René Bernards

MammaPrint, the story of the 70-gene profile

Professor of Molecular CarcinogenesisThe Netherlands Cancer InstituteAmsterdam

Chief Scientific OfficerAgendiaAmsterdam

The breast cancer treatment dilemma

Of 100 women with breast cancer

Only 25% will develop distant metastases

But we treat over 75% of all patientswith chemotherapy

Which means that 50% of all breast cancer patients get a toxic chemotherapy that they did

not need!

High riskLow risk

MammaPrint: improved breast cancer diagnosis

High riskLow risk

78 breast tumors (‘83-’94)patients < 55 years

lymph node negativeno adjuvant therapy

no distant metastasesin at least 5 years (n=44)

distant metastases< 5 years (n=34)

Prognosis Reporter Genes

Identification of the MammaPrint breast cancer prognosis profile

Unbiased full genome gene expression analysis

MammaPrintDiscovery:

Van ‘t Veer et al. (2002)Nature 415, 530-536.

threshold set at 10% false negatives

91 % sensitivity, 73% specificity

MammaPrint prognosis Profile“the 70 gene profile”

van´t Veer et al., Nature 415, p. 530-536, 2002

70 significant prognosis genes

Tum

or s

ampl

es

proliferation

angiogenesis

adhesion to extracellular matrix

local invasion

intravasation, survival, extravasation

proliferation

angiogenesis

adhesion to extracellular matrix

Genes of unknown function (25)

MammaPrint 70 genes are involved in all aspects of tumor cell biology

First validation:Van de Vijver et al. (2002)

New England J. Med. 347, 1999-2009.

295 patients

MammaPrint:Improved Clinical ManagementProfiling vs St Gallen selection

St Gallen:15% in low risk

85% in high risk

MammaPrint improved predictionand more accurate

MammaPrint:40% in good profile60 % in poor profile

met

asta

ses-

free

MammaPrint

met

asta

ses-

free

NEJM 347, p1999-2009, 2002

St Gallen

NEJM 347, p1999-2009, 2002Gene profiling:Reduction adjuvant chemotherapy selectionAvoiding both over- and undertreatmentImproved prognosis prediction

MammaPrint

MammaPrint vs St Gallen guidelines

St Gallen

Second validation:Buyse et al. (2006)

JNCI. 98, 1183-1192.

302 patients

Independent External Validation:Microarray 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% microarrayLow risk

35% microarrayHigh risk

>30% Discordant cases!

Under-treatment!

Over-treatment!

Hazard Ratios highest in first 5 years

Time to distant metastasis

MammaPrint predicts early metastases

JNCI 98, p1183-1192, 2006

Chemotherapy only reduces the early metastases

No effect of Chemotherapy

Effect of ChemotherapyCourtesy: Peter Ravdin

High reproducibility of microarray experiments (99%)

Glas et al, BMC Genomics 2007

Reproducibility; repeat of the experiment Reproducibility; 2 samples, 7 month period

2007

First FDA approved molecular

Diagnostic test for cancer

Time Magazine:

Invention of the year 2007

MammaPrint: improved breast cancer diagnosis

ASSESS clinical RISK AND MammaPrint RISKASSESS clinical RISK AND MammaPrint RISK(adjuvant!online & MammaPrint)(adjuvant!online & MammaPrint)

BOTH HIGH BOTH HIGH RISKRISK

DISCORDANTDISCORDANTRISKRISK

BOTH LOW BOTH LOW RISKRISK

RANDOMIZERANDOMIZEdecision-makingdecision-making

ChemotherapyChemotherapy No chemotherapyNo chemotherapy

Use MammaPrintUse MammaPrintUse clinical riskUse clinical risk

MINDACT study designMINDACT study design

6000 patients, <70 YRS, 1-3 POS NODES6000 patients, <70 YRS, 1-3 POS NODES

highhigh low

low

55% 35% 10%

Recent additional features of the MammaPrint test:

Expanded indications:

all ages

Overall survival HR 2.3, 0.95 CI [ 1.3-4.1], p=0.0049

Met

asta

ses

free

pro

babi

lity

0 5 10 150

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1KM survival curve: Breast cancer > 55 year old

Time(year)

Sur

viva

l Pro

babi

lity

Chi2 = 15.38 P = 8.79e-005(wt power = 0)

Poor

Good

Good prognosis profile

Poor prognosis profile

150 patients

MammaPrint prognosis in postmenopausal

patients

Recent additional features of the MammaPrint test:

Expanded indications:

patients with 1-3 positive lymph nodes

Validation of MammaPrint in patients with

1-3 positive lymph nodes

Milan and NKI series 241 patientsMilan EIO (B Viale): 1994-1998NKI series: 1984-199580% treated adjuvant chemo and/or hormonal therapy

Median Follow Up:Milan: 8.97 years (0-10.9)NKI : 10.4 years (1.6-21.2)

MammaPrint performance in patients MammaPrint performance in patients

with 1with 1-3-3 positive node positive node(s)(s)

Multivariate HR 6.59 (95% CI 1.71 to 25.45; p = 0.006)

N=241breast cancer patients with 1-3 positive lymph node(s)

- Milan & NKI

Breast cancer with 1Breast cancer with 1-3-3 positive node positive node(s)(s)

MammaPrint Distant metastases as first event

Multivariate analysis

TargetPrint: Quantification of ER, PR and HER2

MammaPrint: extensive regulatory approvals

MammaPrint is the first and only IVDMIA

cleared for market by FDA

CAP Accredited

The College of American Pathologists

CLIA registered to be able to test US patients

ISO 17025 accredited and CE mark for European market

MammaPrint is only the “tip of the iceberg” of personalized medicine

Personalized medicine

Who needs treatment?

Which therapy will work best?

Personalized medicine: multiple answers on a single microarray chip

Prognosis?

Will tumor respond to Herceptin?

Will tumor respond to DNA damaging agents?

Is there a hereditarycomponent?

Poor quality biomolecules: poor quality biomarkers!

FreshFresh

RNA integrityFFPEFFPE Protein integrityProtein integrity

Thank you!