1. Individual
prognosis
and
predic1ve
biomarkers.
Pr
Frédérique
PENAULT
LLORCA,
France

2. Prognosis

3. T
N
M
Classical
prognosis
and
predic2ve
factors
• Age
• Grade
• Histological
subtypes
• ER/PR
and
HER2
status
• Ki67
+/-­‐
mito2c
index
• Vascular
invasion
• Tumor
margins
Oldies
but
goldies

4. Grade I
Grade II
Grade III8,9
SBR
grade
modified
by
Elston
and
Ellis
• Standardiza2on
of
tumor
grading
• France
2011:
Gr
I
25%,
Gr
II
50%,
Gr
III
25%
• Lack
of
reproducibility

5. Group 3 - Average prognosis
Medullary, classical lobular,
lobular mixed
Group
1
-­‐
Excellent
prognosis:
Tubular,
invasive
cribriform,
mucinous
Group
2
-­‐
Good
prognosis
Tubular
mixed,
mixed
ductal
NST
and
special
type
like
adenoid
cys1c,
secretory
Group 4 - Poor prognosis
Ductal NST, solid lobular, mixed
ductal NST and lobular,
micropapillary
18
Histological
types
:
morphology
maOers!

6. 18
Histological
types
in
breast
cancer
and
only
4
molecular
groups!

7. RE neg RE pos
C Perou & T Sorlie
Towards
a
simplified
taxonomy
of
breast
cancer?
«
defini2on
of
intrinsic
subtypes
has
proven
efficient
in
defining
prognosis
for
breast
cancer
pa2ents
»

8. Intrinsic
classifica2on
easily
translated
by
IHC
HER2
+
Basal
Triple
nega1ve
ER&PgR
-­‐,
HER
2
-­‐
ER /PgR+
HER2 -,
Ki 67 <
ER /PgR +
HER2 -,
Ki 67 >
Luminal
A
Luminal
B
15 %
15 %
60 %
CK 8, 18, 19
CK 5/6, 14, 17
EGFR, P53, ckit
Pcad
Normal
like
EE 2-3
EE 3
EE 1-2-3
HER2+
ER/
PgR+
Claudin
Low

9. Predic1on

10. Surrogate
defini2on
of
intrinsic
subtypes
of
breast
cancer
«basal-­‐like»
• ER
and
PgR
absent
• HER2
nega2ve
• Approximately
80%
overlap
between
«
triple
nega2ve
»
and
intrinsic
«
basal-­‐like
»
• But
«
triple
nega2ve
»
also
include
good
prognosis
special
types
such
as
medullary
and
adenoid
cys2c
carcinoma
• Staining
for
basal
kera2n
is
considered
insufficiently
reproducible
for
general
use

11. T
N
M
Classical
prognosis
and
predic2ve
factors
• Age
• Grade
• Histological
subtypes
• ER/PR
and
HER2
status
• Ki67
+/-­‐
mito2c
index
• Vascular
invasion
• Tumor
margins
Oldies
but
goldies

12. HER2
Nega1ve
predic1ve
value
(<5% chance to respond to
anti-estrogens or trastuzumab)
HIGH
95%
Posi1ve
predic1ve
value
30-­‐50%
Breast
Cancer
ER/PGR
What
is
the
level
of
predic2on
accuracy
clinically
useful?

13. Ki67
why?
• Defini2on
of
luminal
A
and
B
• Decision
of
CT
for
ER+,
Grade
II
tumors

14. • At
present,
the
enormous
varia2on
in
analy2cal
prac2ce
markedly
limits
the
value
of
Ki67
• An
interna2onal
panel
of
inves2gators
with
substan2al
exper2se
in
the
assessment
of
Ki67
and
in
the
development
of
biomarker
guidelines
was
convened
to
consider
evidence
for
poten2al
applica2ons.

