/- bisphosphonate, monitor BMD  MSK  45% experience arthralgias/stiffness  NSAIDs  Hot flashes  Venlafaxine, gabapentin  Vaginal dryness / dyspareunia  Vaginal moisturizers (Replens), vaginal lubricants

46. OFS IN PREMENOPAUSAL PATIENTS

47. HER-2 POSITIVE BREAST CANCER: 15-20%

48.  Presence increase relative risk of recurrence by 30%.  Immunohistochemistry staining, indertemined followed by CISH/FISH.  Trastuzumab added benefit relative risk reduction.  Treatment for 1 year.  Sequentially with Anthracyclines, but concurrently with Taxanes.  Risk of cardiomyopathy ADJUVANT HER-2 + BREAST CA

49. TREATMENT PER STAGE  Stage I: BCS + RT/Mastectomy (SNLD) +/- Tamoxifen and/or Aromatase Inhibitors (AI’s)  Stage II: (High risk node – and all node +) BCS+RT/Mastectomy+SNLD +or- AXLND Systemic(Chemo/Endocrine/Trastuzumab) Additional locoregional XRT (Mastectomy)  Stage III: (Locally Advanced Breast Cancer) Neoadjuvant systemic therapies/Trastuzumab, Mastectomy+AXLND Locoregional XRT.

50. THANK YOU