Case Study Oncotype DX Breast Cancer Assay

Transcription

1 Case Study Oncotype DX Breast Cancer Assay Steven Shak, MD Chief Medical Officer, Genomic Health IOM Workshop on the Review of Omics-Based Tests November 16, 2010

2 Trastuzumab For Herceptest Positive Breast Metastatic Breast Cancer (1998) NEGATIVE POSITIVE Humanized Anti-HER2 Antibody Immunohistochemistry Assay for HER2 Protein

3 : Technology Advances Sequencing of the human genome Assay technologies to measure gene expression for many genes

4 Biomarker Field A Poor Track Record Bringing Them Into Clinical Practice Many thousands of papers have been published about biomarkers in cancer Very few biomarkers have been proven to have clinical utility and are incorporated in clinical practice

5 Applied Genomics Past, Present, and Future Steven Shak, M.D. Chief Medical Officer Genomic Health, Inc. AACR Pharmacogenomics April 6, 2002

6 Applied Genomics Past Studies in Crop Variation. III. The influence of rainfall on the yield of wheat at Rothamsted J. Agricultural Science, 1921 Ronald Aylmer Fisher Statistical Laboratory, Rothamsted Experimental Station Harpenden England

7 Fisher s Job 90 years of data in leather bound notebooks Different combinations of mineral salts Different strains of wheat Raking over the muck heap

8 Fisher s Tools The Millionaire hand cranked mechanical calculator 1 manuscript 15 tables and 4 graphs 8 months of 12 hr days!!

9 Fisher s Invention The Foundations of Modern Statistical Methods - Regression analysis - Analysis of variance - Analysis of covariance - Randomized controlled experiments Improved Food Supply

10 Lessons from the Past Assay can be key to detection of drug efficacy Need quantitative controlled assays Need rigorous Phase I, II, III approach to assay development

11 11 Roadmap to Establish Clinical Utility Step 1 Define the purpose of the test the specific clinical setting of the patient and the treatment decision to be impacted

12 The Purpose of the Oncoytype DX Test Was Defined Early On Chemotherapy treatment for node negative, ER positive disease (half of all diagnosed breast cancer): Many women offered chemotherapy (assuming all benefit equally), knowing that few benefit Some patients are under-treated, many others are over-treated Clear Need for Better Tools to Select Breast Cancer Patients for Chemotherapy

13 NSABP B-20 Clinical Study Established Benefit of Chemotherapy Proportion Free of Distant Recurrence Tam vs Tam + Chemo All 651 Pts Only 4 out of 100 Women Benefit All Patients Tam + Chemo Tam N Events Years p = 0.02 Fisher et al. JNCI. 1997;89:

14 What We Needed for Node Negative ER Positive Breast Cancer The ability to distinguish truly low risk patients The ability to determine who benefits from chemotherapy Requires patients who are randomized if analyzing time to event

15 Roadmap to Establish Clinical Utility Step 1 Define the purpose of the test the specific clinical setting of the patient and the treatment decision to be impacted Step 2 Create and implement a multi-step, multi-study approach to develop the assay and to provide the evidence regarding analytic performance, clinical validity, and clinical utility to meet the needs of patients, physicians, payors, and regulators

16 16 Roadmap to Establish Clinical Utility Define the purpose Technical feasibility Development studies Clinical validation studies, including comparative effectiveness Analytical methods validation Analytical methods finalization Treatment decision studies Health economic analysis

17 Clinical Questions Relevant to the Decision of Whether to Add Chemotherapy in ER-Positive Breast Cancer What is the baseline risk of distant recurrence with hormonal therapy alone? The test s resolution of risk at low risk is particularly important. What is the estimated absolute benefit of chemotherapy? Even if the risk of recurrence is low, have we excluded that there is a large relative risk reduction with chemotherapy? This requires a study with patients randomized to chemotherapy vs. hormonal therapy alone. What is the reproducibility of the test upon repeated measure? It is important also for the test system to avoid errors arising from variability in sample processing or tumor heterogeneity. Are the clinical trial results generalizable?

18 Technical Feasibility: Required Innovation to Unlock the Block

19 Real-time RT-PCR for RNA Quantification Sensitive Specific Wide dynamic range Reproducible ~800 genes from three 10µ fixed paraffin embedded sections Mature technology used for clinical assays for viral infections Forward Primer Polymerization Strand Displacement and Cleavage of Probe Polymerization Completed Reporter Probe R R R Quencher Q Reverse Primer Q Q Cronin et al. Am J Pathol. 2004;164:35-42.

