1. Adjuvant
chemotherapy
for
T1ab
breast
cancer
in
2014
?
David
Coeffic
Cancer
Ins@tute
of
Reims–
Polyclinique
Courlancy

2. What
we
talk
about
?
• pT1ab
(≤
1
cm)
• pN1
and
pNmic
are
excluded

3. T1abN0
:
is
it
a
real
problem
in
term
of
prognosis?
• The
number
of
clinical
events
could
be
jus@fied
specific
treatment
?
• In
other
words,
there
is
some
clues
that
jus@fy
to
select
predic@ve
sub-­‐type
for
treatment
?

4. Historic
considera@on
We
started,
and
it's
a
«
shame
»,
to
be
interested
in
T1abN0
from
the
@me
there
was
a
talk
about
Her2
!!
But
several
studies
published
in
the
last
decade
strongly
support
the
fact
that
the
metasta@c
poten@al
of
breast
tumors
may
be
present
a
very
early
event,
even
though
the
primary
breast
tumor
is
not
detectable
by
imaging
(Engel,
2003
;
Van’t
Veer,
2002
;
Schmidt-­‐Ki:ler
2003
;
Husemann
2008
et
Podsypanina
2008).

5. Press MF. et al. JCO 1997;15(8):2894-2904 Temps jusqu’à récidive (mois)
Probabilitédesurvie
Tumor size
Events
exist
!!!
§ Retrospective mulicentric study (US)
§ 382 tumoral sample (from surgery)
§ N0 breast cancer
§ Diagnosis < 1990
§ No adjuvant chemotherapy
§ FISH analysis for HER2

6. We
have
found
events
in
T1ab
!
•
n
=
965,
10
%
of
HER2+
•
More
T1a
than
T1b
are
HER2+
•
No
pa@ents
received
Chemotherapy
or
Trastuzumab
•
Median
follow-­‐up:
6.2
years
Gonzalez-Angulo AM. et al – J Clin Oncol 2009
Time to diagnosis (months)
DFS
Time to diagnosis (months)
MetastaticDFS

7. Events
exist,
even
with
treatment
!!
• T1abc
pN0
N
=
2
026
-­‐
T1a-­‐b
=
328
and
T1c
HR
1.71
(p
=
0.01)
DFS
-­‐
67
%
=
adjuvant
chemotherapy
HR
2.03
(p
=
0.003)
OS
-­‐
Median
Follow-­‐up:
12.4
years
Chia
S.
et
al.
J
Clin
Oncol
2008;26:5697-­‐5704
All patients
Time (years)
Surviesansrécidive
(probabilité)
Patient without adjuvant chemotherapy
Time (years)
Surviesansrécidive
(probabilité)

8. Events
exist,
even
with
treatment,
even
for
HER2…
Popula@on
T1a-­‐b
=
328,
HER2+
:
10
%
(n
=
32)
Chia
S.
et
al.
J
Clin
Oncol
2008;26:5697-­‐5704
T1a-b
Time (y)
DFS
OS
T1a-b
Time (y)
DFS
T1a-b,
Without adjuvant chemotherapy
Time (y)

9. In
conlusion
• The
number
of
event
according
to
the
retrospec@ve
study
is
located
between
5
and
10
%
in
no
pretreated
pa@ents
• Events
exist,
even
in
pa@ents
treated,
confirming
the
requirement
for
op@mizing
treatment
• There
is
some
prognos@c
factors
that
seem
obvious
now,
some
of
which
are
also
predictors

