MammaPrint: From Bench to Bedside

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Speaker: Lisette Stork-Sloots, Sr Program Director at Agendia, discusses how their technology, MammaPrint was commercialized.

Part of Dx2010, a workshop at MaRS focused on best practices and regulatory considerations for developing gene-based diagnostic and prognostic tests.

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MammaPrint: From Bench to Bedside

  1. 1. MammaPrint From Bench to Bedside Lisette Stork-Sloots Sr Program Director
  2. 2. AGENDIA AT A GLANCE To improve the quality of life for cancer patients by Mission providing state-of-the-art services that enable safe and effective personalized treatment. Founded 2003 Amsterdam, The Netherlands Industry Molecular Diagnostics Technology Gene Expression Profiling 2 2
  3. 3. Agendia: Milestones Reimbursement FDA starts to regulate FDA Clearance #2 MP Medicare complex diagnostic RNARetain FDA tests Clearance #3 US Launch of MP>61 MammaPrint MammaPrint Launch of FDA Clearance #1 Agendia Inclusion in Foundation MammaPrint MammaPrint Inc Int. Guidelines of Agendia USA (St. Gallen) 2003 2004 2005 2006 2007 2008 2009
  4. 4. Company USA EU/ROW Huntington Beach Amsterdam California The Netherlands ! US Headquarters ! Company Headquarters ! US Sales & Marketing (2008) ! International Sales & Marketing ! Laboratory (Q1 ’09: CLIA, CAP) ! R&D ! Regulatory Affairs ! Quality Assurance ! Laboratory (CLIA, CAP, ISO 4 17025 and QSR)
  5. 5. High Quality Certified Central Labs Huntington Beach, CA & Amsterdam, NL Diagnosis Sampling FDA cleared assay in CLIA registered, Results Surgery Shipping CAP and ISO 17025 accredited lab Report 1 day 5-10 days
  6. 6. Awards MammaPrint® receives important award from the 2008 Dutch Health Minister, Ab Klink TIME magazine “Healthcare Invention of the Year” 2007 Estee Lauder Breast Cancer Research Foundation Award Frost & Sullivan Breast Cancer Diagnostics Award ESMO award for translational research in breast cancer Agendia selected as the 25 brightest start-up companies 2006 by FEMS Business MammaPrint® one of the 5 biggest health breakthroughs 2005 according to Oprah Winfrey 6
  7. 7. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  8. 8. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  9. 9. Breast cancer-10 years survival curve Premenopausal patients, LN- Patients, pre-menopausal, lymph-node negative
  10. 10. The Challenge: Identify those patients who benefit from chemotherapy Cured by surgery Cured by hormonal therapy Most Common Breast Cancer: T1, N0, ER+, Grade 2. Only two patients of 100 benefit from additional chemotherapy
  11. 11. What is expression phenotyping and how is it measured? High Risk Low Risk analysis
  12. 12. Benefit of untreated patients Profiling of the tumor Gene expression profile identifies “low risk” and “high risk” tumors
  13. 13. Identification of a breast cancer prognosis profile breast tumors (‘83-’94) patients < 55 years lymph node negative (LN0) no adjuvant therapy Unbiased full genome gene expression analysis 70 Prognosis Reporter Genes distant metastases no distant metastases < 5 years in at least 5 years
  14. 14. Prognosis Classifier for Breast Cancer 70 significant prognosis genes Good signature Discovery: 78 tumors Van ‘t Veer et al. (2002) threshold Nature 415, 530-536. Poor signature Threshold set with 10% false negatives 91% sensitivity; 73% specificity Metastases: white = + Van ‘t Veer et al Nature 415, p530-536, 2002
  15. 15. MammaPrint: A 70 gene breast cancer prognosis test good profile: First validation: ~4% die of breast cancer ~96% survive et al. (2002) Van de Vijver breast cancer New England J. Med. 347, 1999-2009. poor profile: 295 patients ~50% die of breast cancer ~50% survive breast cancer 40% good profile ; 60% poor profile