20 RT-PCR Technical Feasibility Studies Done Over Two Years Fresh frozen versus FPET Sensitivity and specificity, calibration with RNA controls Variability in preparation Tumor block age Heterogeneity within and between blocks Comparison with IHC/FISH (ER, PR, HER2) Dissection Robotics and miniaturization

21 Analytical Performance of the Oncotype DX Assay Cronin et al. Clin Chem. 2007;53:

22 Genomic Health Clinical Laboratory Continuous Distribution of ER and PR Quantitative ER and PR by Oncotype DX ER: > 3,000-fold range PR: > 1,000-fold range (Shak et al, SABCS 2006) PR Expression (relative to ref genes; log2) First cohort Jun 2004 Mar 2006 n = 10,618 ER- PR+ (0.2%) ER+ PR+ (81.0%) ER- PR- (3.4%) ER+ PR- (15.4%) ER Expression (relative to ref genes; log2)

23 Genomic Health Clinical Laboratory Continuous Distribution of ER and PR Second cohort Apr 2006 Nov 2006 Quantitative ER and PR by Oncotype DX ER: > 3,000-fold range PR: > 1,000-fold range (Shak et al, SABCS 2006) PR Expression (relative to ref genes; log2) n = 9,432 ER- PR+ (0.2%) ER+ PR+ (79.1%) 3 ER- PR- (3.2%) ER+ PR- (17.5%) ER Expression (relative to ref genes; log2)

24 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)

25 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)

26 ER/PR Oncotype DX Reproducibility Thirty-Eight Measurements on 5 Days* PR Expression (relative to ref genes; log2) Day Day Day *Across different reagent lots, machines, operators Day 4 Day 5 ER Expression (relative to ref genes; log2)

27 Importance of Manual Microdissection Enriched Tumor Non-Tumor Whole Section

28 Comparison of Quantitative ER Expression in Enriched Tumor & Whole Section Whole Section ER Expression (relative to ref genes; log2) ER WS r = 0.73, p = skin in NT Pronounced inflammation in NT Enriched ER ET Tissue ER Expression (relative to ref genes; log2)

29 Development Studies: Three Independent Studies for Final Gene Set Selection Tested 250 genes in 447 patients Study Site N Node Status NSABP B-20, Pittsburgh, PA Rush University, Chicago, IL Providence St. Joseph s Hospital, Burbank, CA ER Status Treatment 233 N ER+ Tamoxifen (100%) 78 >10 positive nodes ER+/ Tamoxifen (54%) Chemotherapy (80%) 136 N+/ ER+/ Tamoxifen (41%) Chemotherapy (39%) 21 genes and Recurrence Score (RS) algorithm Paik et al. SABCS Abstract #16. Cobleigh et al. Clin Cancer Res. 2005;11: Esteban et al. Proceedings of ASCO Abstract #3416.

30 Oncotype DX Recurrence Score Result: calculated from 21 different genes 16 CANCER RELATED GENES Estrogen Proliferation HER2 Invasion Others ER PR Bcl2 SCUBE2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GRB7 HER2 Stromelysin 3 Cathepsin L2 CD68 GSTM1 BAG1 5 REFERENCE GENES Beta-actin GAPDH RPLPO GUS TFRC Paik et al. N Engl J Med. 2004;351:

31 Regulatory Pathways for Diagnostic Genomic Assays 31 Who regulates? Laboratory-developed tests Centers for Medicare & Medicaid Services (CMS) Food and Drug Administration (FDA) Manufactured test kits How classified? Low, moderate, or high complexity Class 3 (risk based) Class 2 (risk based) FDA What is it? Lab-developed tests are: Designed, validated, and performed by CLIA-certified lab Not packaged for sale as test kits Performed at labs that developed and validated them Assay kits: Products sold or distributed to laboratories who then perform testing Laboratory may modify assay within the lab and validate under CLIA Assay kits: Products sold or distributed to laboratories who then perform testing Laboratory may modify assay within the lab and validate under CLIA How regulated? Clinical Laboratory Improvements Amendments (CLIA)* Pre-market application process (PMA)** 510(k) Paradigm** Certification vs clearance vs approval Performance characteristics of test established and validated within Lab prior to commercialization Testing/ validation completed Subject to additional accrediting body requirements Data subject to routine inspections under CLIA May be subject to additional state level certification Approval based on sufficient valid scientific evidence Assures that device is safe and effective for intended use(s) Clears device for commercial distribution Substantially equivalent to a legally marketed device not subject to PMA De Novo 510(k) if no predicate device *CLIA reviews analytic performance and clinical significance but is not required to evaluate clinical validity or utility **FDA evaluates analytic performance and clinical validity, but does not evaluate clinical utility; FDA is considering changes that may lead to FDA regulation of all laboratory-developed tests Food and Drug Administration. Available at: Centers for Disease Control and Prevention. Available at:

