rené bernards mammaprint, the story of the 70-gene profile professor of molecular carcinogenesis...
TRANSCRIPT
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René Bernards
MammaPrint, the story of the 70-gene profile
Professor of Molecular CarcinogenesisThe Netherlands Cancer InstituteAmsterdam
Chief Scientific OfficerAgendiaAmsterdam
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The breast cancer treatment dilemma
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Of 100 women with breast cancer
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Only 25% will develop distant metastases
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But we treat over 75% of all patientswith chemotherapy
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Which means that 50% of all breast cancer patients get a toxic chemotherapy that they did
not need!
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High riskLow risk
MammaPrint: improved breast cancer diagnosis
High riskLow risk
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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
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MammaPrintDiscovery:
Van ‘t Veer et al. (2002)Nature 415, 530-536.
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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
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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
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First validation:Van de Vijver et al. (2002)
New England J. Med. 347, 1999-2009.
295 patients
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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
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NEJM 347, p1999-2009, 2002Gene profiling:Reduction adjuvant chemotherapy selectionAvoiding both over- and undertreatmentImproved prognosis prediction
MammaPrint
MammaPrint vs St Gallen guidelines
St Gallen
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Second validation:Buyse et al. (2006)
JNCI. 98, 1183-1192.
302 patients
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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!
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Hazard Ratios highest in first 5 years
Time to distant metastasis
MammaPrint predicts early metastases
JNCI 98, p1183-1192, 2006
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Chemotherapy only reduces the early metastases
No effect of Chemotherapy
Effect of ChemotherapyCourtesy: Peter Ravdin
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High reproducibility of microarray experiments (99%)
Glas et al, BMC Genomics 2007
Reproducibility; repeat of the experiment Reproducibility; 2 samples, 7 month period
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2007
First FDA approved molecular
Diagnostic test for cancer
Time Magazine:
Invention of the year 2007
MammaPrint: improved breast cancer diagnosis
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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%
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Recent additional features of the MammaPrint test:
Expanded indications:
all ages
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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
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Recent additional features of the MammaPrint test:
Expanded indications:
patients with 1-3 positive lymph nodes
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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)
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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
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Breast cancer with 1Breast cancer with 1-3-3 positive node positive node(s)(s)
MammaPrint Distant metastases as first event
Multivariate analysis
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TargetPrint: Quantification of ER, PR and HER2
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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
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MammaPrint is only the “tip of the iceberg” of personalized medicine
Personalized medicine
Who needs treatment?
Which therapy will work best?
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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?
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Poor quality biomolecules: poor quality biomarkers!
FreshFresh
RNA integrityFFPEFFPE Protein integrityProtein integrity
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Thank you!