10. Summary
but
not
limited,
prognos@c
factors
highlighted
on
retrospec@ve
series,
for
DFS
Red:
posi@ve
in
mul@variate
analysis,
Yellow
:
posi@ve
in
univariate
analysis
Author
Journal
Year # Fol Feature 5-
years
Her 2 + Triple N ER - Age Grade KI 67 Embol Node
Livi
Cancer
2012 704
<35
Kwon
BMC
2010 375 61
m
Monocentric
T1Mic
3 M+
<35
1
Cut off
14 %
Cancello
Breast
2011 1691 DFS
=
92,5
%
Cut off
14 %
Theriault
JCO
2012 1012 No treated
< 35 vs
> 50
Hanrahan
JCO
2007 51246 SEER registry
<50
Grade
III
> 6
Fisher
JNCI
2001 235 Including T1c
50 ans
Wood
Ann Surg
2002 282 Monocentric
Nomogramme
2 M+
at 10
y
Grade
cIII
Colleoni
Ann Oncol
2004 425 Including T1
Mic
Cut off
20 %
Kaplan 2009 110 4,2
y
DFS
= 89
%
• Age
and
prolifera@on
are
the
major
and
universal
prognos@c
factors.
• Clinical
Triple
nega@ve
is
also
a
major
factor
• Molecular
factors
that
are
predictors
are
somewhat
interrelated
à
To
go
further,
it
is
urgent
to
have
a
more
individualis@c
approach
based
on
molecular
approach

11. «
Doxa
»
of
@me?
For
example,
three
paths
:
• NCCN
2014
• Permanent
publica@on
screening
• Based
on
the
level
of
evidence
• Saint
Gallen
2011
• Scien@fic
and
intellectualized
approach
• Only
a
consensus
approach
base
on
expert
opinions
• French
experts
consensus
2011
(F
Penault
Llorca
et
al.)
• A
consensus
based
on
a
exhaus@ve
bibliographic
screening

12. HER
2
néga@ve

13. HER2
posi@ve

14. Saint
Gallen
:
a
molecular
approach

15. French
expert
reviews
for
tumors
Her
2
+
** For grade 1 tumors and expressing strongly HR: request a review of HER2 status by FISH
Treatment of patients with breast cancer without lymph node involvement,
HER2 is overexpressed
< 1 cm > 1 cm
HR + ** HR - HR + ER-
All grade
Chemotherapy +
Trastuzumab
§ < 35 ans or
§ High proliferation
(KI67, MI) or
§ and/or grade 2-3
§ and/or embols
+/- Hormonothérapie
Chemotherapy +
Trastuzumab
Hormonotherapy
Chemotherapy +
Trastuzumab
Chemotherapy
+ Trastuzumab
Penault-Llorca F et Coeffic D. Bull Cancer 2011; Jul;98(7):807-25.

16. A
synthesis
?
Size T1a T1b
Her 2+ RH - Her 2+ RH
+
Luminal A Luminal B TN Her 2+
RH -
Her 2+
RH +
Luminal
A
Luminal
B
TN
NCCN 2014 No tt * HT* HT * HT * No tt * TZ + CT HT
TZ+CT
HT
CT
according to
Oncotype
Dx
HT
CT
according to
Oncotype
Dx
CT
Saint Gallen
2011
No tt HT HT HT CT TZ + CT HT
TZ + CT
HT
CT
according to
Oncotype
Dx and
UPA/P1
HT
CT
according to
Oncotype
Dx and
UPA/P1
CT
French
Consensus
Penault
Llorca
2011
TZ + CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
No tt TZ +CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
CT
INCA 2012 No answer No answer No answer No answer
*
CT
si
Mic

17. Size T1a T1b
Her 2+ RH - Her 2+ RH
+
Luminal A Luminal B TN Her 2+
RH -
Her 2+
RH +
Luminal
A
Luminal
B
TN
NCCN 2014 No tt * HT* HT * HT * No tt * TZ + CT HT
TZ+CT
HT
CT
according to
Oncotype
Dx
HT
CT
according to
Oncotype
Dx
CT
Saint Gallen
2011
No tt HT HT HT CT TZ + CT HT
TZ + CT
HT
CT
according to
Oncotype
Dx and
UPA/P1
HT
CT
according to
Oncotype
Dx and
UPA/P1
CT
French
Consensus
Penault
Llorca
2011
TZ + CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
No tt TZ +CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
CT
INCA 2012 No answer No answer No answer No answer
Area
of
consensus
*
CT
si
Mic

