L’HER2-positività: dall’anatamopatologia alla clinica
Cosa altro è importante sapere oltre
l’HER2 status: recettori ormonali, profili di
espressione genica…
Stefania Gori
Oncologia Medica- Perugia
Prognosis of metastatic breast cancer by HER2 status and
trastuzumab treatment
HER2+
25%
13%
HER2+ MBC: worse survival
Dawood S, JCO 2010
1st line therapy of MBC: anti-HER2 agent + CT
RESULTS from randomized trials
Slamon DJ
NEJM 2001
Phase III
Marty M
JCO 2005
Phase IIR
Di Leo A
JCO 2007
(subgroup of pts)
Zhong-Zhen G
SABCS 2010
Phase III
N pts/
arm
Treatment
ORR
DOR
TTP
OS
92
w trastuzumab +
paclitaxel 175
38%*
10.5 mo*
6.9 mo*
22.1 mo*
96
w paclitaxel
16%
4.5 mo
3.0 mo
18.4 mo
92
w trastuzumab+
docetaxel 100
61%*
11.7 mo
11.7 mo*
31.2 mo*
94
docetaxel
34%
5.7 mo
6.1 mo
22.7 mo
49
lapatinib 1500+
paclitaxel 175
63%*
8.0 mo
8.1 mo *
24.0 mo
37
paclitaxel
38%
6.O mo
5.1 mo
19.1 mo
222
lapatinib 1500+
w paclitaxel 80 (3/4)
69%*
9.3 mo
9.7 mo*
(PFS)
27.8 mo*
222
w paclitaxel
50%
5.8 mo
6.5 mo
20.5 mo
* Statistically significant difference versus CT arm
Time from diagnosis (months)
Multivariate model
HER2+ and trastuzumab
HR of death
vs
HER2-negative
0.56; 95% CI 0.45-0.69; p< .0001
Multivariate model
HER2+ and trastuzumab
HR of death
vs
HER2+ no trastuzumab
045; 95% CI 0.33-0.63; p< .0001
Dawood S, JCO 2010
HER2-positive breast cancer
HR status
HER2HER2+
HER2HER2+
HER2+
HER2+
*
*
Time from diagnosis-months
HR-negative
Time from diagnosis-months
HR-positive
Overall survival by Trastuzumab treatment group and according to hormone
receptor status
5y-OS
HER2+
HR8.9 mo
HR- and trastuzumab 17.7 mo
5y-OS
HER2+
HR+
14.5 mo
HR+ and Trastuzumab 29.7 mo
Even in presence of trastuzumab, HR status
is still a prognostic factor in MBC
Dawood S, JCO 2010
HER2+ and HR+ MBC:
Anti-HER2 plus hormonal therapy
ORR
PFS
OS
TAnDEM
Kaufman B
103
Anastrozole+Trastuzumab
4.8%*
5.6 mo*
28.5 mo
JCO 2009
104
Anastrozole
2.4%
3.8 mo
23.9 mo
Letrozole+ lapatinib
28%*
8.2 mo*
34.1 mo
Letrozole+ placebo
15%
3.0 mo
28.6 mo
Schwarzberg LS 111
Oncologist 2010
(219 out of
1,286 =17%)
108
1st line therapy in
HR+ and HER2+ MBC
Poor PS
No/limited visceral metastases
Slowly Progression
 Expression of HR
Good PS
Visceral metastases
Rapidly progressing
Trastuzumab+ Anastrozole
Trastuzumab+ Taxane
Lapatinib+ Letrozole
Lapatinib+ Capecitabine
Neoadjuvant CT in unselected for HER2 status BC
Outcome by pCR and HR status
No.
PFS
5-y
10-y
50%
vs
83%
43%
vs
73%
65%
vs
91%
38%
vs
76%
p
OS
5-y
10-y
67%
vs
84%
59%
vs
84%
84%
vs
96%
41%
vs
96%
p
HR-negative
No pCR
423
pCR
132 (24%)
<.0001
.003
HR-positive
No pCR
pCR
1072
91 (8%)
.002
Guarnieri V, JCO 2006
.04
NEOALTTO1
NEOSPHERE2
Phase III
lapatinib
paclitaxel
R
trastuzumab
paclitaxel
Operable
T >2 cm
Phase II
N=450
lapatinib
trastuzumab
paclitaxel
6
wks
docetaxel +
pertuzumab
L
S
U
R
G
E
R
Y
F
E T
C
X
3
+ 12 wks
L+T
R
Operable
or
LABC/IBC
docetaxel +
trastuzumab
trastuzumab +
pertuzumab
docetaxel +
trastuzumab +
pertuzumab
3
N=417
S
U
R
G
E
R
Y
FECx3 T
FECx3 T
D  FEC T
FECx3 T
34 wks
52 wks of anti-HER2
1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010
52 wks of anti-HER2
NEOALTTO:pCR by Hormone
Receptor Status
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response HR: hormone receptors
NeoSphere: pCR and hormone
receptors status
70
pCR, %  95% CI
60
ER or PR pos
ER and PR neg
50
63.2
40
30
20
36.8
10
0
26.0
5.9
20.0
TH
H, trastuzumab; P, pertuzumab; T, docetaxel
THP
30.0
29.1
17.4
HP
TP
7
CHERLOB: Study plan

