Les signatures multigéniques pronostiques dans le cancer du sein Session thématisée

10èmes Journées Scientifiques du
Cancéropôle Nord-Ouest
10-12 mai 2017, Deauville
Session thématisée
Les Innovations diagnostiques en cancérologie
Les signatures multigéniques
pronostiques dans le cancer du sein
Martine J. Piccart-Gebhart, MD, PhD
Institut Jules Bordet, Brussels, Belgium
Université Libre de Bruxelles
Breast International Group (BIG aisbl), Chair
Disclosures
No conflict of interest with any of the companies
which are marketing gene expression signatures
BREAST CANCER TODAY
Significant Progress Achieved
Incidence
Mortality
Ferlay J. Globocan 2012
BREAST CANCER TODAY
5 year survival rates (SEER)
ADJUVANT SYSTEMIC THERAPY FOR BREAST CANCER TODAY
The Age of Escalation
Targeted
therapy
SX Chemo RT
Targeted
therapy
Endocrine therapy
Cure a substantial
proportion of women
Treatment duration : anywhere from 1 day to 15 years !
ADJUVANT SYSTEMIC THERAPY FOR BREAST CANCER TODAY
The Age of Escalation
More
Patients
Treated
Longer
Drug
Exposure
Therapeutic
Escalation
More
Drugs
TREATMENT ESCALATION
Consequences
The cost threatens to blow up our
health care systems – the ones
that actually pay for treatments!
Many women live longer but
bear the consequences of our
aggressive treatments – and
we can never ignore this!
BREAST CANCER
« Adjuvant »
medical therapies
Lung
Liver
Bone
Localized disease
Curable
But risk of :
•overtreatment
• undertreatment
• wrong treatment
• suboptimal treatment
Generalized disease
Very difficult to cure
ADJUVANT SYSTEMIC THERAPY FOR EARLY BREAST CANCER
Benefit / Risk Balance
Lessons learned from 3 decades of clinical trials
BENEFIT
 Survival
(2 to 12%)
POTENTIAL “HARM”
• Mood alterations
• Thrombo-embolic events
• Arthralgia
• Osteoporosis
LONG-TERM RISKS
• Secondary cancers
• Cardiac toxicity
• Early menopause
•  Cognitive function
… AND SOCIO-ECONOMIC BURDEN
ST. GALLEN DEFINITIONS OF RISK
Low
Intermediate
R
I
S
K
High
Node –
G1
HER2 –
T2
LVI absent
AGE < 35
G2-3 T>2
Only 20% of
patients!
Most difficult
group for CT
decision!
Node –, HER2+
or LVI present
Node + (1-3) and HER2 -
Node + (1-3)
and HER2 +
Node +  4
Other similar guidelines exist : NCCN, ESMO,…
R
I
S
K
IMPROVED RISK ASSESSMENT
OF EARLY BREAST CANCER
THROUGH GENE EXPRESSION PROFILING
L. van ‘t Veer
R. Bernards
78 untreated N ─ primary tumors
295 partially treated N─ / N+ tumors
microarray
44 w/o relapse
at 8 y follow-up
Gene-expression profile
34 with a relapse
within 5 y
5000 genes
231 genes
70 genes
Poor prognosis signature
van ‘t Veer L., Nature 2002; 415 (31) : 530-536
Van de Vijver MJ, N Engl J Med 2002; 347 (24): 1999-2009
B.C. CLINICAL OUTCOME PREDICTION
70-gene profiler outperforms St Gallen criteria
Van de Vijver MJ, N Engl J Med 2002; 347 (24): 1999-2009
Validation of the MammaPrint® signature :
15 years of intensive collaborative work!
2002
2003
Signature External validation
published of the signature by
the TransBIG
network
2007-2011
2016
Conduct of
MINDACT
MINDACT
Results
EORTC-BIG Mindact Trial Design
6.694 node negative & 1-3 node positive women
70-gene signature (Mammaprint®) risk AND
Clinical-Pathological risk
Both low
risk
Discordant
cases
Both high
risk
No
chemotherapy
Randomization
Chemotherapy
Supported by the EU 6th framework grant (7 million euros)
Total cost of trial ≈ 45 million euros!