  16. 16. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  17. 17. Independent External Validation: MammaPrint outperforms all clinical risk assessment High clinical risk Low clinical risk Adjuvant on line! N=222 73% Second validation: Adjuvant on line! N=80 27% Buyse et al. (2006) 27% JNCI. 98, 1183-1192. 35% MammaPrint MammaPrint Low risk High risk 302 patients Over- Under- treatment! treatment! Buyse et al JNCI 2006 35% Discordant cases!
  18. 18. Metastasis-free survival 70 gene profile MammaPrint Adjuvant!Online 10-year DMFS 10-year DMFS 1.0 1.0 90% (85%-96%) 85% (77%-94%) 0.8 0.8 10-year DMFS 10-year DMFS 76% (70%-82%) 0.6 0.6 71% (65%-78%) Probability Probability 0.4 0.4 Patients Events Risk group Patients Events Risk group 0.2 0.2 111 18 Gene signature low risk 80 13 Low clinical risk 191 58 Gene signature high risk 222 63 High clinical risk 0.0 0.0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Year Year 111 108 102 95 92 80 64 43 80 76 72 65 57 48 38 20 222 201 181 166 152 135 110 72 191 169 151 136 117 103 84 49 Number at risk Number at risk Discordant cases better predicted by MammaPrint
  19. 19. MammaPrint has been clinically validated in 2300+ patients Purpose Year Patients (n) Reference Discovery 2002 78 Van’t Veer et al. Nature 615 First Validation 2002 295 Van de Vijver et al. NEJM 347 Independent European Validation 2006 302 Buyse et al J NCI 17 Validation in Dutch patient cohort 2006 123 Bueno de Mesquita et al. Eur J Can 4 Prospective Implementation Study 2007 427 Bueno de Mesquito et al. Lancet Oncol. 8 Validation in US patients 2008 100 Wittner et al. Clin Cancer Res 14 Validation in core biopsies 2008 35 Mayordomo et al. ESMO Meeting Validation in Patients with 1-3 positive LN 2008 241 Mook et al. Breast Cancer Res Treat. Validation in postmenopausal patients 2008 148 Mook et al. (submitted) / SABCS Validation in tamoxifen treated patients 2009 192 Kok et al. (submitted) Validation in German patients 2009 140 Kunz et al. St. Gallen Conference Validation in Japanese patients 2009 118 Ishitobi et al. JJCO Predictiveness for neoadjuvant treatment 2009 167 Straver et al. Breast Cancer Res Treat. Validation in patients with 4-9 positive LN 2009 162 Saghastchian et al. St. Gallen Conference Meta-analysis Predictiveness for adjuvant treatment 2009 1637 Knauer et al. Breast Cancer Res Treat.
  20. 20. MammaPrint has been clinically validated in an international patient cohort Validation Studies Country Reference Years 2006 2007 2008 2009 Independent European study Buyse et al J NCI 17 302 Dutch patient cohort de Mesquita et al. Eur J Can 4 123 Prospective Study de Mesquito et al. Lancet Oncol. 8 427 Core Needle biopsies Mayordomo et al. ESMO Meeting 35 Validation in US patients Wittner et al. Clin Cancer Res 14 100 Validation in 1-3 LN+ patients Mook et al. Breast Cancer Res Treat. 241 Postmenopausal patients (>61) Mook et al. (submitted) / SABCS 148 Patients treated with Tamoxifen Kok et al. (submitted) 121 German patient cohort Kunz et al. St. Gallen Conference 140 Japanese patient cohort Ishitobi et al. JJCO 118 Validation in 4-9 LN+ patients Saghastchian et al. St. Gallen Conf 168 Neoadjuvant predictive study Straver et al. Breast Cancer Res Treat 167 Predictiveness (Meta-analysis) study Knauer et al. Breast Cancer Res Treat 1,637 Neoadjuvant predictive study US Somlo et al. ASCO annual conference 68 20
  21. 21. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  22. 22. Technology Platform: MammaPrint array A dedicated microarray • Produced by Agilent Technologies • features eight identical subarrays per slide, each with 15.000 features • 231 reporter genes , including 70 genes, printed 5x • Plus, 495 normalization genes and std control grid with positive and negative controls Glas et al. 2006 BMC Genomics 7; 278
  23. 23. Overview: Agendia laboratory process
