Breast Cancer & Personalized Medicine

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Clarence Stafford
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1 Principles of Drug Development and Discovery Breast Cancer & Personalized Medicine Grace Leung, Efrat Shalom-Berensohn, Felipe Castro, Kate Burke-Wallace and Shiv Gaglani

for around 502,000 deaths worldwide 1 in every 8 women will get

2 Breast Cancer... 2 nd most common type of Cancer... 5 th most common cause of cancer death in 2006 responsible for around 502,000 deaths worldwide 1 in every 8 women will get breast cancer in her lifetime. Source: World Health Organization (February 2006)

3 - Agenda - Current Therapies and their Efficacy Breast Cancer Patient Flow Overview of Future Therapies Cost Effectiveness Analysis Widespread adoption Issues

Breast Cancer Overview Definition of Breast Cancer: Cancer

milk to the nipple) lobules (glands that make milk).

which incorporates: Surgery Systemic drug therapies (chemo,

4 Breast Cancer Overview Definition of Breast Cancer: Cancer that forms in tissues of the breast ducts (tubes that carry milk to the nipple) lobules (glands that make milk). Breast cancer is treated using a multidisciplinary approach which incorporates: Surgery Systemic drug therapies (chemo, hormone, molecular targeted and Immunotherapeutic agents) Radiotherapy

5 Factors Affecting Treatment Choices Overview 1. Disease stages I - IV (tumor size, regional lymph nodes metastasis; distant metastasis) 2. Is the tumor operable? 3. Pre-menopausal or postmenopausal patient? 4. Risk of disease recurrence 5. Biomarker expression clinically heterogeneous disease Breast Cancer a clinically heterogeneous disease Individuals with the same stage of disease and similar pathological diagnosis experience very different course of disease, reaction to treatment and outcome.

Factors Affecting Treatment Choices Disease Stages I - IV

Stage IIA Tumor 2-5 cm N -/+ or Tumor >5 cm N Stage IIB

cm N + (>3) or Tumor <5 cm N + above collarbone Stage IV

such as bones, organs or lymph nodes far from your breast.

6 Factors Affecting Treatment Choices Disease Stages I - IV Stage I Tumor < 2 cm No spreading to lymph nodes (N -) Stage IIA Tumor 2-5 cm N -/+ or Tumor >5 cm N Stage IIB Tumor <2 cm N + (<3) Stage III Tumor >5 cm N + or Tumor <5 cm N + (>3) or Tumor <5 cm N + above collarbone Stage IV Cancer cells have spread to distant parts of your body, such as bones, organs or lymph nodes far from your breast. Metastasis Source:

7 Factors Affecting Treatment Choices Predictive Biomarkers used in Breast Cancer Breast Cancer Molecular Biomarkers 66% <50 yr 80% >50 yr ER (estrogen receptors) PgR (progesterone receptors) HER2 (human epidermal growth factor receptor-2 ) 20-25% 15% Triple negative (ER- /PgR- / HER2- ) 1-5% Inflammatory Breast cancer Hormone Therapy (e.g. Tamoxifen; Arimidex) Molecular Targeted Therapy (e.g. Herceptin; Tykerb) Chemotherapy Chemotherapy + / - + Chemotherapy Chemotherapy

8 Factors Affecting Treatment Choices Systemic Drug Therapies Choices 1. Chemotherapy Cancer: uncontrolled cell division Aim of chemotherapy: stops cell division Affects normal, healthy cells: severe side effects, toxic 2. Hormone therapy Growth of ER+ and PgR+ breast tumors is controlled by endogenously produced hormones. Aim of hormone therapy: inhibits hormone production Lower toxicity; causes menopause-like symptoms 3. Molecular targeted therapy Herceptin Her2 intercepting protein (FDA approved in 1998; Genentech) Humanized monoclonal antibody that binds to HER2 receptor 42% of patients taking Herceptin in combination with the chemotherapy drug paclitaxel had significant responses (vs. 16% with paclitaxel alone.) Only works on patients over-expressing Her2 Administrate intravenously; Expensive ($70,000); Cardiac dysfunction in 2-7% of cases 4. Immunotherapeutic agents Use of the immune system to reject cancer Either through use of patient's own immune system that is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs New generation of therapies to bring a cure to cancer