18. Size T1a T1b
Her 2+ RH - Her 2+ RH
+
Luminal A Luminal B TN Her 2+
RH -
Her 2+
RH +
Luminal
A
Luminal
B
TN
NCCN 2014 No tt * HT* HT * HT * No tt * TZ + CT HT
TZ+CT
HT
CT
according to
Oncotype
Dx
HT
CT
according to
Oncotype
Dx
CT
Saint Gallen
2011
No tt HT HT HT CT TZ + CT HT
TZ + CT
HT
CT
according to
Oncotype
Dx and
UPA/P1
HT
CT
according to
Oncotype
Dx and
UPA/P1
CT
French
Consensus
Penault
Llorca
2011
TZ + CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
No tt TZ +CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
CT
INCA 2012 No answer No answer No answer No answer
Area
of
disagreement
*
CT
si
Mic

19. Problems
are
not
yet
solved!
• The
ques@ons
that
we
will
live
• Her2
tumors:
should
we
take
into
account
the
size
and
/
or
the
HR
status
?
• TN:
What
are
the
predictors
of
efficacy
to
chemotherapy?
For
which
sub-­‐group?
• Beyond
the
size,
which
predictors
for
chemotherapy
in
luminal
?

20. Her
2
+
disease

21. Decision criterias in the « real life » for
T1ab Her 2
Trastuzumab
(n=93)
No Trastuzumab
(n=112)
P value
(Fisher test)
T1a
T1b
16 (17%)
77 (83%)
36 (32%)
76 (68%)
0.016
Grade 1
Grade 2-3
3 (3%)
89 (97%)
17 (16%)
90 (84%)
0.004
HR +
HR -
40 (43%)
53 (57%)
81 (72%)
31 (38%)
<0.001
MI =1
MI =2-3
24 (40%)
36 (60%)
58 (67%)
28 (33%)
0.001
Embols
No
Yes
72 (78%)
20 (22%)
95 (88%)
13 (12%)
0.085
*
Log-­‐rank
test
was
used
Julien Peron. Study AERIO/UNICANCER, SABCS 2011.

22. HER
2
+
as
a
prognos@c
factor
in
T1ab
?

23. Retrospec@ve
studies,
Her
2
breast
cancer
T1,
N0,
M0.
Study Only
T1a-b
#
T1a
T1b
HER2+
(%)
Median
follow-up
(Y)
Adjuvant
treatment
Press No 382 ? (Fish) ? No
Black No 27
47
100 5.6 ?
Joensuu No 49
264
12 9.5 No
Tavey No 230 6.9 6.5 ?
Chia No 103
225
6.4 12.4 67 %
Curigliano Yes 85
65
100 4.5 Yes
Gonzalez-Angulo Yes 323
642
10 6.2 No
Peron
San Antonio 2011
Yes 52
153
100 ? 40 %
Rouanet
San Antonio 2011
Yes 131
572
5,9 ? No

24. Events
exist!!!
§ Retrospective Finnish
study.
§ 852 patients with
pT1N0M0 breast cancer
between 1991 and 1992.
§ Multivariate analysis
§ Median Follow-up : 9,5
years.
§ Only 5 % received
adjuvant chemotherapy
Joensuu H. et al. Clin. Cancer Res. 2003;9:923-930
Années de suivi Années de suivi
Années de suivi Années de suivi
Surviesansmaladieà
distance
Surviesansmaladieà
distance
T1ab T1c
IHC
CISH
HER2 is a poor prognostic factor even when the tumor is small (T1ab,
T1c).

25. HER2
expression
is
the
major
risk
factor
for
recurrence
in
pT1a-­‐b,
NO
breast
cancer:
Clinical
implicaAons
from
a
French
regional
populaAon-­‐based
study
of
703
paAents
Rouanet P, Roger P, Daures JP, Rousseau E, Romieu G,
Mathieu A, Cretin J, Barneon G, Granier M, Maran-
Gonzalez A, Thibault S. Boissiere F, Bibeau F.
ONCO Languedoc-Roussillon Network