Tumor
biology
MammaPrint®
Low vs High genomic risk
Tumor
anatomy
VERSUS
(+ a few biological features)
Adj.! Online
Low vs High clinical risk
Hypothesis : the Genomic assay will outperform the Clinical criteria by reducing
the prescription of adjuvant chemotherapy WITHOUT IMPAIRING OUTCOME
More specifically: clinically high risk patients with a low risk gene signature
randomized not to receive CTX should have a 5 year DMFS of ≥ 92%
The MINDACT study: Patient demographics
N = 6693
Median age =
Node Node +
T1 tumours
Grade 2
HR positive
HER2+
55y
79%
21%
72%
49%
88%
10%
Discordant
N=2745
N=1806
clinical Low/
genomic Low
clinical High/
genomic High
N=592
N=1550
clinical Low/
genomic High
clinical High/
genomic Low
Clinical « low risk »
(50%)
Clinical « high risk »
(50%)
ER
status
HER2
status
Grade
Nodal status
N─
HER2 negative
ER positive
well differentiated
1-3 positive
nodes
moderately
differentiated
poorly
differentiated
OR
undifferentiated
N─
1-3 positive
nodes
N─
1-3 positive
nodes
Tumor size
Clinical Risk
in MINDACT
≤ 3cm
C-low
3.1-5 cm
C-high
≤ 2 cm
C-low
2.1-5 cm
C-high
≤ 2 cm
C-low
2.1-5 cm
C-high
Any size
C-high
≤ 1 cm
C-low
1.1-5 cm
C-high
Any size
C-high
C-high risk : expected 10 y OS < 92% with endocrine therapy alone (as per Adjuvant! Online)
The MINDACT study at a median follow-up of 5 years
N = 6693 women
N = 672 relapses
208 deaths
N = 362 distant relapses
Clinical outcome of the MINDACT population
at 5y median follow-up
DMFS IN ALL 4 RISK GROUPS
Clinical outcome of the MINDACT population
at 5y median follow-up
DISCORDANT RISK GROUPS: PRIMARY TEST
The primary analysis population
The primary statistical test
(DMFS at 5Y)
Discordant risks
c-Low /g-High
c-High/g-Low
RANDOMIZATION
No chemotherapy
N = 748
No change in risk
post enrollement
and no CT received
N = 644
CT
Null Hypothesis: set at 92%
Observed 5Y DMFS = 94.7%
95% CI ≈ 92.5 – 96.2% excludes 92% !!!
MINDACT: whole population vs “key subgroup”
MINDACT
High clin risk/low genomic risk
(N=1550)
MINDACT
Entire population (N=6693)
T1
T2
T3
27%
1%
T3
79%
52%
3+ nodes
22%
G2
G1
49%
29%
Er‒ PR‒
12%
HER2+
9,5%
4%
N0
2+ nodes
G3
54%
1+ node
21%
G1
42%
T2
N0
N1-3
T1
72%
33%
10%
5%
6%
G2
64%
G3
29%
Er‒ PR‒
2%
HER2+
8%
•
•
Low proportion
Less confidence
in the results?
Can we be sure that modern
pathology is not also able to
distinguish “indolent” luminal
cancers from “aggressive” ones?
Discordances between central immunohistochemical and
molecular breast cancer subtyping in the MINDACT trial “luminal” tumors
(N=4718)
Molecular subtyping based on
BluePrint and MammaPrint®
Pathological subtyping
Luminal A
Luminal B
ER+ and PgR ≥ 20%
and HER2and Ki67 < 20%
ER+ and PgR < 20%
and/or Ki67 ≥ 20%
and HER2-
Can we be sure that
adjuvant CT does not
provide a benefit in the
“discordant” groups?
