1. 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

2. HER2+ MBC: worse survival
Prognosis of metastatic breast cancer by HER2 status and trastuzumab treatment
HER2+
25%
13%
OS a 5 anni del 13% circa nelle pts HER2- positive rispetto a circa il 25% delle pts HER2-negative (p<.0001)
Dawood S, JCO 2010
HER2+ MBC: worse survival

3. 1st line therapy of MBC: anti-HER2 agent + CT
RESULTS from randomized trials
N pts/
arm
Treatment
ORR
DOR
TTP OS
Slamon DJ
NEJM 2001
Phase 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 M
JCO 2005
Phase IIR 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 A
JCO 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 G
SABCS 2010
222
w paclitaxel 80 (3/4)
69%*
50%
9.3 mo
5.8 mo
9.7 mo* (PFS)
6.5 mo
27.8 mo*
20.5 mo
* : Risultati significativamente superiori, dal punto di vista statistico, rispetto al braccio di controllo senza agente anti-HER2 .
* Statistically significant difference versus CT arm

4. Time from diagnosis (months)
Multivariate model
HER2+ and trastuzumab vs HER2-negative
HR of death ; 95% CI ; p< .0001
Multivariate model
HER2+ and trastuzumab vs HER2+ no trastuzumab
HR of death ; 95% CI ; p< .0001
Dawood S, JCO 2010

5. HER2-positive breast cancer
HR status

6. * * HR-negative HR-positive
HER2-
HER2-
HER2+
HER2+
HER2+
HER2+ * *
Time from diagnosis-months Time from diagnosis-months
HR-negative
HR-positive
Overall survival by Trastuzumab treatment group and according to hormone receptor status
5y-OS y-OS
HER HER2+
HR mo HR mo
HR- and trastuzumab mo HR+ and Trastuzumab mo

7. Even in presence of trastuzumab, HR status is still a prognostic factor in MBC
Dawood S, JCO 2010

8. HER2+ and HR+ MBC: Anti-HER2 plus hormonal therapy
ORR
PFS OS
TAnDEM
Kaufman B
JCO 2009
103
104
Anastrozole+Trastuzumab
Anastrozole
4.8%*
2.4%
5.6 mo*
3.8 mo
28.5 mo
23.9 mo
Schwarzberg LS
Oncologist 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

9. 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
Lapatinib+ Letrozole
Trastuzumab+ Taxane
Lapatinib+ Capecitabine

10. Outcome by pCR and HR status
Neoadjuvant CT in unselected for HER2 status BC
Outcome by pCR and HR status
No.
PFS
5-y
10-y p OS
HR-negative
No pCR
pCR
423
132 (24%)
50% vs
83%
43%
73%
67%
84%
59%
HR-positive
1072
91 (8%)
65%
91%
38%
76%
96%
41%
<.0001
.003
Studio retrospettivo- M.D. ANDERSON
.002
.04
Guarnieri V, JCO 2006

11. R R NEOALTTO1 NEOSPHERE2 L T L+T Phase III SURGERY FEC X 3 Phase II S
lapatinib
trastuzumab
paclitaxel
+ 12 wks
6 wks
docetaxel + pertuzumab L
SURGERY
FECx3 T
FEC X 3
docetaxel + trastuzumab T
FECx3 T R
Operable
T >2 cm R
Operable or LABC/IBC
trastuzumab + pertuzumab
D  FEC T
L+T
docetaxel + trastuzumab + pertuzumab
FECx3 T 3
34 wks
52 wks of anti-HER2
52 wks of anti-HER2
1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010

12. NEOALTTO:pCR by Hormone Receptor Status
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response HR: hormone receptors

13. NeoSphere: pCR and hormone receptors status70 60
ER or PR pos
ER and PR neg 50
63.2 40
pCR, %  95% CI 30 20
36.8
30.0 10
29.1
26.0
20.0
5.9
17.4 TH
THP HP TP
H, trastuzumab; P, pertuzumab; T, docetaxel 7

