Treatment Options for Breast Cancer in Low- and Middle-Income Countries: Adjuvant and Metastatic Systemic Therapy

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Women s Empowerment Cancer Advocacy Network (WE CAN) Conference Bucharest, Romania October 2015 Treatment Options for Breast Cancer in Low- and Middle-Income Countries: Adjuvant and Metastatic

1 Women s Empowerment Cancer Advocacy Network (WE CAN) Conference Bucharest, Romania October 2015 Treatment Options for Breast Cancer in Low- and Middle-Income Countries: Adjuvant and Metastatic Systemic Therapy 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 Breast Cancer Systemic Therapies Drug treatments that can attack cancer cells throughout the body Endocrine therapy Chemotherapy Targeted therapy

of Breast Cancer Tumor ER and HER2 status are CRITICAL in

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

4 Treatment of Early Stage Breast Cancer (Adjuvant Therapy) Breast cancer is most curable when detected early Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence Multidisciplinary care is 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

5 Is Screening or Adjuvant Systemic Therapy More Important in Breast Cancer Survival? U.S. Breast Cancer Death Rates Both matter! Berry D et al, NEJM 353: , 2005

6 Treatment of Metastatic Breast Cancer Metastatic breast cancer is not curable, but is treatable Goals: Control and regression of disease Prolongation of life Improvement in symptoms and quality of life

7 Metastatic Breast Cancer Survival in USA: Impact of New Agents Endocrine therapy + Chemotherapy + Targeted therapy Giordano S et al, Cancer 100:44-52, 2004

8 WHO Model List of Essential Medicines 19 th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Endocrine therapy: Tamoxifen Anastrozole (Arimidex) Leuprolide (Lupron) Chemotherapy: Doxorubicin (Adriamycin) Cyclophosphamide (Cytoxan) Paclitaxel (Taxol) Docetaxel (Taxotere) Chemotherapy (cont): Fluorouracil (5-FU) Methotrexate Carboplatin Gemcitabine (Gemzar)** Capecitabine (Xeloda) Vinorelbine (Navelbine) Targeted Therapy Trastuzumab (Herceptin)

9 UN/WHO Global Monitoring Framework for Non-communicable Diseases: Targets for 2025

10 Endocrine Therapy

11 Endocrine Therapy in Breast Cancer Aromatase inhibitors (anastrozole, letrozole, exemestane), ovarian suppression (leuprolide, goserelin) SERMS (tamoxifen, toremifene), SERDS (fulvestrant) Estrogen Estrogen Receptor Cell Growth and Division Endocrine therapy is effective only in ER-positive breast cancer ER/PR staining: CRITICAL IN SELECTING THERAPY!

12 WHO Model List of Essential Medicines 19 th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Endocrine therapy: Tamoxifen Anastrozole (Arimidex) Leuprolide (Lupron)

13 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 doesn t impact recurrence in ER negative breast cancer Adjuvant tamoxifen significantly reduces recurrence in ER positive breast cancer Tamoxifen effective in both pre- and postmenopausal women

14 Adjuvant (Early Stage) Endocrine Therapy in Breast Cancer Tamoxifen: substantial clinical efficacy, low cost, and several decades of use throughout world Still the standard for premenopausal women Reasonable for many postmenopausal women Longer duration (> 5 years) may benefit some patients Aromatase inhibitors: additional small reduction in breast cancer recurrences (and deaths) compared to tamoxifen Only effective in postmenopausal women Side effects different (?better) Ovarian suppression Only effective in premenopausal women Addition to tamoxifen (or aromatase inhibitors) may add benefit in subset of young 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 WHO Model List of Essential Medicines 19 th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Chemotherapy: Doxorubicin (Adriamycin) Cyclophosphamide (Cytoxan) Paclitaxel (Taxol) Docetaxel (Taxotere) Fluorouracil (5-FU) Methotrexate Chemotherapy (cont): Carboplatin Gemcitabine (Gemzar)** Capecitabine (Xeloda) Vinorelbine (Navelbine)

18 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 (doxorubicin, epirubicin) better than CMF regimens Taxanes (paclitaxel, docetaxel) add to anthracyclines Not all patients/tumors benefit from chemotherapy! ER-negative, high grade, and HER-2+ tumors get most benefit from chemotherapy

19 Chemotherapy Dose Matters Adjuvant Chemotherapy - 20 Year Follow-up Milan Study Bonadonna G et al, N Engl J Med 332: 901-6,1995 Probability of Relapse-free Survival Control <65% of dose 65-84% of dose >85% of dose Disease-free survival Probability of Overall Survival Giving < 85% of full dose is the same as no chemo Overall survival Years after Mastectomy Years after Mastectomy If chemotherapy is given, it should be given at full dose

20 European School of Oncology Guideline: Chemotherapy for Metastatic Breast Cancer Cardosa F et al, J Natl Cancer Inst 101: , 2009 Sequential single agent chemotherapy is generally the preferred choice Less toxicity than combination chemo No data to support optimal sequence Combination chemotherapy is 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

21 Targeted Therapy

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

23 WHO Model List of Essential Medicines 19 th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Targeted Therapy Trastuzumab (Herceptin)

24 Adjuvant (Early Stage) HER2 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-targeted therapy Pertuzumab approved in the US in combination with chemotherapy and trastuzumab in the preoperative setting

25 European School of Oncology Guideline: HER2 Targeted Therapy for Metastatic Breast Cancer Cardosa F et al, J Natl Cancer Inst 101: , 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

26 Complications of Breast Cancer Bone Metastases Hypercalcemia Radiation therapy Pain Spinal cord compression Orthopedic surgery Fractures Bone is the most common initial site of metastatic recurrence in breast cancer

27 European School of Oncology Guideline: Bone Metastases in Breast Cancer Cardosa F et al, J Natl Cancer Inst 101: , 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 These agents reduce fractures, the need for radiation or surgery, and other complications Should be continued even in presence of disease progression

28 The Future of Cancer Treatment: Precision (Personalized) Medicine

29 Identifying Targets for Cancer Therapy EGFR HER2 Therapies approved or in development for many of these pathways P P P ALK or ROS1 SOS SHC GRB2 BRAF P MEK NRAS KRAS HRAS PI3K P P P PTEN P PDK P P AKT P P mtor P ERK S6K P CDK4/6

Ongoing NCI MATCH (Molecular Analysis for Therapy Choice) Clinical Trial http://deainfo.nci.nih.gov/advisory/ncab/164_1213/conley.

30 Ongoing NCI MATCH (Molecular Analysis for Therapy Choice) Clinical Trial pdf Genomic Profiling of Tumor Actionable mutation detected Study Agent 1 Continue until progression Progressive disease Eligibility: Metastatic solid tumors and lymphomas that have progressed on > 1 line of therapy Access to many drugs in development: currently > 40 drugs pledged Check for additional actionable mutation Study Agent 2

Systemic Treatment of Breast Cancer: Summary Main principles of modern oncology Multidisciplinary treatment Evidence-based medicine Individualized (tailored) therapy Primary goals of therapy

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

Adjuvant Systemic Therapy in Early Stage Breast Cancer

Adjuvant Systemic Therapy in Early Stage Breast Cancer Julie R. Gralow, M.D. Director, Breast Medical Oncology Jill Bennett Endowed Professor of Breast Cancer Professor, Global Health University of Washington