26. Disease Recurrence
• 5-­‐year
DFS
rates
were
74%
and
95%
in
pa@ents
with
HER2-­‐posi@ve
and
HER2-­‐nega@ve
tumors,
respec@vely
(p<0.0001)
• According
to
the
immunohistochemical
phenotype
DFS-­‐5
years
were
• 95%
for
ER+/PR+/HER2-­‐
(n=614/87%)
• 91%
ER-­‐/PR-­‐/HER2-­‐
(n=47/6.7%)
• 69%
ER+/PR+/HER2+
(n=25/3.5%)
• 81%
ER-­‐/PR-­‐/HER2+
(n=17/2,4%)
• In
univariate
analysis,
HER2
posi@ve
tumors
(p=0.017),
phenotype
classifica@on
(p=0.02)
and
adjuvant
treatment
(p=0.013)
were
significant
prognos@c
factors
• In
mul@variate
analysis,
only
pa@ents
with
HER2+
tumors
had
higher
risks
of
recurrence
(hazard
ra@o
[HR],
2.41;
95%
CI;
[1.06-­‐5.53];
p<0.05)
than
those
with
HER2-­‐
tumors.

27. Benefit
of
Trastuzumab
in
T1N0
?

28. Avantage
AC-TH
Avantage
AC-T
1.0
0.0
2.0
Node
-­‐
Node
+
HR
-­‐
HR
+
Tumor
size
<
2cm
Tumor size ≥ 2cm
AC-­‐TH
vs
AC-­‐T
1.0
0.0
2.0
Node
-­‐
Node
+
HR
-­‐
HR
+
Tumor
size
<
2cm
Tumor size ≥ 2cm
TCH
vs
AC-­‐T
Avantage
TCH
Avantage
AC-­‐T
BCIRG
006
:
Subgroup
analysis
(OS)
Slamon
et
al.
SABCS
2006

29. A
french
retrospec@ve
pragma@cal
study
!
o Mul@centric
study
o 96
T1a-­‐b,
N0
invasive
breast
cancers
o Micro
invasion
and
mul@focal
tumor
are
excluded
o Median
size:
8
mm
(2
–
10
mm)
o 25
(20
%)
≤
5
mm
o Adjuvant
treatment:
for
«
poor
prognosis
»
(high
grade
and/or
HR-­‐)
o 40
pa@ents
were
treated
o 90
%
(37/40)
of
pa@ents
received
chemotherapy
+
trastuzumab
o 7
%
(3/40)
of
pa@ents
received
trastuzumab
alone.
Rodriguez et al. – ASCO 2009

30. Rodriguez
et
al.
ASCO
2009
40 « poor prognosis » 56 « good prognosis »
No recurrence 9 % of recurrence
Trastuzumab
§ Recurrences only in the "Good prognosis" group: 9% vs 0%
§ Recurrences could probably be avoided, perhaps, by an effective treatment in
the "Good prognosis" group.
…
pragma@cal
results

31. Systemic
Adjuvant
Treatment
Of
T1a
and
T1b
N0M0
HER2+
Breast
Carcinomas;
an
AERIO/UNICANCER
Study
Julien Péron1, Jean Sebastien Frenel2, Yann Vano3, Johanna Wasserman4,5,
Laurence Albiges-Sauvin4,6, Manuel Rodrigues4,7, Anne Vincent-Salomon7, Paul
Cottu7 1Centre Léon Bérard , Lyon, France ; 2Centre René Gauducheau ,
Nantes, France ; 3Centre Antoine Lacassagne, Nice, France ;
4Association pour l’Enseignement et la Recherche des Internes en Oncologie ;
5Centre René Huguenin, Saint Cloud, France ; 6Institut Gustave Roussy, Villejuif,
France ; 7Institut Curie, Paris, France
• Trastuzumab/CT
treatment
led
to
a
lower
risk
of
recurrence
(p=0.004)
• Among
51
T1a
tumors,
16
pa@ents
received
TZM/CT.
One
recurrence
occurred
among
treated
pa@ents
and
3
among
untreated
pa@ents.