14. CHERLOB: Study plan   A    B   C  LVEF R A C N O D R O E S M IZ T A C O R E B I P S Y S U R G E Y    B
Lapatinib 1500 mg continuous daily dose (CDD)
121 pts
II-IIIA
T>2cm   C
Lapatinib 1000 mg CDD
5 FU 600 mg/m2
Epi 75 mg/m2
CTX 600 mg/m2
 LVEF
Paclitaxel 80 mg/m2
Trastuzumab 2 mg/kg
Guarneri V, ASCO 2011 #507 14

15. [TITLE]
Guarneri V, ASCO 2011 #507

16. [TITLE]

17. Stato dei Recettori ormonali
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

18. Stato dei Recettori ormonali
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-

19. Gene- expression profiling
HER2-positive breast cancer
Gene- expression profiling

20. Luminal A
Luminal A
Luminal B
Luminal B
HER2+
HER2+
Basal
Basal
OS months
RFS months
cDNA microarrays
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:

21. Immunohistochemical identification of breast tumour intrinsic subtypes.
Carey L A, JAMA 2006; 295:

22. 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
high
any
HER2-enriched
Basal-like
absent
Cytokeratin 5/6 +
and /or HER1+
Cheang MCU, JNCI 2009; 101:736-50
Cheang MCU, JNCI 2009;101:736-50

23. Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab
Knauer M, BJC 2010; 103:

24. 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
Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab
Knauer M, BJC 2010; 103:

25. 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

26. HER2-positive breast cancer
p95-HER2 status

27. p95HER2 is expressed in 30% of HER2+ BC
Trastuzumab
…by either proteolytic shedding of ECD1
or by alternative initiation of translation of the HER2 mRNA2
p95HER2
1. Codoni-Servat J, Cancer Res 1999;59: Anido J, EMBO J 2006; 25:

28. p95HER2 testing: rationale
p95HER2 is an NH(2)-terminally truncated form of HER2 that lacks the trastuzumab binding site
p95HER2 is expressed in approximately 30% of HER2 positive breast cancer patients
Preclinical and initial clinical evidence suggest that p95HER2 confers resistance to trastuzumab
p95HER2 might retain sensitivity to kinase inhibitors
Molina, et al. Clin Cancer Res 2002;8:347-53; Scaltriti, et al. J Natl Cancer Inst 2007; 99(8):628-38 28

29. p95HER2 and Response to Trastuzumab
46 patients with MBC treated with trastuzumab1
1Scaltriti, M JNCI 2007

30. p95HER2 and Reponse to Trastuzumab
29 patients with EBC treated with neoadj. trastuzumab
(CherLob)2
46 patients with MBC treated with trastuzumab1
1Scaltriti, M JNCI 2007
2Guarneri, V et al. ASCO 2011 #507

31. GeparQuattro: p95HER2 and Response to Trastuzumab (N=145 patients treated with EC+T  Doc+T)
(>20% strongly positive for 611 CTF)
(≤20% strongly positive for 611 CTF)
Loibl S et al, ASCO 2011 Abstr #530

32. 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% 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 evaluated
In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluated
Guarneri V- ASCO 2011 #507

33. p95HER2 and clinical response to lapatinib (PFS)
Results from 68 and 156 MBC pts
Lapatinib monotherapy-
EGF20009
Lapatinib+ capecitabine-
EGF100151
Scaltriti M, Clin Cancer Res 2010

34. CherLob: p95HER2 and Response to Lapatinib (N=59 patients treated with CT+L or CT +TL)
(>80% strongly positive for 611 CTF)
(≤80% strongly positive for 611 CTF)
Guarneri, V et al. ASCO 2011 #507

