Women’s Empowerment Cancer Advocacy Network (WE CAN) Conference

1. Women’s Empowerment Cancer Advocacy Network (WE CAN) Conference Treatment Options for Breast Cancer: Adjuvant and Metastatic Systemic Therapy Dar es Salaam, Tanzania, September 2014 Julie R. Gralow, M.D. Jill Bennett Endowed Professor of Breast Cancer Director, Breast Medical Oncology Professor, Global Health University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance

2. Why Tanzania Has a Special Place in My Heart Summit of Mt. Kilimanjaro 19,340 feetFebruary 7, 2009

3. Importance of Pathology: Not all Breast Cancers Are the Same!! Estrogen Receptor (ER) + 75% of Breast Cancer HER-2 + 20-25% of Breast Cancer Tumor ER and HER2 status critical in selecting therapy in both early stage and metastatic breast cancer

4. African Women More Likely to Have: • Young onset breast cancer • High grade (aggressive) tumors • High proliferative tumors • ER negative tumors • “Triple negative” (ER-/PR-/HER2-) tumors

5. Breast Cancer Systemic Therapies • Drug treatments that can attack cancer cells throughout the body • Endocrine therapy • Chemotherapy • Biologically-targeted therapy

6. WHO Essential Medicine List for Adults 18th Edition (April 2013) • Antineoplastics relevant to treatment of breast/cervical cancer • Tamoxifen • Doxorubicin (Adriamycin) • Cyclophosphamide (Cytoxan) • Paclitaxel (Taxol) • Docetaxel (Taxotere) • Fluorouracil (5-FU) • Methotrexate • Carboplatin • ??Trastuzumab (Herceptin) – proposed for addition

7. Treatment of Early Stage Breast Cancer • Breast cancer most curable when detected early • Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence • Multidisciplinary care critical for best outcomes • Surgery • Radiation therapy • Adjuvant systemic (drug) therapy reduces risk of recurrence and death • Should be tailored to the patient and tumor

8. Incremental Benefit of Adjuvant Treatments in Early Stage Breast Cancer in USA chemotherapy + endocrine therapy + HER2 targeted therapy chemotherapy + endocrine therapy mastectomy No surgery Survival

9. Treatment of Metastatic Breast Cancer • Metastatic breast cancer is not curable, but can be very treatable • Goals: • Control and regression of disease • Prolongation of life • Improvement in symptoms and quality of life

10. Choices in the Treatment of Metastatic Breast Cancer • Choice of treatment is based on many factors: • Patient age, menopausal status, general health and functional status • Tumor ER status, HER-2 status • Previous treatments • Extent and sites of disease • Available therapies in the patient’s country

11. Metastatic Breast Cancer Survival in USA: Impact of New AgentsGiordano S et al, Cancer 100:44-52, 2004

12. Endocrine Therapy in Breast Cancer SERMS (tamoxifen), SERDS Aromatase inhibitors, ovarian suppression Cell Growth and Division Estrogen Estrogen Receptor • Endocrine therapy effective only in ER-positive breast cancer • ER/PR staining: CRITICAL IN SELECTING THERAPY!

13. Adjuvant (Early Stage) Endocrine Therapy in Breast Cancer Tamoxifen has substantial clinical efficacy, less cost, and several decades of use throughout world Still the standard for premenopausal Reasonable for many postmenopausal Longer duration (> 5 years) may benefit many patients Adjuvant aromatase inhibitors: small differences in recurrences (and in some trials deaths) Side effects different Ovarian suppression effective as a sole treatment Still unclear whether it adds to chemo/tamoxifen

14. Early Breast Cancer Trialists’ Collaborative Group Clinical Trials of Tamoxifen in Early Stage Breast Cancer: Disease-free Survival ER Negative ER Positive tamoxifen control Adjuvant tamoxifen significantly reduces recurrence in ER positive breast cancer Adjuvant tamoxifen doesn’t impact recurrence in ER negative breast cancer Tamoxifen effective in both pre- and postmenopausal women

15. Endocrine Therapy for Metastatic Breast Cancer • Endocrine therapy is the preferred choice for ER+ metastatic breast cancer • Less side effects than chemotherapy • Exceptions: • Concern or proof of endocrine resistance • Need for fast response (location, symptoms)

16. Chemotherapy

17. Adjuvant (Early stage) Chemotherapy in Breast Cancer Adjuvant chemotherapy reduces recurrences and deaths Reducing dose from that proven to be effective in clinical trials reduces benefit Chemotherapy drugs have significant side effects For unselected patients/tumors: anthracyclines better than CMF regimens taxanes add to anthracyclines – expensive Not all patients/tumors benefit from chemotherapy! ER-negative, high grade, HER-2+ tumors get most benefit from chemotherapy

18. Chemotherapy Dose MattersAdjuvant Chemotherapy - 20 Year Follow-upMilan Study Bonadonna G et al, N Engl J Med 332: 901-6,1995 Disease-free survival Overall survival Control 1.0 1.0 <65% of dose 0.9 0.9 65-84% of dose 0.8 0.8 >85% of dose 0.7 0.7 0.6 0.6 Probability of Overall Survival 0.5 0.5 Probability of Relapse-free Survival 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 5 10 15 20 5 10 15 20 Years after Mastectomy Years after Mastectomy If chemotherapy is given, it should be given at full dose

19. European School of Oncology Guideline: Chemotherapy for Metastatic Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 • Sequential single agent chemotherapy generally preferred choice • Less toxicity than combination chemo • No data to support optimal sequence • Combination chemotherapy reserved for patients with: • rapid clinical progression • life-threatening visceral metastases • need for rapid symptom/disease control • Chosen regimen should be evidence-based, with proven efficacy and acceptable toxicity

20. Biologically-Targeted Therapy

21. Four US FDA-Approved Drugs with HER-2 as a Target 20-25% of breast cancers overexpress HER2 Pertuzumab Anti-HER-2 Antibody HER-2 Trastuzumab (Herceptin) Anti-HER-2 Antibody cancer cell nucleus Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor T-DM1 Antibody-Drug Conjugate cell division Only effective for HER2+ breast cancer

22. Adjuvant (Early Stage) HER-2 Targeted Therapy • Anti-HER2 monoclonal antibody trastuzumab (Herceptin) for 1 year is standard • Reduces recurrence by 1/2 & deaths by 1/3 when added to chemo in early stage breast cancer • Trastuzumab going off patent soon, and prices will drop • All regimens include chemotherapy in addition to HER2 targeting therapy

23. European School of Oncology Guideline: HER2 Targeted Therapy for Metastatic Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 • Anti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable) • Optimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknown

24. Complications of Breast Cancer Bone Metastases Radiationtherapy Hypercalcemia Pain Spinal cordcompression Orthopedicsurgery Fractures The bone is the initial site of recurrence in 35-40% of breast cancer patients

25. European School of Oncology Guideline: Bone Metastases in Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 • Bone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastases • Bisphosphonates (pamidronate, zoledronic acid) • RANK ligand inhibitor (denosumab) • Agents should be started early, if possible before onset of bone symptoms • Should be continued even in presence of disease progression

26. Systemic Treatment of Breast Cancer: Summary • Main principles of modern oncology • Multidisciplinary treatment • Evidence-based medicine • Individualized (tailored) therapy • Keep in mind goals of therapy • Adjuvant: curative intent • Metastatic: incurable but treatable • Include psychosocial and supportive care and symptom-related interventions • Include patient preferences and active participation • Patients, families and caregivers should be invited to participate in decision-making