MammaPrint: From Bench to Bedside

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




High-throughputlab & informatics




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




High-throughputlab & informatics





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

0.2

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

0.8

1.0

0 2 4 6 8 10 12 14

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









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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1

Date

Mam

maP

rint

Inde

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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








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.








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!