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

Halsted Radical Mastectomy

SURGERY CHEMORADIATION Sequential therapy

CHEMO SURGERYRADIATION Sequential therapy

EPIDEMIOLOGY

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

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  5,000 women will die from breast cancer. This represents 14% of all cancer deaths in women in  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

Canadian Cancer Statistics 2014

RISK FACTORS IN BREAST CANCER

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

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

SYSTEMIC THERAPIES FOR BREAST CANCER

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

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

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?

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

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

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

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

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: 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

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: x HER2 group score – 0.34 x ER group score x proliferation group score x invasion group score 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

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)

ADJUVANT CHEMOTHERAPY

PRINCIPLES OF CHEMOTHERAPY  Oxford Overview ( ): 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

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

 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:

 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+

EXTENDED TAMOXIFEN: ASCO GUIDELINES 2014

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

EXTENDED TAMOXIFEN: ATLAS

 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

TAMOXIFEN: SERM (SELECTIVE ESTROGEN RECEPTOR MODIFIER)

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

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

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

AROMATASE INHIBITORS

 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

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

OFS IN PREMENOPAUSAL PATIENTS

HER-2 POSITIVE BREAST CANCER: 15-20%

 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

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.

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