C
O
R
E

121
pts
II-IIIA
T>2cm
B
I
O
P
S
Y
Paclitaxel 80
R
A
N
D
O
M
I
Z
A
T
I
O
N
mg/m2

A

B

Lapatinib 1500 mg continuous daily dose (CDD)


S
U
R
G
E
R
Y
C
Lapatinib 1000 mg CDD
5 FU 600 mg/m2
Epi 75 mg/m2
CTX 600 mg/m2
Trastuzumab 2 mg/kg
 LVEF
Guarneri V, ASCO 2011 #507
[TITLE]
Guarneri V, ASCO 2011 #507
[TITLE]
HER2- positività:
Stato dei Recettori ormonali
Setting metastatico
• Lo stato dei recettori ormonali identifica
sottogruppi con diversa prognosi,
indipendentemente dal trattamento con
trastuzumab
• Possono essere identicabili , da un punto di vista
clinico, sottogruppi di pts HR+ candidabili a
terapia di 1a linea con ormonoterapia + agente
antiHER2
HER2- positività:
Stato dei Recettori ormonali
Setting neoadiuvante
• Predice il tasso di pCR ottenibile con CT+
agenti anti-HER2
pCR % inferiore nei tumori HR+ vs HR-
HER2-positive breast cancer
Gene- expression
profiling
Luminal A
Luminal A
Luminal B
Luminal B
HER2+
Basal
OS months
HER2+
Basal
RFS months
Survival analysis of the 49 breast cancer patients , uniformly treated in a
prospective study, based on different gene expression classification
Sorlie T, PNAS 2001; 98:10869-10874
Immunohistochemical identification of breast tumour intrinsic subtypes.
Carey L A, JAMA 2006; 295: 2492-2502
Ki-67 labeling index is important in the distinction between
Luminal A and Luminal B-HER2 -negative subtypes
ER and/orPgR
HER2
Ki-67
Cytokeratin
Luminal A
positive
negative
low (<14%)
--
Luminal B
positive
negative
high
--
positive
positive
any
--
HER2-enriched
negative
positive
--
--
Basal-like
absent
negative
--
Cytokeratin 5/6 +
and /or HER1+
Cheang MCU, JNCI 2009; 101:736-50
Cheang MCU, JNCI 2009;101:736-50
Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not
receive CT or trastuzumab
Knauer M, BJC 2010; 103:1788-93
The 70-gene prognosis signature is an
independent prognostic indicator that identifies a
Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not
subgroup
of HER2-positive early BC with a
receive
CT or trastuzumab
Knauer M, BJC 2010; 103:1788-93
favorable long-term outcome
Mechanisms of resistance to
trastuzumab
Prevention of trastuzumab binding to HER2
Inhibition of immune-mediate mechanisms
Upregulation of signaling pathways downstream of HER2
Upregulation of alternative growth factor receptor –
signaling pathways
HER2-positive breast cancer
p95-HER2 status
p95HER2 is expressed in 30% of HER2+ BC
Trastuzumab
p95HER2
…by either
proteolytic
shedding of
ECD1
or by
alternative
initiation of
translation of
the HER2
mRNA2
1. Codoni-Servat J, Cancer Res 1999;59:1196-201 2. Anido J, EMBO J 2006; 25:3234-44
p95HER2 and Response to Trastuzumab
46 patients with MBC
treated with trastuzumab1
1Scaltriti,
M JNCI 2007
p95HER2 and Reponse to Trastuzumab
46 patients with MBC
treated with trastuzumab1
1Scaltriti,
M JNCI 2007
V et al. ASCO 2011 #507
2Guarneri,
29 patients with EBC
treated with neoadj. trastuzumab
(CherLob)2
GeparQuattro:
p95HER2 and Response to Trastuzumab
(N=145 patients treated with EC+T  Doc+T)
P<0.0001
(>20% strongly positive for 611 CTF) (≤20% strongly positive for 611 CTF)
Loibl S et al, ASCO 2011 Abstr #530
pCR rate according to p95HER2 expression:
p95HER2 status does not predict pCR rate following treatment with CT+
trastuzumab or lapatinib or the combination of both
Cut-off at 80%
P= 0.44
60
54%
P= 0.68
50
P= 1
40
33.3%
35.7%
33%
30%
30
25%
20
10
p95 +
n=2/6
p95 –
n=7/23
p95 +
n=3/12
p95 –
n=5/14
p95 +
n=3/9
p95 –
n=13/24
0
Arm A (CT + T)
Arm B (CT +L)
Arm C (CT + T + L)
In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluated
Guarneri V- ASCO 2011 #507
p95HER2 and clinical response to lapatinib (PFS)
Results from 68 and 156 MBC pts
Lapatinib monotherapy-
Lapatinib+ capecitabine-
EGF20009
EGF100151
Scaltriti M, Clin Cancer Res 2010
