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 !