The 21 Gene Oncotype DX Assay and The NCI-Sponsored TAILORx Trial. Steven Shak Chief Medical Officer Genomic Health October 4, 2007

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1 The 21 Gene Oncotype DX Assay and The NCI-Sponsored TAILORx Trial Steven Shak Chief Medical Officer Genomic Health October 4, 2007

2 Biomarkers Thousands of publications on biomarkers in cancer Few biomarkers used as diagnostics in clinical practice Insufficient use of biomarkers to guide drug development or to optimize clinical trials

3 Two Initiatives in Cancer Diagnostics Led to the TAILORx Trial NCI Initiative - PACCT Industry efforts to optimize and standardize tumor tissue assay methodology

4 Program for the Assessment of Cancer Clinical Tests (PACCT) Background: NCI program designed to ensure that development of the next generation of laboratory tests is efficient and effective identify barriers to development and develop new components of the program as needed Goals: To ensure translation of new knowledge about cancer and new technologies to clinical practice To develop more informative laboratory tools to help maximize the impact of cancer treatments

5 Genomic Health Founded 2000 Focus Cancer Gene expression in paraffin tumor blocks Clinical study collaborations High-complexity CLIA lab testing service for treatment decisionmaking

6 Critical Success Factors Precision and reproducibility for measurement of expression of each gene (standardization and quantitation) Multi-step development process, with rigorous comparison to standard measures Prospectively designed studies on archival tissue Establishing clinical utility and gaining reimbursement

7 Precision and Reproducibility of RT-PCR using Oncotype DX Study Design Oncotype DX reproducibility study over time (5 days), machine, reagent lots, operator

8 ER/PR Oncotype DX Reproducibility: Single Measurement ER- PR+ ER+ PR+ PR Expression (relative to ref genes;log2) ER- PR- ER+ PR ER Expression (relative to ref genes;log2)

9 ER/PR Oncotype DX Reproducibility: Eight Measurements on Day ER- PR+ ER+ PR+ PR Expression (relative to ref genes; log2) ER- PR- ER+ PR ER Expression (relative to ref genes; log2)

10 ER/PR Oncotype DX Reproducibility: Thirty-Eight Measurements on 5 Days PR Expression (relative to ref genes; log2) Day Day Day Day 4 Day 5 ER Expression (relative to ref genes; log2)

11 Precision and Reproducibility for Each Gene ER: > 3,000-fold range PR: > 1,000-fold range High precision and reproducibility (SD < 0.4 units) 12 ER- PR+ 11 PR Expression (relative to ref genes; log2) Quantitative ER and PR by Oncotype DX in 10,618 breast cancers* ER+PR ER-PR- 2 *Shak et al, SABCS 2006 `` ER+PR ER Expression (relative to ref genes; log2)

12 Precision and Reproducibility Reveal Breast Cancer Heterogeneity Three Major Types 15 HER2 Expression (relative to ref genes; log2) ER Expression (relative to ref genes; log2)

13 Precision and Reproducibility Reveal Breast Cancer Heterogeneity Three Major Types 15 HER2 Expression (relative to ref genes; log2) HER2+ Triple Neg* ER+HER2- (luminal?) ER Expression (relative to ref genes; log2)

14 Oncotype DX 21 Gene Recurrence Score: Development and Validation Technical Feasibility Research Studies Rush Providence NSABP B-20 (n=447) Assay Method Finalization Clinical Validation Study - Prognosis NSABP Study B-14 (n=668) Community Based Study - Prognosis Kaiser Permanente (n=790) Treatment Response Studies Tamoxifen Response: NSABP Study B-14 Placebo (n=645) Chemotherapy Response: NSABP Study B-20 (n=651), Milan Neoadjuvant (n=89)

15 Collaborations/Acknowledgements Drs. Paik, Bryant, Tang, Costantino, Wolmark (NSABP) Drs. Habel and Quesenberry, Kaiser Permanente Drs. Mena and Esteban (Providence-St. Josephs Medical Center) Drs. Cobleigh and Bitterman (Rush University Medical Center) Dr. Gianni (Istituto Milano) Drs. Sledge, Miller, Badve (Indiana University) Drs. Esteva, Sahin, Hortobagyi (MDACC) NCI and the Cooperative Groups Genomic Health colleagues Breast cancer advocates Patients and their families

16 Prospectively Designed Studies on Archival Tissue Methodology to ensure rigor Prespecified methods, endpoints, analysis plan Formal blinding and unblinding (typical for Phase III drug trials) Study selection and design critical Excellence in biostatistics Consistent results in multiple independent studies to establish validity

17 Implications Clinical trials have always been individualized (usually clinical eligibility criteria) Genomic assays provide insight into individual differences relevant to stratification, event rates, treatment effect More frequently, standardized quantitative genomic assays will be used to individualize clinical trials

18 Discussion