This document discusses late breast cancer metastases. It defines late metastases as those occurring more than 5 years after initial treatment. The document notes that according to some studies, 10-15% of breast cancer patients experience late recurrence, and this risk is higher in node-positive patients who did not receive chemotherapy. The document also suggests histological type and intrinsic molecular subtype may influence late recurrence risk. Specifically, triple negative breast cancer and HER2-positive breast cancer may have higher risks without chemotherapy and HER2-targeted treatment, respectively. The document concludes that predicting late metastasis could help improve outcomes by identifying patients still sensitive to endocrine therapy and finding new targets to prevent late recurrence.

1. Can we predict it ?
Late metastasis
Joseph
Gligorov
MD,
PhD
ESO
Advanced
Breast
Cancer
Task
Force
APHP-­‐HUEP-­‐Tenon,
Paris
InsDtut
Universitaire
de
Cancérologie
Université
Pierre
&
Marie
Curie,
Sorbonne
Universités

2. Conflict
of
interest
• Amgen®
• Genomic
Health®
• Eisai®
• Roche-­‐Genentech®
• Nanostring
®
• Novar;s
®
Clinical
trials
support,
advisory
boards,
speaker

3. DEFINITIONS
AND
IMPORTANCE

4. Defini;ons
&
importance
• Late:
• Metastasis:
.
micro
mets
?
.
macro
mets
?
.
the
way
we
detect
the
mets
?
• Importance:
.
Is
it
frequent
?
.
Is
it
life
threatening
?
.
Is
breast
cancer
mortality
s;ll
important
as
a
main
risk
of
early
death
aNer
a
long
period
of
follow-­‐up
?
0
2
5
10
15
years
?

5. Defini;ons
&
importance
• Late:
• Metastasis:
.
micro
mets
?
.
macro
mets
?
.
Clinical
events
.
Local
or
distant
mets
?
• Importance:
.
Let’s
see
the
datass
it
frequent
?
.
Is
it
life
threatening
?
.
Is
breast
cancer
mortality
s;ll
important
as
a
main
risk
of
early
death
aNer
a
long
period
of
follow-­‐up
?
0
2
5
10
15
years

6. FREQUENCY
OF
LATE
METASTATIS

8. Influence
of
chemo
and
pN
status

9. Influence
on
mortality

10. Conclusion
1
• According
to
EBCTCG
publica;on
– Overall
breast
cancer
popula;on
treated
in
adjuvant
seXng
with
tamoxifen
present
an
absolute
risk
of
late
recurrence
aNer
5
years
between
10-­‐15%
– This
risk
is
higher
in
pN+
popula;on
who
do
not
receive
chemotherapy
(#
20%)
compared
to
pN0
with
or
without
chemotherapy
(7
to
8%)
• The
influence
of
adjuvant
tamoxifen
– is
s;ll
clear
between
5
to
10
years
in
ER
&
PR
posi;ve
disease
– Is
less
clear
aNer
5
years
in
PR
&/or
ER
poor
disease
• Risk
of
late
recurrence
clearly
impact
mortalit

11. MORE
RECENT
DATA

12. Influence
of
histological
type
Pestalozzi et al., J Clin Oncol 26:3006-3014.2008

13. Prat A, Perou CM. Molecular Oncology 2011
Clinical-­‐pathological
characterisDcs
of
the
current
intrinsic
subtypes
of
breast
cancer

14. Informa;ons
from
neoadjuvant
data
Luminal
A
Luminal
B/HER2-­‐
Luminal
B/HER2+++
HER2+++
non
luminal
Triple
nega;ve
?

15. Rates
of
distant
recurrences
and
breast-­‐specific
survival
in
TNBC
and
other
breast
cancers.
RFS OS
Dent R et al. Clin Canc Res 2007

17. HR+
HR-­‐

18. Time
to
distant
recurrence
Smoothed
hazard
rate
curves
for
risk
of
recurrence

19. Clearly
in:
-­‐pN+
populaDon,
-­‐
premenopausal
women
at
Dme
of
tamoxifen
ITT
:
intent-­‐to-­‐treat
COX
:
cox
regression
model
IPCW
:
inverse
probability
of
censoring
weighted
SCC
:
Shao,
Chang,
Chow
model