9 BC Treatment - History Challenges faced by physicians to treat specific patients Treatment planning for N, ER+ disease was based on: Traditional prognostic factors with limited predictive power (tumor size, patient age) or poor reproducibility (tumor grade) Immunohistochemistry (IHC) markers (e.g., Ki-67: a cellular marker for proliferation) lack standardization and validation Limited insight into relative benefits of chemotherapy for different individuals Chemotherapy treatment for N, ER+ disease: Many women are offered chemotherapy, knowing that few can benefit from it. Prior to 2007, guidelines assumed all patients benefit equally Some patients are under-treated, many others are over-treated

10 Factors Affecting Treatment Choices Personalized Medicine Information about a patient's genotype or gene expression profile could be used to tailor medical care to an individual's needs. These genetic tests examine the cancerous tissues and can help to determine: 1. How aggressive is the cancer (prognosis)? 2. What is the benefit from treatment (prediction)?

BC Treatment - personalized medicine Commercially available gene assays Oncotype DX - clinically validated, multi-gene (21) assay the Oncotype DX Recurrence Score

11 BC Treatment - personalized medicine Commercially available gene assays Oncotype DX - clinically validated, multi-gene (21) assay the Oncotype DX Recurrence Score assay predicts likelihood of recurrence (prognostic); and magnitude of adjuvant treatment benefit for chemotherapy (predictive); standardized and quantitative essay

12 BC Treatment - personalized medicine Commercially available gene assays MammaPrint a gene expression profiling service measuring the activity of 70 genes predicts the risk of metastasis in breast cancer patients Patient Critiria: Age < 55, ER+, ER-

13 BC Treatment - personalized medicine Drug Resistance Assay (DRA) Drug Resistance is the principal reason for the failure of chemotherapy DRA measures the ability of pharmaceuticals and other therapies to stop cancer cells (taken from an individual patient) from dividing and growing. To select chemotherapeutic agents that have the greatest likelihood of being clinically effective; and to exclude agents unlikely to be effective. Cancer patients are consequently spared the morbidity of ineffective chemotherapy. The result is improved response rates and prolonged survival of cancer patients.

BC Treatment - Unmet need "Triple-Negative" Inflammatory Breast cancer The greatest unmet need of all breast cancer patients is a cure: many drugs are used for

14 BC Treatment - Unmet need "Triple-Negative" Inflammatory Breast cancer The greatest unmet need of all breast cancer patients is a cure: many drugs are used for stages III and IV but they only act to control the progression of the disease and improve quality of life. However, in most cases, survival is not greatly extended.

15 - Agenda - Current Therapies and their Efficacy Breast Cancer Patient Flow Overview of Future Therapies Cost Effectiveness Analysis Widespread adoption Issues

Patient Flow (PF) Breast Cancer Personalized Medicine will change the current reality in PF Source of information about Breast Cancer Internet Physicians Press Friends Partner Media

approach will change the current flow and be a key lever in the process (molecular diagnosis + personalized treatments) Influencers for decision making Conversation w/doctor

16 Patient Flow (PF) Breast Cancer Personalized Medicine will change the current reality in PF Source of information about Breast Cancer Internet Physicians Press Friends Partner Media Type Article in Internet Article in Press TV Info materials in Pharmacy Ad in press Ad in internet Patient Flow = Understand the treatment decision making process Personalized Medicine approach will change the current flow and be a key lever in the process (molecular diagnosis + personalized treatments) Influencers for decision making Conversation w/doctor Conversation w/ partner Conversation w/ pharmacists Internet Consulted specialty: GPs Gynecologist Oncologist Other Diagnosis Results Diagnosis Treatment Response Emotional reasons for decision making

