Download MammaPrint - Belgian Breast Meeting 2015

MammaPrint, the story of
the 70-gene profile
René Bernards
Professor of Molecular Carcinogenesis
The Netherlands Cancer Institute
Amsterdam
Chief Scientific Officer
Agendia
Amsterdam
The breast cancer treatment dilemma
Of 100 women with breast cancer
Only 25% will develop distant metastases
But we treat over 75% of all patients
with chemotherapy
Which means that 50% of all breast cancer
patients get a toxic chemotherapy that they did
not need!
MammaPrint: improved breast cancer diagnosis
Low risk
High risk
Low risk
High risk
Identification of the MammaPrint breast
cancer prognosis profile
78 breast tumors (‘83-’94)
patients < 55 years
lymph node negative
no adjuvant therapy
Unbiased full genome
gene expression analysis
Prognosis Reporter Genes
distant metastases
< 5 years (n=34)
no distant metastases
in at least 5 years (n=44)
MammaPrint
Discovery:
Van ‘t Veer et al. (2002)
Nature 415, 530-536.
MammaPrint prognosis Profile
“the 70 gene profile”
Tumor samples
70 significant prognosis genes
van´t Veer et al., Nature 415, p. 530-536, 2002
threshold set at 10% false negatives
91 % sensitivity, 73% specificity
MammaPrint 70 genes are involved in all
aspects of tumor cell biology
proliferation
angiogenesis
intravasation, survival, extravasation
adhesion to extracellular matrix
local invasion
adhesion to extracellular matrix
proliferation
angiogenesis
Genes of unknown function (25)
First validation:
Van de Vijver et al. (2002)
New England J. Med. 347, 1999-2009.
295 patients
MammaPrint:Improved Clinical Management
Profiling vs St Gallen selection
St Gallen
metastases-free
MammaPrint
MammaPrint:
40% in good profile
60 % in poor profile
NEJM 347, p1999-2009, 2002
St Gallen:
15% in low risk
85% in high risk
MammaPrint
improved prediction
and more accurate
MammaPrint vs St Gallen guidelines
Gene profiling:
Reduction adjuvant chemotherapy selection
Avoiding both over- and undertreatment
Improved prognosis prediction
NEJM 347, p1999-2009, 2002
Second validation:
Buyse et al. (2006)
JNCI. 98, 1183-1192.
302 patients
Independent External Validation:
Microarray outperforms all clinical risk assessment
High clinical risk
Adjuvant on line! N=222
73%
Low clinical risk
Adjuvant on line! N=80
27%
27%
microarray
Low risk
Overtreatment!
Buyse et al JNCI 2006
>30% Discordant
cases!
35%
microarray
High risk
Undertreatment!
MammaPrint predicts early metastases
Time to distant metastasis
10
9.14
7.54
4.68
4.52
3.5
3.24
2.33
2.13
1
96%
Cumulative
proportion
of
events
75%
100%
83%
62%
50%
39%
29%
0.1
2
3
4
5
7
10
Censoring time (in years)
Hazard Ratios highest in first 5 years
JNCI 98, p1183-1192, 2006
15
none
Adjusted
hazard
ratio
for
gene
signature
Chemotherapy only reduces the early
metastases
No effect of Chemotherapy
Courtesy: Peter Ravdin
Effect of Chemotherapy
High reproducibility of microarray experiments
(99%)
Reproducibility; repeat of the experiment
Glas et al, BMC Genomics 2007
Reproducibility; 2 samples, 7 month period
MammaPrint: improved breast cancer diagnosis
First FDA approved molecular
Diagnostic test for cancer
2007
Time Magazine:
Invention of the year 2007
MINDACT study design
6000 patients, <70 YRS, 1-3 POS NODES
ASSESS clinical RISK AND MammaPrint RISK
(adjuvant!online & MammaPrint)
55%
BOTH HIGH
RISK
10%
35%
DISCORDANT
RISK
BOTH LOW
RISK
RANDOMIZE
decision-making
Use clinical risk
high
Chemotherapy
high
Use MammaPrint
low
low
No chemotherapy
Recent additional features of the
MammaPrint test:
Expanded indications:
all ages
MammaPrint prognosis in postmenopausal
patients
KM survival curve: Breast cancer > 55 year old
1
0.9
Good prognosis profile
Metastases free probability
0.8
Survival Probability
0.7
0.6
Poor prognosis profile
0.5
0.4
Poor
Good
0.3
0.2
0.1
0
150 patients
Chi2 = 15.38 P = 8.79e-005(wt power = 0)
0
5
10
15
Time(year)
Overall survival HR 2.3, 0.95 CI [ 1.3-4.1], p=0.0049
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 patients
Milan EIO (B Viale): 1994-1998
NKI series: 1984-1995
80% 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
with 1-3 positive node(s)
N=241breast cancer
patients with 1-3 positive
lymph node(s)
- Milan & NKI
Multivariate HR 6.59 (95% CI 1.71 to 25.45; p = 0.006)
Breast cancer with 1-3 positive node(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
ISO 17025 accredited and CE
mark for European market
CLIA registered to be able to
test US patients
CAP Accredited
The College of American
Pathologists
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?
Is there a hereditary
component?
Will tumor respond
to DNA damaging agents?
Poor quality biomolecules: poor quality biomarkers!
FFPE
Fresh
RNA integrity
Protein integrity
Thank you!