Efficacy: CT vs no CT in discordant risk groups
Intent-to-treat analysis
Distant Metastasis Free Survival
c-Low/g-High
Distant Metastasis Free Survival
c-High/g-Low
Allocated
Treatment
strategy
CT
no CT
% at 5 Year(s)
(95% CI)
Hazard Ratio
p-value
(adjusted
(adjusted Cox model)
logrank)
(95% CI)
95.9
0.78
(94.0, 97.2)
(0.50,1.21)
94.4
(92.3, 95.9)
1.00
Allocated
Treatment
strategy
CT
0.267
no CT
% at 5 Year(s)
(95% CI)
95.8
(92.9, 97.6)
95.0
(91.8, 97.0)
Hazard Ratio
p-value
(adjusted Cox (adjusted
model)
logrank)
(95% CI)
1.17
(0.59,2.28)
1.00
Allocated to:
Allocated to:
Small CTX benefit not
ruled out… but ≤ 2%
0.657
No suggestion of any
CT benefit
Adjuvant therapy decision-making
NEVER FORGET THAT…
The « low-enough » risk
that justifies treatment
de-escalation… is a
patient’s decision!
« High risk » does not
mean that the
treatment will work!
Practical use of MammaPrint® in the clinic
Start by evaluating the
“Clinical Risk”
*
Clinical risk
“LOW”
Clinical risk
“HIGH”
Treatment according
to guidelines
Discuss with patient if she
would value a < 2% gain in
DMFS with adjuvant CTX
*Exclude women with T3 or N2─ 3+ ?
NO
YES
Order MammaPrint® test
Proceed
with CTX
In 48% of patients it will
come back “low risk”
allowing for adjuvant CTX
sparing
Are there ways
to forgo
GEPs???
Dr M de Block – Minister of Health
More than 15 years of research…
and still a lot of controversy
regarding who can be spared
adjuvant chemotherapy and who
does not need extended adjuvant
endocrine therapy!!!
SYSTEMIC THERAPY FOR EARLY BC
Gene Signatures assisting with decision making
OnCoG
GI
oncoDNA
/Myriad
Most useful in Node negative disease
Ribinikar D - ASCO Educational Book 2016
Proliferation genes drive the prognostic power
of GEP signatures
Original signature
Proliferation genes
Original signature
Non-Proliferation genes
Sotiriou C, et al. N Engl J Med. 2009; Wirapati P, et al. Breast
Cancer Res. 2008; Sotiriou C, et al. Nat Rev Cancer. 2007
LOE 1A
(Prospective Validation)
MINDACT
(MammaPrint)
TAILORX
(Oncotype Dx)
RxPONDER
(Oncotype Dx)
ASTER70
(Genomic Grade)
Reported
Partial results reported
Expected final results
2017
Expected results
2022
Expected results
2018
Adjuvant therapy decision-making
NEVER FORGET THAT…
The « history » of luminal BC
extends beyond 5 years, with late
relapses seen particularly
if large T a/o N+
SABCS 2016
New data regarding MammaPrint®
An ultra low risk cut-off identifies N-
postmemopausal women with
excellent 20-year outcomes
Molecular definition of “Indolent”
70 gene Prognosis Signature: “Ultra-low Threshold”
70 significant prognosis genes
Ultralow
Threshold
van´t Veer et al., Nature ,2002
Threshold derived from TRANSBIG with 25-year follow-up and no metastatic events
In women with breast cancer and WITHOUT ANY SYSTEMIC THERAPY
This presentation is the intellectual property of the author. Contact them at [email protected] permission to reprint and/or distribute.
Validation in the
STO 3 Trial
postmenopausal
women, <3cm, N0
tumors
Stockholm: 1976-1991
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All Patients by 70 Gene,
Ultralow, low≠ultralow, high
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Intergroup TAILORx Trial (N=10,253)
Trial Assigning IndividuaLized Options for Treatment
Node Negative ER+ and/or PgR+ HER2
negative (IHC 0-1+ or FISH [-])
21-Gene Recurrence Score Assay
RS <11
Hormonal
Therapy*
16%
Results released in 2015
RS 11 - 25
Randomize
Hormonal Rx*
vs
Chemotherapy*
+
Hormonal Rx*
67%
RS >25
Chemotherapy*
+
Hormonal Rx*
17%
*Choice of therapy at investigator discretion including option of
adjuvant chemotherapy trials
TAILORx: RS 0-10
N=1626 / 88 events at median follow-up of 69 months
Rate of freedom from recurrence at distant site :
99.3% (95% ci: 98.7-99.6)
Distant recurrences N=10
Locoregional recurrences
N=8
Contralateral BC (invasive)
N=15
Other primary cancers
N=43
30 deaths (12 w/o cancer)
Sparano J.A. et al, N Engl J Med, Nov 19, 2015
Stage (N) still matters
Prognostic Signatures are not good enough
if high tumor burden!