17 - Agenda - Current Therapies and their Efficacy Breast Cancer Patient Flow Overview of Future Therapies Cost Effectiveness Analysis Widespread adoption Issues

10 patent protected molecules (Abraxane,Capxol, Doxil, Caelyx, Furtulon, Gemzar, Ixempra, Myocet, Taxotere, Xeloda) + 6 generic molecules (5-fluorouracil,

Personalized Therapies Today: 3 patent protected molecules (Avastin, Herceptin and Tykerb) Future: 61 molecules in phase II and III (4 late stage) Endocrine Therapies

18 Overview of Future Therapies $4.8 Billion invested in R&D for Breast Cancer Source: National Cancer Institute s Office of Science Planning and Assessment Cytotoxic Therapies aka Chemotherapy Today: 10 patent protected molecules (Abraxane,Capxol, Doxil, Caelyx, Furtulon, Gemzar, Ixempra, Myocet, Taxotere, Xeloda) + 6 generic molecules (5-fluorouracil, cyclophosphamide, doxorubicin, epirubicin, paclitaxel and vinorelbine) Future: 30 molecules in phase II and III (2 late stage) Molecular target therapies aka Personalized Therapies Today: 3 patent protected molecules (Avastin, Herceptin and Tykerb) Future: 61 molecules in phase II and III (4 late stage) Endocrine Therapies aka hormone-based targeted therapy Today: 7 patent protected molecules (Afema, Arimidex, Aromasin, Fareston, Faslodex, Lupron and Zoladex) + 1 generic molecule (Tamixifen) Future: 7 molecules in phase II and III Immunotherapeutic agents aka Use of immune system to target cancer Today: 0 therapies Future: 4 molecules in phase II

19 - Agenda - Current Therapies and their Efficacy Breast Cancer Patient Flow Overview of Future Therapies Cost Effectiveness Analysis Widespread adoption Issues

20 Cost Effectiveness Analysis Soaring Costs of Cancer Treatments $80 Cancer Treatment Spending in the U.S. ($Bil) $60 $40 $20 $ Source: National Cancer Institute Who pays for treatment? Payers (e.g., insurance companies, government/society) Do the benefits of treatment justify high treatment costs?

21 Cost Effectiveness Analysis Do benefits of personalized medicine for BC justify the cost to society? Herceptin: personalized medicine treatment option To determine cost effectiveness from societal perspective: Measure incremental costs of treatment with Herceptin (costs above and beyond those of standard chemotherapy treatment) Quantify the benefits that Herceptin provides above and beyond the benefits of chemotherapy alone

22 Cost Effectiveness Analysis Results: Herceptin is Cost Effective Source: Garrison, Lubeck, et al., 2006 For an average Herceptin-eligible patient, over lifetime Incremental Costs Above & Beyond Chemo. Costs Diagnostic tests Herceptin treatment cost Herceptin infusion, administration Incremental Benefits Above & Beyond Chemo. Benefits Increase in quality-adjusted life years (QALYs) (QALY method quantifies both life extension and quality of life) Cost = $ 46,997 Benefit = 1.7 QALYs Incremental Cost/QALY = $ 46, = $ 27,637 $ 27,637 is widely considered to be well worth one additional QALY, so Herceptin is cost-effective

23 - Agenda - Current Therapies and their Efficacy Breast Cancer Patient Flow Overview of Future Therapies Cost Effectiveness Analysis Widespread adoption Issues

24 Players & Stakeholders Levers of Widespread Adoption 1. Patients and Families 2. Physicians 3. Hospitals and Clinics 4. Medical Diagnostic Companies 5. Payers: Insurance Government

25 Players & Stakeholders Program for the Assessment of Clinical Cancer Tests (PACCT) Cancer Diagnosis Program (CDP) at the National Cancer Institute Goal: smoothen bench-to-bedside transition of cancer diagnostics

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