35. HER2- positività: p95 HER2 Setting metastatico
p95HER 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

36. HER2-positive breast cancer
PTEN status

37. (a negative regulator of Akt activities)
IHC expression of PTEN
(a negative regulator of Akt activities)
EGF, TGF-α P
EGFR
HER2
PI(4,5)P2
PI3-K
SOS
PI(3,4,5)P3 P
PTEN
Grb2
RAS-GDP
RAS-GTP
PDK1,2
GTP
PDK1,2
TKI
Akt/PKB
RAF
Members of the human EGF receptor (HER/erbB) family include EGF receptor (EGFR), HER2, HER3, and HER4
After ligand binding, receptors complex with themselves (homodimers) or with other erbB family members (heterodimers)
Cellular responses to signaling are diverse because signals are generated through multiple ligands and receptors
EGFR and HER2 are promising targets because
They are expressed or overexpressed in many cancers
In some cancers, overexpression is associated with poor clinical outcome
Blocking EGFR or HER2 could interrupt signaling through several pathways
PI3-K (promotes cell survival, protein synthesis, and metabolic processes)
RAS-RAF (involved in metabolic processes and in controlling cell cycle, migration, shape, proliferation, and differentiation)
Targeting EGFR or HER2 has been studied in breast, lung, and other cancers
Novartis Oncology has investigational agents that inhibit the activity of EGFR and HER2 in early-phase clinical trials
MEK
Survival pathway
ERK
Proliferation pathway

38. P < 0.001
Nagata Y, Cancer Cell 2004

39. PTEN Impact on Sensitivity or Resistance to Trastuzumab
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

40. PTEN status negative (Nagata score <9): 60%
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).

42. Gianni L, ASCO 2008 #504

43. NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
Background
NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
Arm A (1232 pts) R A N D O M I Z E AC T
HER2 positive (FISH ratio ≥2
or IHC 3+ >10%)
Arm B (1216 pts) AC T H
Arm C (1057 pts)
As a brief background, N9831 was a phase III intergroup trial led by the North central cancer Treatment group. This trial examined standard chemotherapy with sequential or concurrent trastuzumab in primary breast cancer pts with HER2-positive disease. Our present analyses included pts randomized to Arms A &C and does not include data from Arm B as these data are not released by the IDMC. HER2 positivity was classified as having a FISH ratio of greater to or equal to 2 or IHC staining in greater than 10% cells.
The NCCTG trial N9831 compared 3 regimens:
Group A: 4 cycles of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m2/wk) for 12 weeks
Group B: 4 cycles of AC followed by 52 weeks of Herceptin® (trastuzumab) after the completion of 12 weeks of weekly paclitaxel (80 mg/m2/wk) therapy
Group C: 4 cycles of AC followed by 52 weeks of Herceptin beginning on day 1 of 12 weeks of weekly paclitaxel (80 mg/m2/wk) therapy
Hormonal therapy/XRT, if administered, was initiated after chemotherapy
Inclusion criteria for this trial included the following:
Invasive BC resected by lumpectomy/mastectomy plus axillary dissection with pathologically involved axillary nodes
No locally advanced or distant disease
Normal hematologic, hepatic, and renal function
No prior anthracycline or taxane therapy
No significant sensory or motor neuropathy
HER2 positivity by FISH or 3+ by IHC
Verified centrally in N9831
Normal left ventricular ejection fraction
No past or active cardiac disease, including history of myocardial infarction or congestive heart failure, angina pectoris requiring medication, arrhythmia requiring medication, clinically significant valvular disease, uncontrolled hypertension, LVH, or cardiomegaly on CXR
n=3,505 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
Romond et al. N Engl J Med. 2005;353:1673.
Herceptin® (trastuzumab) PI. November 2006. 43

44. 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

45. 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)

46. HER2-positive breast cancer
HER3 status

48.   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%)
30 pts
Background: HER3 signalling might contribute to resistance to trastuzumab. To clarify the role of HER3 in HER2-positive breast cancer, it is important to evaluate the level of HER3 and its correlations with clinical outcome in metastatic breast cancer (MBC) patients treated with trastuzumab.
B. HER3-positive
(positive tumour cells >50%)
31 pts
HER3 status by IHC was not significantly associated with clinical outcome

49. HER3-negative status by IHC in HER2-positive MBC: longer OS and TTP
Gori S et al, TUMORI 2011 in press

50. NOAH trial
Gianni L, ASCO 2008

51. 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

52. THANK YOU !