  24. 24. MammaPrint is stable and reproducible 70-Gene Prognostic Assay Experiment 2 70-Gene Prognostic Assay Experiment 1 Glas et al. 2006 BMC Genomics 7; 278
  25. 25. MammaPrint is stable and reproducible 1 LRC: 0.8 Mean MPI: 0.686 0.6 Stdev: 0.033 0.4 MammaPrint Index 0.2 0 -0.2 -0.4 HRC; Mean MPI: -0.503 -0.6 Stdev: 0.028 -0.8 LRC (n=284 HRC (n=284) -1 Oct-2005 May-2006 Nov-2006 June-2007 Dec-2007 July-2008 Date
  26. 26. Regulatory Approval of MammaPrint MammaPrint is the first molecular diagnostic test cleared by FDA ISO 17025 accredited and CE marked for European market CLIA registered College of American Pathologists (CAP) accredited 26
  27. 27. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  28. 28. RASTER trial; an implementation study • Implementation of MammaPrint is feasible in Dutch community hospitals • 427 Consecutive patients with a MammaPrint result (51% LR, 49% HR) • 30-40% Discordance between prognosis according to clinical guidelines and MammaPrint • Adding MammaPrint to clinical guidelines led to a treatment change in 27% of the patients • Less adjuvant chemotherapy would be given when the data based on MammaPrint alone are used, which might spare patients from adverse effects. Bueno-de-Mesquita et al., Lancet Oncology, Vol 8, 2007
  29. 29. MammaPrint “From Bench to Bedside” Research microarray profile Clinical validation studies High-throughput lab & informatics Regulatory accreditation Commercially Guidelines available diagnostic test Prospective feasibility study Reimbursement
  30. 30. Health Economics – “The Big Picture” In order to bring a product to market successfully two basic elements that are key; 1) Legal requirements (e.g. FDA clearance, CE mark) - Is the product safe and effective? (technical/clinical validity) 2) Reimbursement - Is it reasonable and necessary? (clinical utility)
  31. 31. Health Economics – “The Big Picture” F1 Payment Reimbursement E1 E2 E3 Coverage Coding Pricing Evidence Dossier D1 D2 Private Payers Governmental Payers o Clinical Utility (demand & impact) C1 C2 C3 o Clinical Validation Key Opinion Professional Patient Leaders Societies Advocacy o Technical Validation B1 o Health Economics Evidence dossier A1 Basic Requirements
  32. 32. Health Economics: definitions ! LY: measure of gains or losses in quantity of life (mortality) ! QALY: A QALY combines gains or losses in both quantity of life (mortality) and quality of life (morbidity) ! ICER: Incremental Cost-Effectiveness Ratio between the two alternative programs, the difference in costs (incremental cost) is compared to their difference in outcomes (incremental effect) by dividing the former by the latter
  33. 33. Base Case Model: Results Total Cost Effect Incremental Cost Incremental ICER ($) ($) Effect ($) Life Years (LY) AS 162 140 21.596 - - - MP 163 580 21.739 1 440 0.143 10 059 Quality-Adjusted Life Years (QALY) AS 162 140 21.065 - - - MP 163 580 21.218 1 440 0.153 9 428 ! The overall costs of MP-guided treatment was $1,140 higher than AS guided treatment ! The overall LY and QALY gains associated with the use of MP were 0.14 and 0.15 year, respectively ! The ICER was $10, 059 per LY and $9,428 per QALY, well within the commonly accepted threshold values (e.g., $50, 000-$100, 000 per QALY) 33
  34. 34. MammaPrint is included in the International St. Gallen Expert Consensus Recommendations “In an important change from the previous St. Gallen conference, the Panel supported the use of a validated multi-gene profiling assay, if readily available, as an adjunct to high quality phenotyping of breast cancer in cases in which the indication for adjuvant chemotherapy remained uncertain.” Goldhirsch et al. (2009) Annals of Oncology (published online June17)
  35. 35. THANK YOU!

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