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MammaPrint From Bench to Bedside
Lisette Stork-Sloots
Sr Program Director
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AGENDIA AT A GLANCE
MissionTo improve the quality of life for cancer patients by 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
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Agendia: Milestones
2003 2004 2005 2006 2007 2008
Foundationof Agendia
Launch ofMammaPrint
FDA Clearance #1MammaPrint
FDA Clearance #2 MP RNARetain
MammaPrintInclusion in
Int. Guidelines (St. Gallen)
Agendia Inc
USA
FDA starts to regulate complex diagnostic
tests
2009
US Launch of MammaPrint
FDA Clearance #3 MP>61
Reimbursement Medicare
EU/ROWAmsterdam
The Netherlands
USAHuntington Beach
California
Company
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! US Headquarters
! US Sales & Marketing (2008)
! Laboratory (Q1 ’09: CLIA, CAP)
! Company Headquarters
! International Sales & Marketing
! R&D
! Regulatory Affairs
! Quality Assurance
! Laboratory (CLIA, CAP, ISO 17025 and QSR)
High Quality Certified Central Labs Huntington Beach, CA & Amsterdam, NL
DiagnosisSurgery
SamplingShipping
FDA cleared assay in CLIA registered, CAP and ISO 17025 accredited lab
Results Report
1 day 5-10 days
Awards
2008 MammaPrint® receives important award from theDutch Health Minister, Ab Klink
2007
TIME magazine “Healthcare Invention of the Year”
Estee Lauder Breast Cancer Research Foundation Award
Frost & Sullivan Breast Cancer Diagnostics Award
ESMO award for translational research inbreast cancer
2006 Agendia selected as the 25 brightest start-up companies by FEMS Business
2005 MammaPrint® one of the 5 biggest health breakthroughs according to Oprah Winfrey
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MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughput lab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility study
Reimbursement
Guidelines
MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughputlab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility study Reimbursement
Guidelines
Breast cancer-10 years survival curve
Patients, pre-menopausal, lymph-node negative
Premenopausal patients, LN-
The Challenge:Identify those patients who benefit from chemotherapy
Most Common Breast Cancer: T1, N0, ER+, Grade 2.
Cured by hormonal therapy
Only two patients of 100 benefit from additional chemotherapy
Cured by surgery
What is expression phenotypingand how is it measured?
High Risk
Low Riskanalysis
Benefit of untreated patients
Profiling of the tumor
Gene expression profile identifies “low risk”and “high risk” tumors
breast tumors (‘83-’94)patients < 55 years
lymph node negative (LN0)no adjuvant therapy
no distant metastasesin at least 5 years
distant metastases< 5 years
70 Prognosis Reporter Genes
Identification of a breast cancerprognosis profile
Unbiased full genome gene expression analysis
Good signature
Poor signature
threshold
70 significant prognosis genes
Prognosis Classifier for Breast Cancer
78 tumors
Threshold set with 10% false negatives91% sensitivity; 73% specificity
Van ‘t Veer et al Nature 415, p530-536, 2002
Metastases: white = +
Discovery:Van ‘t Veer et al. (2002)Nature 415, 530-536.
MammaPrint: A 70 gene breast cancer prognosis test
40% good profile ; 60% poor profile
good profile:~4% die of breast cancer~96% survive breast cancer
poor profile:~50% die of breast cancer~50% survive breast cancer
First validation:Van de Vijver et al. (2002)
New England J. Med. 347, 1999-2009.
295 patients
MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughputlab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility study Reimbursement
Guidelines
Independent External Validation:MammaPrint outperforms all clinical risk assessment
Buyse et al JNCI 2006
High clinical risk Adjuvant on line! N=22273%
Low clinical risk Adjuvant on line! N=8027%
27% MammaPrint
Low risk
35% MammaPrint
High risk
35% Discordant cases!
Under-treatment!
Over-treatment!
Second validation:Buyse et al. (2006)
JNCI. 98, 1183-1192.
302 patients
Year
Pro
babi
lity
0.0
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0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14
Patients Events Risk group
111 18 Gene signature low risk191 58 Gene signature high risk
111 108 102 95 92 80 64 43191 169 151 136 117 103 84 49
Number at risk
10-year DMFS90% (85%-96%)
10-year DMFS71% (65%-78%)
Year
Pro
babi
lity
0.0
0.2
0.4
0.6
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1.0
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Patients Events Risk group
80 13 Low clinical risk222 63 High clinical risk
80 76 72 65 57 48 38 20222 201 181 166 152 135 110 72
Number at risk
Metastasis-free survival
10-year DMFS85% (77%-94%)
10-year DMFS76% (70%-82%)
Discordant cases better predicted by MammaPrint
70 gene profile MammaPrint Adjuvant!Online
MammaPrint has been clinically validated in 2300+ patients
Purpose Year Patients (n) ReferenceDiscovery 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-analysisPredictiveness for adjuvant treatment 2009 1637 Knauer et al. Breast Cancer Res Treat.
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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
MammaPrint has been clinically validated in an international patient cohort
MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughput lab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility study Reimbursement
Guidelines
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
Overview: Agendia laboratory process
70-Gene Prognostic Assay Experiment 1
70-G
ene
Prog
nost
ic A
ssay
Exp
erim
ent
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MammaPrint is stable and reproducible
Glas et al. 2006 BMC Genomics 7; 278
MammaPrint is stable and reproducible
Oct-2005 May-2006 Nov-2006 June-2007 Dec-2007 July-2008-1
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Date
Mam
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LRC (n=284HRC (n=284)
LRC:
Mean MPI: 0.686
Stdev: 0.033
HRC;
Mean MPI: -0.503
Stdev: 0.028
Regulatory Approval of MammaPrint
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MammaPrint is the first molecular diagnostic test cleared by FDA
ISO 17025 accredited and CE markedfor European market
CLIA registered
College of American Pathologists(CAP) accredited
MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughput lab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility studyReimbursement
Guidelines
RASTER trial; an implementation study
Bueno-de-Mesquita et al., Lancet Oncology, Vol 8, 2007
• 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.
MammaPrint “From Bench to Bedside”
Research microarray profile
Clinical validation studies
High-throughput lab & informatics
Regulatory accreditation
Commercially available
diagnostic test Prospective
feasibility study
Reimbursement
Guidelines
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)
Evidence dossier
Basic Requirements
Key OpinionLeaders
ProfessionalSocieties
Patient Advocacy
Private Payers Governmental Payers
Coverage Coding Pricing
Reimbursement
Payment
A1
B1
C1 C2 C3
D2D1
E1 E2 E3
F1
Health Economics – “The Big Picture”
Evidence Dossier
o Clinical Utility (demand & impact)
o Clinical Validation
o Technical Validation
o Health Economics
! 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
Health Economics: definitions
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Base Case Model: Results
Total Cost
($)
Effect Incremental Cost ($)
Incremental Effect
ICER ($)
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)
“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 chemotherapyremained uncertain.”
Goldhirsch et al. (2009) Annals of Oncology (published online June17)
MammaPrint is included in the International St. Gallen Expert Consensus Recommendations
THANK YOU!