32 Analytical Methods Finalization: CLIA Regulations All assay methods and procedures defined prior to clinical validation studies, for example: Specimen eligibility Reagent qualification Instrument validation Controls and calibrators Linearity, precision, reproducibility

33 21 Gene Recurrence Score CLIA-Certified and CAP-Accredited Reference Laboratory Process Oncotype DX Number of Standard Operating Procedures (SOPs) and Forms Category Number of SOPs Number of Forms Equipment Finance 1 0 Histopathology 6 6 IT Materials Management 7 6 Pre and Post Analytical 13 3 Production and Quality Control QA Safety and Facilities 4 0 Total

34 Clinical Validation for Prognosis: NSABP B-14 Distant Recurrence Objective: Prospectively validate RS as predictor of distant recurrence in N, ER+, tam-treated patients Design Randomized Placebo not eligible Tamoxifen eligible Registered Tamoxifen eligible Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan

35 Proportion Without Distant Recurrence Clinical Validation for Prognosis: NSABP B-14 Distant Recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Paik et al. N Engl J Med. 2004;351: Distant Recurrence Over Time All Patients, n = 668 RS <18, n = 338 RS 18-30, n = 149 RS 31, n = Years *10-year Distant Recurrence comparison between low-and high-risk groups: P < year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 10 year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10 year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% P <0.001

36 Oncotype DX Clinical Validation: The Kaiser Permanente Study* *Habel et al, Breast Cancer Res. 2006;8:R25.

37 Methods Study Design Study Population Case-control Kaiser Permanente pts <75 yr in 14 Northern California hospitals diagnosed with node-negative BC , no chemotherapy (n=4964) Cases: Deaths from BC (n=220) Controls: Randomly selected, matched on age, race, diagnosis year, KP facility, tamoxifen (n=570) Data Sources Cancer registry, medical records, archived diagnostic slides, and tumor blocks

38 Risk of BC Death at 10 Years: ER+, Tam+ Patients % of % of 10-yr Risk Classifier Cases Controls Absolute (n=55) (n=150) Risk 1 Recurrence Score Low (<18) % 2 Intermediate (18-30) % High (>31) % 1 Based on methods by Langholz and Borgan, Biometrics 1997;53: Consistent with 3.0% absolute risk of breast cancer death in similar population of tamoxifen-treated patients in NSABP B-14.

39 Clinical Validation for Prediction: NSABP B-20 Objective: To determine the relationship between RS and chemotherapy benefit in N-, ER+ patients Tam + MF Randomized Tam + CMF Tam Multicenter study with pre-specified 21-gene assay, algorithm, endpoints, analysis plan Paik S, et al. J Clin Oncol. 2006;24:

40 Clinical Validation for Prediction: NSABP B Proportion without Distant Recurrence All patients RS <18 RS RS 31 Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen N Events PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy p=0.02 p=0.61 p=0.39 p< % absolute benefit from tamoxifen + chemotherapy Years Paik S, et al. J Clin Oncol. 2006;24:

41 Comparative Effectiveness NSABP B-14 & B-20: Small Tumors Have High RS Disease and High Recurrence Risk 100 p=0.001 Recurrence Score % 25% 30% 33% 20% 19% 23% 21% 0 64% 56% 46% 46% N=110 N=318 N=196 N=24 1 cm cm cm >4 cm Clinical Tumor Size Paik et al. N Engl J Med. 2004;351: l; Paik S, et al. J Clin Oncol. 2006;24:

42 NCCN Guidelines in NSABP B-14 Distribution of patients with node negative, ER positive breast cancer based on patient age, tumor size, and tumor grade 7% recur 15% recur NCCN Low Risk NCCN High Risk