32. Californian
registry
on
cause-­‐specific
mortality
Pa@ents
with
breast
cancer
N0,
T1a
or
T1b,
HER2
+
Chew et al. J Clin Oncol 2010,28(suppl):abstract 583
All cases
n = 20 188
2000 – 2004
n = 9 409
2005 – 2007
n = 10 779
HER2
Positive
Negative
n (%)
3 196 (15.8)
16 992 (84.2)
n (%)
1 579 (16.8)
7 830 (83.2)
n (%)
1 617 (15)
9 162 (85)

33. Hormone
receptors
Weigh@ng
factor
in
the
management
?
Then
what
about
the
size
(T1a)
?

34. Her
+
/
HR
+,
good
prognosis
?
• T1abc
pN0
N
=
2
026
-­‐
T1a-­‐b
=
328
and
T1c
HR
1.71
(p
=
0.01)
DFS
-­‐
67
%
=
adjuvant
chemotherapy
HR
2.03
(p
=
0.003)
OS
-­‐
Median
Follow-­‐up:
12.4
years
Chia
S.
et
al.
J
Clin
Oncol
2008;26:5697-­‐5704
All patients
Time (year)
DFS
No adjuvant treatment
Time (year)
T1/RH
Time (year)
DFS
Surviesansrécidive
(probabilité)

35. No
reason
to
consider
a
difference
between
T1a
and
T1b,
why
?
• Because
the
size
is
a
con@nuous
variable
• Because
the
size
is
partly
a
subjec@ve
variable
• Because
the
limits
of
5
mm
or
10
mm
were
arbitrarily
set
• Finally,
because
there
are
few
data
in
bibliography…

36. Rakkhit R. et al. SABCS 2008
T1ab HER2 + DFS
1A : DFS / HER + or -
1B : DFS
HR : HR + et HER -
Triple negative
HER2 : HER2+

37. Mul@variate
analysis
Gonzalez-Angulo AM. et al – J Clin Oncol 2009
Survie sans récidive Survie sans récidive à distance
HR 95 % IC p HR 95 % IC p
HER2 positif vs négatif 2.68 (1.44 – 5) 0.002 5.30 (2.23 – 12.62) 0.0002
RH positif vs négatif 0.41 (0.23 – 0.72) 0.002 0.59 (0.25 – 1.37) 0.219
Âge et diagnostic 0.96 (0.94 – 0.98) 0.001 0.73 (0.32 – 1.7) 0.467
Grade 3 vs grade 1-2 1.34 (0.78 – 2.41) 0.320 0.97 (0.94 – 1) 0.080
Stade Ib versus Ia 1.59 (0.91 – 2.78) 0.103 1.47 (0.68 – 3.18) 0.329

38. Benefit
of
chemotherapy
/
Risk
?

39. Cardiotoxicity
Median follow-up
Patients number
12-39 mois
> 4000
2 ans
1056
39 mois
116
1 an
1677
2 ans
718
2 ans
1068
2 ans
579
3 ans
216
Treatment No
Trastu
Docetaxel
Carbopla@n
+
Trastu
9
weeks
an@-­‐micro
tubules
+
trastu
follow
by
FEC
x
3
Anthra then Trastu AC x 4 , then Trastu +
Taxane
ICC
NYHA
Grade 3 - 4
Control
arm
BCIRG
006
FinHER
HERA
N-­‐9831
BCIRG
006
N-­‐9831
B31
3.5
4.1
2.5
1.6
0.6
0
0.4
0-­‐0.8
0
1
2
3
4

40. 256
paAents
StraAficaAon
N+/N-­‐
LVEF
>
50%
Good
safety
profil,
no
grade
3/4
toxicity,
except
grade
IV
neutropeny
But
stop
treatment
for
9
paAents
due
to
FEV
decrease
HercepAn
12
months
6
mg/kg
/3
w
/
3
w.
4
cycles
J1
J8
J15
75mg/m2
600mg/m2
HercepAn
C
T
Cycle
1,
J1
➔
4
mg/kg
90
min,
then
2
mg/kg/w
C
T
C
T
C
T
Jones
SE
et
al.
SABCS
2008,
poster
2111
Phase II – docétaxel cyclophosphamide
trastuzumab

41. Summary
(1)
The
risk
of
recurrence
of
breast
cancer
HER2
+
for
small
tumors
without
lymph
node
involvement
is
• 9-­‐23
%
at
5
years
• about
2.5
@mes
greater
than
in
disease-­‐HER2
nega@ve

42. Summary
(2)
• Her
2
predictor
of
efficacy
of
trastuzumab?
The
answer
is
YES
• Receptor
status
and
size,
weigh@ng
factor
of
decision?
Probably
NO
• It
should
probably
take
into
account
the
risk-­‐benefit
ra@o
and
associated
comorbidi@es
in
choosing
treatment,
but
that
does
not
prohibit
an@
Her
2
treatment
(and
chemotherapy)
for
small
tumors.