Trans ATAC
(Oncotype DX)
NKI Validation
(MammaPrint)
LN-
Dowsett et al., J Clin Oncol. 2010
LN+
Van de Vijver et al., NEJM 2002
SABCS 2016 (Sestak et al)
Head to head comparison of several signatures
and their added value beyond a clinical
treatment score in Node ─ or Node + patients
from ATAC treated with endocrine therapy only
• Clinical treatment score: N status, T size,
grade, age, therapy
• Signatures: RS (Oncotype-DX), BCI, ROR score
(Prosigna)*, EndoPredict Clinical**
*incorporates T size
** incorporates T size and nodal status
Head to head comparison of multigene
prognostic signatures in the ATAC trial
N = 818 women (591 N─, 227 N+)
10 year distant
recurrence rate
5-10 year distant
recurrence rate
29%
14%
10%
6%
N─
N+
N─
N+
San Antonio Breast Cancer Symposium – December 6-10, 2016
Prognostic value years 0-10 – node-negative
CTS
31,8
IHC4
30,6
43,8
BCI
RS
% Improvement
22,8
ROR
EPclin
50,8
40,6
Likelihood Ratio χ2
IHC4
31.8
BCI
31.8
RS
31.8
ROR
31.8
EPclin
31.8
17,1
22,5
53.8%
70.8%
33.3%
10,6
23,7
15,2
74.5%
47.8%
Likelihood Ratio ∆χ2
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San Antonio Breast Cancer Symposium – December 6-10, 2016
Prognostic value years 0-10 – node-positive
IHC4
BCI
RS
ROR
EPclin
% Improvement
40,2
CTS
6,3
9,6
6,4
15,5
35,6
Likelihood Ratio χ2
IHC4
40.2
4,8
11.9%
BCI
40.2
5,2
12.9%
RS
40.2
5.0
12.3%
ROR
40.2
6.0
14.9%
EPclin
40.2
8,5
21.1%
Likelihood Ratio ∆χ2
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Prognostic (± predictive) value of
multigene signatures in years 0-10
• Node negative disease: all signatures show
added value beyond the Clinical Treatment
Score and identify 55 to 70% of patients as
having a 10y risk of distant metastases ranging
between 3 and 6.6%
• Node positive disease: the added value of the
signatures is inexistent or modest (ROR,
EndoPredict Clinical)
EndoPredict Clinical identifies 19% of patients
with a 10y risk of distant mets below 6%
San Antonio Breast Cancer Symposium – December 6-10, 2016
Prognostic value years 5-10 –
node-negative
IHC4
6,6
19,5
BCI
RS
ROR
EPclin
% Improvement
16,6
CTS
3,4
31,3
24.0
Likelihood Ratio χ2
IHC4
16.6
BCI
16.6
RS
16.6
ROR
16.6
EPclin
16.6
20.0%
3,3
11,2
67.5%
11.4%
1,9
18,4
10,3
111.0%
62.0%
Likelihood Ratio ∆χ2
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 6-10, 2016
Prognostic value years 5-10 –
node-positive
% Improvement
16.0
CTS
IHC4
1.0
IHC4
16.0
1,2
7.5%
BCI
3,1
BCI
16.0
1,8
11.3%
RS
1,1
RS
16.0
1.1
6.9%
ROR
16.0
4.1
25.6%
EPclin
16.0
ROR
EPclin
7,3
14,9
Likelihood Ratio χ2
4,4
27.5%
Likelihood Ratio ∆χ2
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Prognostic (± predictive) value of
multigene signatures in years 5-10
• Node negative disease: added value is seen for
BCI, ROR and EndoPredict Clinical.
EndoPredict Clinical identifies 73.5% of
patients with a risk of distant relapse of 4.3%
• Node positive disease: a modest added value
is seen for signatures that combine genomic
with anatomic information. EndoPredict
Clinical, for examples, identifies 22% of
patients with a risk of distant relapse of 3.3%
What about the “predictive”
power of the gene signatures for:
- CTX benefit
- Endocrine therapy benefit
?
