Cosa altro è importante sapere oltre l’HER2 status: recettori ormonali, profili di
espressione genica…
L’HER2-positività: dall’anatamopatologia alla clinica
Stefania GoriOncologia Medica- Perugia
Dawood S, JCO 2010
HER2+
HER2+ MBC: worse survival
Prognosis of metastatic breast cancer by HER2 status and trastuzumab treatment
13%
25%
1st line therapy of MBC: anti-HER2 agent + CT RESULTS from randomized trials
N pts/arm
Treatment ORR DOR TTP OS
Slamon DJNEJM 2001Phase III
92
96
w trastuzumab + paclitaxel 175
w paclitaxel
38%*
16%
10.5 mo*
4.5 mo
6.9 mo*
3.0 mo
22.1 mo*
18.4 mo
Marty MJCO 2005Phase IIR
92
94
w trastuzumab+docetaxel 100
docetaxel
61%*
34%
11.7 mo
5.7 mo
11.7 mo*
6.1 mo
31.2 mo*
22.7 mo
Di Leo AJCO 2007(subgroup of pts)
49
37
lapatinib 1500+paclitaxel 175
paclitaxel
63%*
38%
8.0 mo
6.O mo
8.1 mo *
5.1 mo
24.0 mo
19.1 mo
Zhong-Zhen GSABCS 2010Phase III
222
222
lapatinib 1500+w paclitaxel 80 (3/4)
w paclitaxel
69%*
50%
9.3 mo
5.8 mo
9.7 mo* (PFS)
6.5 mo
27.8 mo*
20.5 mo
* Statistically significant difference versus CT arm
Dawood S, JCO 2010
Multivariate model HER2+ and trastuzumab vs HER2-negative
HR of death 0.56; 95% CI 0.45-0.69; p< .0001
Time from diagnosis (months)
Multivariate model HER2+ and trastuzumab vs HER2+ no trastuzumab
HR of death 045; 95% CI 0.33-0.63; p< .0001
HR status
HER2-positive breast cancer
HR-negative HR-positive
Overall survival by Trastuzumab treatment group and according to hormone receptor status
HER2+
HER2+
HER2+
HER2+
HER2-HER2-
5y-OS 5y-OSHER2+ HER2+HR- 8.9 mo HR+ 14.5 moHR- and trastuzumab 17.7 mo HR+ and Trastuzumab 29.7 mo
Time from diagnosis-months Time from diagnosis-months
**
Dawood S, JCO 2010
Even in presence of trastuzumab, HR status is still a prognostic factor in MBC
HER2+ and HR+ MBC:Anti-HER2 plus hormonal therapy
ORR PFS OS
TAnDEMKaufman BJCO 2009
103
104
Anastrozole+Trastuzumab
Anastrozole
4.8%*
2.4%
5.6 mo*
3.8 mo
28.5 mo
23.9 mo
Schwarzberg LSOncologist 2010(219 out of 1,286 =17%)
111
108
Letrozole+ lapatinib
Letrozole+ placebo
28%*
15%
8.2 mo*
3.0 mo
34.1 mo
28.6 mo
1st line therapy in HR+ and HER2+ MBC
Poor PSNo/limited visceral metastasesSlowly Progression Expression of HR
Good PSVisceral metastasesRapidly progressing
Trastuzumab+ Anastrozole
Lapatinib+ LetrozoleTrastuzumab+ Taxane
Lapatinib+ Capecitabine
No. PFS 5-y 10-y p
OS 5-y 10-y p
HR-negative
No pCR
pCR
423
132 (24%)
50%vs83%
43%vs73%
67%vs84%
59%vs84%
HR-positive
No pCR
pCR
1072
91 (8%)
65%vs91%
38%vs 76%
84%vs96%
41%vs96%
Guarnieri V, JCO 2006
Neoadjuvant CT in unselected for HER2 status BC
Outcome by pCR and HR status
<.0001 .003
.04.002
3
1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010
SURGERY
lapatinib
trastuzumab
lapatinibtrastuzumab
paclitaxel
paclitaxel
paclitaxel
+ 12 wks6 wks
docetaxel + trastuzumab
FEC X
3
L
T
L+T
34 wks
trastuzumab + pertuzumab
docetaxel + pertuzumab
docetaxel + trastuzumab +pertuzumab
SURGERY
FECx3 T
FECx3 T
D FEC T
FECx3 T
52 wks of anti-HER2 52 wks of anti-HER2
NEOALTTO1
Phase III
NEOSPHERE2
Phase II N=450 N=417
ROperable
T >2 cm
ROperable or LABC/IBC
NEOALTTO:pCR by Hormone Receptor Status
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response HR: hormone receptors
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR posER and PR neg
NeoSphere: pCR and hormone receptors status
20.026.0
17.4
36.8
29.1 30.0
63.2
5.9
pCR,
%
95%
CI
H, trastuzumab; P, pertuzumab; T, docetaxel 7
5 FU 600 mg/m2
Epi 75 mg/m2
CTX 600 mg/m2
Paclitaxel 80 mg/m2 Trastuzumab 2 mg/kg
RANDOMIZATION
Lapatinib 1000 mg CDD
Lapatinib 1500 mg continuous daily dose (CDD)
CORE
BIOPSY
SURGERY
A
B
C
CHERLOB: Study plan
LVEF
121 pts
II-IIIA
T>2cm
Guarneri V, ASCO 2011 #507
[TITLE]
Guarneri V, ASCO 2011 #507
[TITLE]
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- positività:Stato dei Recettori ormonali
Gene- expression profiling
HER2-positive breast cancer
Survival analysis of the 49 breast cancer patients , uniformly treated in a prospective study, based on different gene expression classification
OS months RFS months
Sorlie T, PNAS 2001; 98:10869-10874
Luminal A
Luminal A
Luminal B
Luminal B
HER2+ HER2+
Basal Basal
Immunohistochemical identification of breast tumour intrinsic subtypes.