19. MOLECULAR
SIGNATURES

20. T
N
M
Yes
,
we
have
molecular
biology
!
• Age
• Grade
• Histological
subtypes
• ER/PR
and
HER2
status
• Vascular
invasion
• Tumor
margins

21. Centralized tests

22. MammaPrint
(Agendia, NL)
HR+ ET HR - / HER2- , T < 5cm, N ≤ 3
Fresh frozen=> FFPE
DNA array
70 GENES
CELL CYCLE/ PROLIFERATION
SIGNAL TRANSDUCTION
INVASION, METASTASIS, ANGIOGENESIS
« CENTRALIZED » TEST
RECENTLY ADAPTATED TO FFPE
Group of genes (« signatures »)
EARLY RECURRENCE (Dg < 5 ans)
PROGNOSTIC
GOOD SIGNATURE :
LOW RISK
POOR SIGNATURE :
HIGH RISK
HR
+&
HR-­‐

23. MammaPrint – RESULTATS
UNE BONNE SEPARATION GLOBALE A BAS/HAUT RISQUE
MAIS SANS CAPACITE DE RECONNAÎTRE
LES TUMEURS DE TRES BON OU DE TRES MAUVAIS PRONOSTIC
attendre les résultats de l’étude MindAct
(MicroArray in Node-Negative Disease May Avoid ChemoTherapy)

25. 80
genes
56
GENES
70
GENES
Where
are
the
proofs
Formalin
fixed,
paraffin
included
samples
Redundant
genes?
Valida2on
of
blue,
target
et
theraprint?
?

26. OncotypeDX
(Genomic Health, USA)
HR+ / HER2- , T1-3, N-/N+
FFPE specimens
qRT-PCR
21 GENES
PROLIFERATION, OESTROGENE,
HER2, INVASION (16 GENES) + REFS (5 GENES)
« CENTRALIZED » TEST
(recurrence score) RS
Late recurrence (10 years)
Benefit from adjuvant TT
PROGNOSTIC AND PREDICTIVE
LOW RISK :
+ HORMONOTHERAPY / - CHEMOTHERAPY
INTERMEDIATE RISK :
DISCUSSION
LOW RISK :
+ HORMONOTHERAPY / + CHEMOTHERAPY

27. Decentralized tests

28. EndoPredict
(Sividon, GE)
HR+ / HER2- , T1-2, N0
FFPE
qRT-PCR
7 GENES SIGNATURE
PROLIFERATION, OESTROGENES
« LOCAL » TEST
(SPECIAL EQUIPMENT IS REQUIRED)
SCORE OF RECURRENCE EP SCORE
LATE AND EARLY RECURRENCES
(5 & 10 YEARS)
PROGNOSIS
LOW RISK
HIGH RISK
UBE2C
BIRC5
DHCR7
STC2
AZGP1
IL65T
RBBP8
MGP

29. Prosigna (PAM50)
(NanoString Technology, USA )
IDENTIFICATION OF « MOLECULAR3 SUBTYPES »
(LumA, LumB, HER2-enrichi, Basal)
FFPE
DNA ARRAY WITH BARCODES
(1 gene = 1 barcode)
50 GENES
« LOCAL » TEST
(SPECIAL EQUIPMENT IS REQUIRED)
LATE AND EARLY RECURRENCES
(5 & 10 YEARS)
PROGNOSIS
LOW RISK (ROR)
Intermediate risk
HIGH RISK (ROR)

30. Conclusion
• Accurate
pathology
tes2ng
is
essen2al
for
individual
pa2ent
selec2on
and
treatment
design
(subtypes
/
IHC
based
intrinsic
classifica2on/grading)
• Tissue
prepara2on
is
the
KEY
for
accurate
biomarkers
evalua2on
• Gene
signatures
may
provide
increased
confidence
for
treatment
decision
– Oncotype
Dx®
is
recommended
by
St
Gallen’s
Panel
of
experts
(also
by
ASCO,
NCCN)
– The
other
signatures
are
either
recommended
to
a
lesser
extend
or
very
promizing
• However,
even
using
gene
signatures,
there
will
be
cases
for
which
treatment
decision
will
not
be
straighjorward

31. Conclusion
• For
the
2me
being
pathology
cannot
be
safely
replaced
by
molecular
assays
• Advantages
of
combining
two
approaches
should
be
discussed
– The
target
popula2on
will
be
the
ER+,
HER2-­‐,
N-­‐
(Luminal
Breast
Cancer)
and
not
grade
3
• Predic2ve
tests
are
awaited!

33. Source:
Weigelt,
Reis-­‐Filho
&
Swanton,
Ann.
Oncol.
2012;Suppl
10:x211
?
?