43 Reclassification by the Recurrence Score in NSABP B-14 Patients Many patients are reclassified 28% Reclassified Potential for Change In Treatment Decision 49% Reclassified Potential for Change In Treatment Decision Oncotype DX Low Risk Reclassified -- Oncotype DX Intermediate Risk Reclassified -- Oncotype DX High Risk NCCN Low Risk NCCN High Risk Reclassified -- Oncotype DX Low Risk Oncotype DX Intermediate Risk Oncotype DX High Risk

44 Reclassification by the Recurrence Score in NSABP B-14 Patients Recurrence rates at 10 years 33% 19% <5% 7% 15% 30% 14% 8% Oncotype DX Low Risk Reclassified -- Oncotype DX Intermediate Risk Reclassified -- Oncotype DX High Risk NCCN Low Risk NCCN High Risk Reclassified -- Oncotype DX Low Risk Oncotype DX Intermediate Risk Oncotype DX High Risk

45 Treatment Decisions Are Changed: Overall Impact of RS on Treatment Decisions (7 Studies in 912 Patients) Treatment plan after RS Treatment plan prior to Oncotype DX Treatment plan after RS 88% 12% 38% 62% 52% 48% CT + HT HT Overall, the RS led to a 37% change in treatment decisions 33% from CT+HT HT 4% from HT CT+HT Hornberger J, et al. SABCS Poster P

46 Cost Effectiveness of Oncotype DX* Survival. RS-guided therapy is associated with a gain in individual life expectancy of 2.2 years compared with tamoxifen alone, whereas it is associated with similar life expectancy to that seen with the chemotherapy and tamoxifen strategy Costs. RS guided therapy is estimated to provide a net cost savings of $2256 compared with chemotherapy and tamoxifen with an incremental cost-effectiveness ratio of $1944 per life year saved compared with tamoxifen alone *Lyman et al, Cancer. 2007;109:

47 All the Payors Need to be Addressed Individually Technology Evaluation Center Florida, California, Michigan, Alabama, New York, Delaware, New Jersey, Pennsylvania, South Carolina, Arkansas, Idaho, Montana, North Dakota, Minnesota, Kansas, Arizona

48 Systems and Trained Personnel To Deliver Quality and Service ORDER ENTRY INTAKE PATHOLOGY ANALYTICAL LABORATORY REPORT FULFILLMENT MATERIAL RETURN Online Fax Insurance Provider Phone Benefits Investigation Fax Request FedEx Specimen Retrieval Pathology Review Extraction Quantitation Results Generation Report Delivery FedEx Materials Return Order Entry Patient Information Retrieval Specimen Accessioning Histopathology gdna Detection Reverse Transcription QPCR Billing Online, Fax FedEx Reimbursement SARP CRM GEMTools (LIMS) SARP CRM OnBase EDI Services Material Manager Result Generation Service EDI Services Material Manager Online Portal Data Services Report Delivery Online Portal Electronic Claim PAS HARP 48

49 Extensive Clinical Validation More than 4,000 Patients Studied in 13 Trials Study Type No. Pts Nodal Status Providence Exploratory 136 Neg Rush Exploratory 78 Pos NSABP B-20 Exploratory 233 Neg NSABP B-14 Prospective 668 Neg MD Anderson Prospective 149 Neg Kaiser Permanente Prospective Case-Control 790 Cases/Controls Neg NSABP B-14 Prospective Placebo vs Tam 645 Neg Milan Exploratory 89 Neg/Pos NSABP B-20 Prospective Tam vs Tam+Chemo 651 Neg ECOG 2197 Exploratory and Prospective 776 Neg/Pos SWOG 8814 Prospective Tam vs Tam+Chemo 367 Pos ATAC Prospective Tam vs AI 1231 Neg/Pos Japan BCRG Study Prospective 280 Neg/Pos

50 Oncotype DX Breast Cancer Recurrence Score Recurrence Score based on quantitative RT-PCR analysis of 21 genes Widely used and reimbursed Over 190,000 tests since launch in 2004 Reimbursed by Medicare and major payers in US Provided for patients in >60 countries Incorporated in the published treatment guidelines

51 Biomarker Field Principles for Success 1. Delivering what patients, physicians, regulators, and payors need a) Most importantly, tests must be Fit for Purpose with evidence relevant to that specific purpose b) Consistent results across multiple well-designed studies c) Test must be shown to have value beyond traditional measures 2. Technical innovation brought to standardized implementation 3. Requires collaboration (a team with all accountable), and the skills, processes, and resources to do it right