43. TN
tumour

44. Preamble
(valid
for
the
remainder
of
the
slides
in
forward
and
reverse)
No
prospec@ve
randomized
clinical
study
reports
the
benefit
of
adjuvant
chemotherapy
for
tumor
size
≤
10
mm
and
pN0
and
whatever
immunohistochemical
subtype
considered

45. About
TN
• All
tumors
"triple
nega@ve"
does
not
correspond
to
the
"basal-­‐like"
phenotype
defined
by
the
classifica@on
of
Peru
and
Sorlie
• «
Basal
Like
»
• SBR
=
high,
low
differen@a@on
• High
KI
67
• CK
5-­‐6
+
and
CK-­‐17+,
EGFR
+,
BRCA1
+
/
-­‐
• "Basal-­‐like"
between
58
and
67
years
=
7%
of
breast
tumors
(1)
1.
Sihto
H,
2008,
Clin
Cancer
Res

46. Associations of different TNBC subtypes.
Turner N C , and Reis-Filho J S Clin Cancer Res
2013;19:6380-6388

47. Basal-like 1: cell cycle,
DNA repair and
proliferation genes
Basal-like 2: Growth factor
signaling (EGFR, MET, Wnt,
IGF1R)
IM: immune cell
processes (medullary
breast cancer)
M: Cell motility and
differentiation, EMT
processes
MSL: similar to M but
growth factor signaling, low
levels of proliferation genes
(metaplastic cancers)
LAR: Androgen receptor
and downstream genes,
luminal featuresLehmann et al JCI 2011

48. Summary
of
retrospec@ve
series
T1ab
with
more
than
10%
of
TN
Author
Year
Number of patients Follow-up Summary of data Multivariate analysis
Kaplan
2009
110 4,2 year 89 % TN
X
6.6
risk
of
recurrence
vs
RH+
HER2-­‐
ayer
adjustemnt
on
size,
age
et
adjuvant
chemotherapy
(Y
or
N)
Curigliano
2009
95 60 months 5 events, 0 M+ Her 2+
Kwon
2012
56 pt1ab 61 months DFS-­‐5
years
92.5%
Only
one
metasta@c
recurrence
for
a
TN
Age
<35
and
TN
are
the
only
two
parameters
impacting
DFS
(HR=
4.91
et
4.96)
no
Her
2
Park (issue de Kwon)
2011
Only 33 TN 61 months OS-5 years= 90 %
Ho
2012
Only 194 TN, with
Tmic
113
adjuvant
chemotherapy
Often
CMF
73 months DFS-­‐5
years
=
95%
11
metasta@c
recurrence

49. Come-­‐back
to
consensus
Size T1a T1b
Her 2+ RH - Her 2+ RH
+
Luminal A Luminal B TN Her 2+
RH -
Her 2+
RH +
Luminal
A
Luminal
B
TN
NCCN 2014 No tt * HT* HT * HT * No tt * TZ + CT HT
TZ+CT
HT
CT
according to
Oncotype
Dx
HT
CT
according to
Oncotype
Dx
CT
Saint Gallen
2011
No tt HT HT HT CT TZ + CT HT
TZ + CT
HT
CT
according to
Oncotype
Dx and
UPA/P1
HT
CT
according to
Oncotype
Dx and
UPA/P1
CT
French
Consensus
Penault
Llorca
2011
TZ + CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
No tt TZ +CT HT
TZ + CT
according to
age, KI67,
MI,grade
embols
CT
INCA 2012 No answer No answer No answer No answer

50. In
summary
(1)
• Global
trend
to
provide
chemotherapy
for
small
TN
but
s@ll
no
consensus
for
T1a
• Given
the
narrowness
of
the
benefit
of
chemotherapy
for
T1ab,
it
should
take
the
following
precau@ons
• Consider
any
TN
pT1ab
low
grade
as
suspect
of
not
being
a
"basal-­‐
like
»
• Do
not
hesitate
to
ask
a
second
look
on
histology
• Repeat
IHC
HER2
and
HR
• Repeat
evalua@on
of
SBR
and
growth
factors
• Remove
histological
subtype
from
TN
known
as
good
prognosis
:
adenoid
cys@c
carcinoma,
androgene
receptor
+,
apocrine