Carey L A, JAMA 2006; 295: 2492-2502
Cheang MCU, JNCI 2009;101:736-50
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
Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab
Knauer M, BJC 2010; 103:1788-93
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 subgroup of HER2-positive early BC with a 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
p95-HER2 status
HER2-positive breast cancer
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 Trastuzumab46 patients with MBC
treated with trastuzumab1
1Scaltriti, M JNCI 2007
46 patients with MBC treated with trastuzumab1
29 patients with EBC treated with neoadj. trastuzumab
(CherLob)2
1Scaltriti, M JNCI 20072Guarneri, V et al. ASCO 2011 #507
p95HER2 and Reponse to Trastuzumab
GeparQuattro:p95HER2 and Response to Trastuzumab
(N=145 patients treated with EC+T Doc+T)
P<0.0001
Loibl S et al, ASCO 2011 Abstr #530
(>20% strongly positive for 611 CTF) (≤20% strongly positive for 611 CTF)
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
p95 –n=7/23
30%
35.7%
54%
0
10
20
30
40
50
60
Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L)
p95 –n=13/24
p95 –n=5/14
p95 +n=3/12
33.3%
25%
33%
p95 +n=2/6
p95 +n=3/9
Cut-off at 80%
P= 1
P= 0.68
P= 0.44
In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluatedGuarneri V- ASCO 2011 #507
p95HER2 and clinical response to lapatinib (PFS)
Results from 68 and 156 MBC pts
Scaltriti M, Clin Cancer Res 2010
Lapatinib monotherapy-
EGF20009
Lapatinib+ capecitabine-
EGF100151
Setting metastatico• p95HER2+ resistenza al trastuzumab 1
• Lapatinib efficace sia nei tumori p95HER2+ che p95HER- 2
Setting neoadiuvante• Risultati contrastanti 3-4
HER2- positività:p95 HER2
1. Scaltriti 2007; 2.Scaltriti 2010; 3.Guarneri ASCO 2011; 4.Lobi ASCO 2011
PTEN status
HER2-positive breast cancer
Proliferation pathway
Grb2
Survival pathway
Akt/PKB
MEK
ERK
PI3-K
RAF
PI(4,5)P2PI(3,4,5)P3
PTEN
P
P
P
P
EGF, TGF-α
EGFR HER2
PDK1,2PDK1,2RAS-GTP
SOS
GTP
PRAS-GDP
TKI
IHC expression of PTEN
(a negative regulator of Akt activities)
P < 0.001
Nagata Y, Cancer Cell 2004
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
BackgroundBackground
Perez EA – ASCO 2011
Gori S, et al
PTEN status evaluated by IHC in 45 HER2+ MBC treated with trastuzumab-based therapy was not significantly associated with outcome (ORR, TTP, OS).
PTEN status negative (Nagata score <9): 60% (Nagata score <4): 15%
Gianni L, ASCO 2008 #504
NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
RANDOMIZE
RANDOMIZE
HER2 positive (FISH ratio ≥2or IHC 3+ >10%)
Arm A (1232 pts)
Arm C (1057 pts)
Arm B (1216 pts)
ACT
ACT
H
H
ACT
= 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)
n=3,505
Perez EA. Protocol NCCTG-N9831
BackgroundBackground
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: 631sPerez EA, et al. J Clin Oncol 2011; 29(15s)Part I: 631s
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- positività:PTEN status
HER3 status
HER2-positive breast cancer
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
IHC expression of HER3 in HER2+ MBC (immunoperoxidase, 400 x)
A. HER3–negative (positive tumour cells 50%)
30 pts
A B
B. HER3-positive (positive tumour cells >50%)
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
OS from start of herceptin125,0100,075,050,025,00,0
Cum
Surv
ival
1,0
0,8
0,6
0,4
0,2
0,0
HER3 >50%-censoredHER3 <= 50%-censoredHER3 >50%HER3 <= 50%
HER3 cut-off 50%
log rank= 0.304
TTP_from start trastuzumab80,060,040,020,00,0
Cum
Surv
ival
1,0
0,8
0,6
0,4
0,2
0,0
HER3 >50%-censoredHER3 <= 50%-censoredHER3 >50%HER3 <= 50%
HER3 cut-off 50%
log rank= 0.131
Gori S et al, TUMORI 2011 in press
NOAH trial
Gianni L, ASCO 2008
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
Oltre lo stato di HER2- positivitàCONCLUSIONI
THANK YOU !