High proliferative breast cancers
may benefit from adjuvant chemotherapy
CMF regimen
LN-
Paik et al., JCO 2006
CAF regimen
LN+
Albain et al., Lancet Oncology 2009
Breast Cancer Index
Algorithmic combination of proliferation related
gene signature (Molecular Grade Index) and an
estrogen signaling pathway signature
(Hox B13/IL17 BR, H/I)
Summary of BCI Predictive (H/I) Validation Data
▪ H/I shown to be a significant predictor of endocrine benefit in 3
randomized trial cohorts
Study
Cohort
Treatment
Stockholm
(n=600)1
Adjuvant tamoxifen vs H/I High HR: 0.35 (0.19-0.65); p=0.0005
untreated
H/I Low HR: 0.67 (0.36-1.24), p=0.2
0.003
TransATAC
(n=665)2
Adjuvant anastrozole
vs tamoxifen
0.004
MA.17
(n=249)3
Extended letrozole vs H/I High OR: 0.33 (0.15-0.73); p=0.006
placebo
H/I Low OR: 0.58 (0.25-1.36), p=0.21
Predictive analysis
Interaction
P value
H/I High HR: 0.51 (0.27-0.97); p=0.04
H/I Low HR: 1.33 (0.65-2.71), p=0.4
0.03
▪ Results suggest generalizability as an endocrine response
biomarker
1. Zhang Y, et al. Clin Cancer Res. 2013;19(15):4196-205. 2. Sgroi D, et al. Lancet Oncol. 2013 Oct;14(11):1067-76. 3. Sgroi et al, J Natl Cancer Inst. 2013;105:1036-1042
Which signature for which patient?
Luminal BC patients, aged ≥ 40y, No or N1-3+ at diagnosis
Low clinical risk as
per MINDACT
SIGNATURE
High clinical risk as
per MINDACT
Patient willing to have
CTX for very small
benefit
Patient unwilling to
have CTX for small
benefit
SIGNATURE
SIGNATURE
-
Prognosis within 5y
most relevant (N─)
Prognosis within 10y
most relevant (N+)
MammaPrint®
Oncotype
EndoPredict, BCI, ROR
EndoPredict,
BCI, ROR
Not accepted by guidelines
Which signature for which patient?
Luminal BC patients, aged ≥ 40y, No or N1-3+ after 5y
of endocrine therapy (and no CTX!)
Node ─
Node +
BCI, ROR, EndoPredict Clinical all useful
Only ROR and EndoPredict Clinical
add value but in a modest way
EndoPredict Clinical identifies
73% of patients with a distant
relapse risk of 4.3%
EndoPredict Clinical identifies
22% of patients with a distant
relapse risk of 3.3%
Not accepted currently by guidelines
TAILORING OF SYSTEMIC THERAPY FOR EARLY BC
Multi Gene Signatures – Time to move to the next chapter
Bardelli A et al Cancer Cell 10.1016/j.ccell.2017.01.002
BREAST Data Center Team
BIG HeadquartersTeam
Institut Jules Bordet Team
BIG Executive Board 2014-2018
Backups
EBCTCG, submitted (2017)
EBCTCG, submitted (2017)
EBCTCG, submitted (2017)
EBCTCG, submitted (2017)
EBCTCG, submitted (2017)
Reclassification with molecular subtyping
•
Molecular Subtyping
classified 54% as Luminal A
among the Luminal B by
Pathological Subtyping (PS).
•
MS classified 38% as Luminal
(A and B) and 5% as Basaltype among the HER2+ by PS.
•
MS classified 5% as Luminal
(A and B) among the TN
cases by PS.
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or
distribute.
Adjuvant! Online for breast cancer (Updated version)
used for a standardized approach to “Clinical Risk”
P. Ravdin
Interpretation of the ATAC multigene
signature comparison study
• All patients received endocrine treatment!
• Node negative disease: all signatures show
added value and perform well in years 0-10
and in years 5-10
• Node positive disease: the performance of the
signatures is more modest and only the ones
that integrate tumor burden are useful; more
research here is needed…