51. In
summary
(2)
• Rela@ve
benefit
of
chemotherapy
with
taxanes
and
anthracyclines,
whatever
the
size
and
histologic
subtype,
is
about
30%
according
to
the
Oxford
meta-­‐analysis
updated
in
2012
• However,
absolute
benefit
is
depend
on
the
risk
of
relapse,
and
the
risk-­‐benefit
• It
seems
reasonable
to
give
chemotherapy
only
for
following
profiles
• pT1B
• No
major
comorbidi@es
• Grade
3,
high
prolifera@on
index
• Regimen
of
chemotherapy
will
be
dictated
according
to
the
bibliography
(3
FEC
100-­‐3
Doce
etc…)
or
according
to
personal
convic@on
(4
TC,
pla@num
compounds)

52. Luminal
subtype

53. Retrospec@ve
data
from
NSABP
2001
J
Natl
Cancer
Inst
1024
pa@ents
pT1ab
HR
+
Tam
vs
CT-­‐TAM
<
50
y,
HR
-­‐
HzR
=
0,61
Benefit : 13%
0,39 x 38.8
DFS-­‐8
years
=
trend
for
CT-­‐TAM
vs
TAM
alone
Impac@ng
parameters
in
mul@variate
analysis
Age
(cut-­‐off
=
50
years)
Size
(1
cm
vs
<
1
cm)
<
50
y,
N-­‐,
HR
+
HzR
=
0,64
Benefit : 10%
0,36 x 27.4
Oxford
meta-­‐analysis
2011

54. Prognosis
approach
does
not
allow
a
predic@ve
vision
• But,
«
honestly
»,
chemotherapy
may
respond
to
laws
of
predictability,
according
to
mechanisms
of
ac@on
?
In
absence
of
randomized
prospec@ve
study
answering
to
our
ques@on,
is
there
a
path
to
solve
the
problem..

55. L’approche
de
la
sta@s@que
modélisée
Adjuvant
Online
• Un site web qui permet d’évaluer le pronostic individuel
• SG et SSR à 10 ans
• Utilise le suivi des patientes traitées entre 1988 et 1992 et enregistrées sur
le « Surveillance Epidemiology and End-Results Registry » (SEER).
• 10% des patientes USA traitées sur cette période
• Patientes de 36 à 59 ans avec enregistrement de la taille et du grade tumoral, du
statut hormonal et de l’atteinte ganglionnaire axillaire.
• Evaluation statistique du bénéfice individuel des traitements
médicamenteux adjuvants
• Utilisation du bénéfice constaté de l’HT et de la CT adjuvante par la Méta-
analyse de l‘Early Breast Cancer Trialists’ Collaborative Group
• TAM, CMF, AC, TT séquentiel avec Taxanes
• Utilisation du bénéfice constaté des traitements adjuvants modernes dans
les études adjuvantes randomisées récentes

56. AOL
:
unperfectly
approach
• No suitable for particular histology
• Tubular, papillar, mucinous, medullary
• No suitable for lobular
• No suitable for T1ab N-
• Under-estimation for efficacy of hormonotherapy
• AOL!
Ignores
the
prognosis
value
of:
• Ki67,
Mito@c
Index
• HER2
• PR
and
Quan@ta@ve
expression
of
ER

57. Je
vous
propose
une
simula@on
d’AOL
!
• On
par@ra
du
concept
de
Saint
Paul
:
un
gain
addi@onnel
de
5
%
pour
la
récidive
à
10
ans
en
plus
de
l’hormonothérapie
• On
fera
varier
les
paramètres
d'âge
et
de
grade
histologique,
par
tranche
d’âge
de
5
ans
• On
fera
3
simula@ons
différentes
basées
sur
l’état
général
• On
re@endra
comme
conven@on
• Chimiothérapie
:
3
FEC
100
–
3
TXT
• Hormonothérapie
:
TAM
jusqu’à
45
ans,
traitement
séquen@el
à
50
ans,
traitement
par
IA
exclusif
au
delà