21. Conclusion
2
• Histological
type
might
influence
the
risk
of
late
relapse
• Intrinsic
subtypes
might
also
influence
the
risk
of
late
relapse
and
par;cularly
according
to
the
efficacy
of
systemic
treatments
– Chemotherapy
for
TNBC
– an;HER2
treatments
for
HER2
posi;ve
BC
• the
main
popula;on
for
which
the
iden;fica;on
of
a
late
risk
of
relapse
remains
the
most
important
is
the
HR
posi;ve
popula;on
• We
have
possible
treatment
op;ons
to
propose
to
the
pa;ents

22. CAN
WE
PREDICT
LATE
METASTASIS
?

23. New
considera;ons
• Target
popula;on
is
HR
posi;ve
popula;on
• Predic;ng
late
metastasis:
2
informa;ons
– Prognos;c:
improving
OS
– Predic;on:
• defining
popula;on
s;ll
sensi;ve
to
endocrine
treatment
• Trying
to
find
new
targets
to
prevent
late
relapse

24. ROR
score
was
calculated
using
the
test
variables
that
include:
• Pearson
correlaDons
with
prototypical
gene
expression
profiles
for
the
four
intrinsic
Subtypes
• ProliferaDon
score
• Pathologic
tumor
size
OP
pN0
pN+

25. transATAC
study:
PAM50
vs
Oncotype
Dx
vs
IHC4
(RE,
RP,
HER2,Ki67)

26. Clinical
variables
Sestak
I
et
al,
JNCI
2013

27. Trans ATAC & ABCSG-8
Distant recurrence – post 5 years
San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013
Courtesy of Sestak I et al.
ChangeinLRχ2Statistic
94.1
67.9
0
10
20
30
40
50
60
70
80
90
100
CTS ROR
Univariate Multivariate
HR (95% CI) for IQR
Univariate
CTS
Nodal status, grade, tumour size, age, treatment
1.96 (1.73-2.21)
ROR score (PAM 50) 2.69 (2.12-3.43)
61.4
35.3
Multivariate*
1.80 (1.57-2.06)
2.07 (1.63-2.64)
*When added to other score
10
20
30
40
50
60
70
80
90
100
0

28. Luminal A vs Luminal B
according to PAM50
San Antonio Breast Cancer – Cancer Therapy and Research Center at UT Health Science Center – December 10-14, 2013
HR (95% CI) P-value
Luminal A (N=1530 (71.6%)) - -
Luminal B (N=542 (25.4%)) 2.89 (2.07- 4.02) <0.0001
051015
5 6 7 8 9 10
Follow-up time [years]
Luminal B
Luminal A
Distantrecurrence(%)
4.1%
12.9%
051015
Courtesy of Sestak I et al.

29. E-module in Oncotype Dx is
predictive of late reccurence
Among women with tumours
most sensitive to oestrogen,
with a high E-module score,
the recurrence rate more
than doubled from 5.7% in
the first five years to 13.6%
in the subsequent five years.
However, if they had a low
E-module score, there was
little difference in recurrence
rates between the first five
years and the next five
years: 10.3% versus 12.3%.”
Dowsett M et al. EBCC 2014

30. Breast
Cancer
Index:
• Molecular
Grade
Index
• HOXB13/IL17BR

31. The
predic;ve
value
of
the
marker
seems
depedent
of
the
previous
treatment
exposure
…
Sgroi
et
al.
Lancet
Oncol
2013

32. Endopredict
clinicalscore
was
calculated
using:
• ProliferaDon
associated
genes
• HR
associated
genes
• Clinical
parameters
(tumour
size
&
nodal
status)

33. Dubsky
P
et
al.
BJC
2013
ER
pathway
seems
to
be
the
“driver”…

35. Mikempergher
L
et
al.
Mol
Oncology
2013

36. Conclusion
3
• Clinical
parameters
s;ll
remains
crucial
for
evalua;ng
the
risk
of
late
relapse
(pN,
pT)
• ER
pathway
ac;va;on
seems
to
be
crucial
also
and
maight
help
to
“predict”
the
benefit
of
prolonged
endocrine
treatment
in
popula;ons
at
risk
of
late
relapse
• New
approaches
and
signatures
might
help
us
to
find
new
tools
in
pa;ent
at
risk
of
late
relapse
and
not
candidate
for
prolonged
endocrine
treatment

37. THANKS