HER2- positività:
p95 HER2
Setting metastatico
• p95HER2+
resistenza al trastuzumab 1
• Lapatinib efficace sia nei tumori p95HER2+ che
p95HER- 2
Setting neoadiuvante
• Risultati contrastanti 3-4
1. Scaltriti 2007; 2.Scaltriti 2010; 3.Guarneri ASCO 2011; 4.Lobi ASCO 2011
HER2-positive breast cancer
PTEN status
IHC expression of PTEN
(a negative regulator of Akt activities)
EGF, TGF-α
HER2
EGFR
PI(4,5)P2
PI(3,4,5)P3
PI3-K
P
P
P
P
Grb2
SOS
P
RAS-GDP
PTEN
GTP
PDK1,2
PDK1,2
Akt/PKB
RAS-GTP
TKI
RAF
Survival pathway
MEK
ERK
Proliferation pathway
P < 0.001
Nagata Y, Cancer Cell 2004
Background
PTEN Impact on Sensitivity or
Resistance to Trastuzumab
• Preclinical data suggest PTEN loss associated with trastuzumab
resistance
– O’Brien 2010; Stemke-Hale 2008; Saal 2005;
Nagata 2004
• Clinical data available to date: limited and conflicting
– PTEN loss associated with trastuzumab resistance
• Dave 2011; Esteva 2010 ; Razi SE 2011
– PTEN loss NOT associated with trastuzumab resistance
• Fabi 2010; Gori 2009; Yonemori 2009
Perez EA – ASCO 2011
Gori S, et al
PTEN status negative (Nagata score <9): 60%
(Nagata score <4): 15%
PTEN status evaluated by IHC in 45 HER2+ MBC treated with
trastuzumab-based therapy was not significantly associated with
outcome (ORR, TTP, OS).
Gianni L, ASCO 2008 #504
Background
NCCTG N9831 Trial Incorporating Trastuzumab in
Adjuvant Therapy
Arm A (1232 pts)
HER2 positive
(FISH ratio ≥2
or
IHC 3+ >10%)
n=3,505
R
A
N
D
O
M
I
Z
E
AC
T
Arm B (1216 pts)
AC
T
H
Arm C (1057 pts)
AC
T
H
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= H (trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 51)
Perez EA. Protocol NCCTG-N9831
Conclusions
• Data and results were similar across both
analyses
• In contrast to some preclinical and limited
clinical studies, loss of PTEN protein
expression was not associated with
decreased tumor sensitivity to adjuvant
trastuzumab
– Data demonstrate benefit of treating HER2+
breast cancer pts with adjuvant trastuzumab
regardless of PTEN protein expression status
Perez EA, et al. J Clin Oncol 2011; 29(15s)Part I: 631s
HER2- positività:
PTEN status
Setting metastatico
• Risultati contrastanti
PTEN –: ORR % inferiori rispetto ai PTEN+ (Nagata Y, Cancer Cell 2004)
Nessuna differenza in outcome tra PTEN- e PTEN + (Gori S, Ann Oncol 2009)
Setting neoadiuvante
• Espressione di PTEN non è associata a pCR
(NOAH- Gianni L, ASCO 2008)
Setting adiuvante
• PTEN-negatività non si correla ad una ridotta DFS nei
gruppi trattati con Trastuzumab
(Perez EA; ASCO 2011)
HER2-positive breast cancer
HER3 status
HER3 status by immunohistochemistry in HER2-positive
metastatic breast cancer patients treated with trastuzumab:
correlation with clinical outcome.
Gori S et al, TUMORI 2011 in press
A
B
IHC expression of HER3 in HER2+ MBC
(immunoperoxidase, 400 x)
A. HER3–negative
(positive tumour cells 50%)
B. HER3-positive
(positive tumour cells >50%)
30 pts
31 pts
HER3 status by IHC was not significantly
associated with clinical outcome
HER3-negative status by IHC in HER2-positive MBC:
longer OS and TTP
A
1,0
1,0
HER3 cut-off 50%
HER3 cut-off 50%
HER3 <= 50%
HER3 <= 50%
HER3 >50%
HER3 >50%
HER3 <= 50%-censored
HER3 <= 50%-censored
HER3 >50%-censored
0,8
0,6
0,6
Cum Survival
Cum Survival
HER3 >50%-censored
0,8
0,4
0,4
log rank= 0.131
log rank= 0.304
0,2
0,2
0,0
0,0
0,0
25,0
50,0
75,0
100,0
OS from start of herceptin
125,0
0,0
20,0
40,0
60,0
80,0
TTP_from start trastuzumab
Gori S et al, TUMORI 2011 in press
NOAH trial
Gianni L, ASCO 2008
Oltre lo stato di HER2- positività
CONCLUSIONI
1. I tumori HER2+ non sono un gruppo
omogeneo
2. Ad oggi, nei tumori HER2+, l’unico altro
dato a disposizione utile a fini prognostici e
terapeutici, è lo stato dei recettori ormonali
THANK YOU !