58. Addi@onal
benefit
of
chemotherapy
over
10
years
in
risk
of
recurrence
in
addi@on
to
hormone
therapy,
according
to
age
and
histologic
grade
for
a
T1ab
tumor
with
Adjuvant
OnLine!
Age 30 y.
TAM
35 y.
TAM
40 y.
TAM
45 y.
TAM
50 y.
TAM-IA
55 y.
IA
60 y.
IA
65 y.
IA
70 y.
IA
Grade 1 7,7 5,2 5,3 5,3 3,4 3,3 2,7 2,8 2,5
Grade 2 9,1 6,3 6,3 6,3 4 4 3,3 3,3 3,1
Grade 3 10,6 7,3 7,4 7,4 4,7 4,7 3,8 3,9 3,6
Good
health,
IK
100
%
Age 30 y.
TAM
35 y.
TAM
40 y.
TAM
45 y.
TAM
50 y.
TAM-IA
55 y.
IA
60 y.
IA
65 y.
IA
70 y.
IA
Grade 1 7,7 5,3 5,2 5,1 3,2 2,7 2,7 2,5 2,2
Grade 2 9,1 6,2 6,2 6,1 3,8 3,1 3,1 3 3,7
Grade 3 10,6 7,3 7,4 7,3 4,6 4,6 3,7 3,5 3,2
Evolu@onnary
Health
state,
depending
on
the
age
Age 30 y.
TAM
35 y.
TAM
40 y.
TAM
45 y.
TAM
50 y.
TAM-IA
55 y.
IA
60 y.
IA
65 y.
IA
70 y.
IA
Grade 1 7,5 4,9 4,9 4,5 2,2 2,3 1,4 0,7 0,4
Grade 2 8,9 6 5,7 5,5 3,1 2,8 1,7 1 0,4
Grade 3 10,3 7 6,6 6,4 3,7 3,2 1,9 1 0,4
Poor
general
condi@on,
2
significant
comorbidi@es

59. Other
approaches,
other
perspec@ves…
• More
personalized
sta@s@cal
approach:
"No€ngham
Prognos@c
Index"
taking
into
account
the
expression
of
HR
and
Her2
Oncotype
Dx
• Hormone
therapy
signatures
• UPA/P1

60. Oncotype DX®
16 cancer genes and 5 referent genes from three study
60
Paik et al. N Engl J Med. 2004;351:2817-2826.
Catégorie SR (0-100)
Low risk RS < 18
Intermediate risk 18 < RS < 31
High risk RS ≥ 31
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
OESTROGENES
ER
PR
Bcl2
SCUBE2
INVASION
Stromelysine 3
Cathepsine L2
HER2
GRB7
HER2
REFERENCE
Beta-actine
GAPDH
RPLPO
GUS
TFRC
GSTM1 BAG1
CD68
RS =
+ 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1

61. Oncotype DX® Validation Clinique:
RS used as a continuous prognostic factor
• The recurrence score predicts the likelihood of beneficial
effects of chemotherapy and the risk of recurrence at 10
years
61
Paik et al. N Engl J Med. 2004;351:2817-2826.
My SR is 30. What is the risk of
recurrence in 10 years?

62. NSABP B-20: Many Small Tumors Have
Intermediate to High Recurrence Score® Disease
Paik S, et al. J Clin Oncol. 2006;24:3726-3734.
33%
20% 19% 23% 21%
46%
N = 110 N = 318 N = 196 N = 24
RecurrenceScore
≤1 cm 1.1-2 cm 2.1-4 cm >4 cm
Clinical tumor size
0
20
40
60
80
100
P=0.001
64% 56% 46%
16% 25% 30%

63. WSG-­‐Plan
B
study
(n=2551
)
Gluz
O,
et
al.
SABCS
2011
63
Risque
intermédiaire
risk (18-30)
Risque élevé
(≥31)
Risque faible
(<18)
Ki-67 <14 Ki-67 ≥14 Central grade
3%
36%
61%
19%
43%
38%
37%
63%
5%
39%
56%
30%
39%
31%
uPA/PAI-1
1 2 3 low high