HER 2 nel carcinoma della...

Confidential

HER 2nel carcinoma della

ProstataSylvie Ménard

Dept. of Experimental OncologyIstituto Nazionale Tumori

Milan, Italy

Molecular Biology Unit, INT, Milan

ConfidentialMolecular Targeting Unit, INT, Milan17 ottobre 2007

HER2 può essere usato come target terapeutico nel carcinoma

della prostata ormone-indipendente?


HER2 è upmodulato dal trattamento anti-ormonale

• Nel 25% dei casi ormone-indipendenti HER1 e HER2 sono overespressi: ciò giustifica lo sviluppo di terapie anti HER 1 e 2 (BartlettJM, J.Pathol 2005)

• Overespressione di HER2 associata alla progressione verso l’indipendenza da androgeni (JNCI 2000, Dec 6, 92(23) p1918)

• Casi ormone-indipendenti esprimono alti livellidi HER2 e di AR (Edwards J, BJC 2003/Chen CD, Nat.Med. 2004)


Il pathway di HER2 è attivato nel carcinoma della prostata ormone-indipendente: possibili interventi

terapeutici

• Anticorpi anti-HER2 : Trastuzumabe Pertuzumab (2C4)

• Inibitori tirosin-chinasici: PKI-166


Studio di Slamon

• Ca. mammari 3+ o FISH+ mostrano 30% di CR+PR

• Ca. mammari 2+ FISH- mostrano 1% diCR+PR


Livelli di iperespressione di HER2 dopo terapia ormonale

4/49 (8.2%)10/49 (20.4%)34/49 (69.3%)Post-HR

2/49 (4.1%)8/49 (16.3%)24/49 (48.9%)Pre-HR

6/98 (6.1%)18/98 (18.3%)58/98 (59.1%)All cases

HER2

Intense ModerateIHC-positive

Immunohistochemistry results (Bartlett JM ,J.Pathol. 2005)


Trials clinici con agenti anti-HER2 nel carcinoma della prostata

• Trial fase 2 con Herceptin su 18 pz: 2 SD (Zioda A, Prostate 2004)

• Trial fase 2 su HER2 overesprimenti non condotto per carenza di casi HER2+ (Lara PN, Cancer 2004)

Confidential

DEMETRA Study

§ 440 breast carcinoma patients treated with trastuzumab for metastatic disease with 36 months median follow-up

§ 280 with complete information: response, treatment and follow-up

- 119 stop at progression- 151 continue after progression


Confidential

151 119

0.0000

17 months 39 months

Survival in patients with metastatic disease


Confidential

7

0.00000.03

Survival in patients with metastatic disease(79 patients continue, 44 patients stop)


Confidential

151

0.0000 0.0000

Survival in patients with metastatic disease( 72 patients continue, 75 patients stop)


Confidential

Analysis of NSABP31Trial

S. PaikASCO2007


Confidential

RR of ACTH/ACT for DFS (NSABP B-31)

FISH+ (1588) –

FISH- (207) –

IHC 3+ (1488) –

IHC <3 (299) –

FISH- & IHC <3 (174) –

0.00 0.25 0.50 0.75 1.00 1.25 1.50I I I I I I

Interaction p=0.60 for FISHInteraction p=0.26 for IHC

RR

Note: RR adjusted for ER and nodal status

Cat

egor

ies

(N)


Confidential

HER2 gene copu number and RR of ACTH/ACT (interaction p=0.59)

Over 10 (1235) –

4 to 10 (355) –

2 to 4 (137) –

0 to 2 (68) –

0.00 0.50 1.00 1.50I I I

RR of ACTH/ACT

Cop

y nu

mbe

rca

tego

ries

(N)


Confidential

Distribution of Herceptest IHC scores among cases received for HER2 testing at a large reference lab

FISH-IHC 1+/2+ = 46% of all cases

IHC No. (%)Score (N=1575)

0 595 (38)

1+ 549 (35)

2+ 216 (14) 190 non-amplified

3+ 215 (13)

From Perez et al., Mayo Clin. Pro. 77:48-54,2002 Molecular Biology Unit, INT, Milan


• 2C4 mAb (impedisce dimerizzazioneHER2/3) inibisce la crescita di impianti di CaP ormone-indipendenti ed esprimenti basso HER2 (Agus DB, Cancer Cell 2002)

Confidential

Agus et al., J. Clin. Oncol. 2007

41 patients with CRPC in progression after 1 or 2 chemo (one with taxane), castrated by LHRH agonists

Phase II with pertuzumab in Castration-resistantprostate carcinoma

Confidential

Agus et al., J. Clin. Oncol. 2007

Use of a validated normogram

Confidential

Legrier et al., Br. J. Cancer 2007


Valore prognostico di HER2 circolante

2.93-206.4424.6040

2.39-75.4313.4335

1.95-27.567.3430

1.59-10.074.0125

1.3-3.682.1920

1.06-1.341.1915

.49-.87.6510

0.18-0.71.365

95% CIMortality RRHER2/neu (ng/ml)

Osman I, The Journal of Urology 2005


> 14.0 ng/mL

Range

Mean

SerumHER2

3/60 (5%)

7.6-16

11

No cancer(N=60)

8/67 (11.9%)

6.1-19.8

11.2

ClinicallyLocalizedDisease(N=67)

8/77 (10.4%)

7.3-23

11.9

RisingPSA (N=77)

7/42 (16.7%)

5.2-28.9

11.6

ClinicalMetastases(N=42)

11/33 (33%)

6.4-40.7

13.9

ClinicalMetastases, Castrate (N=33)

Osman I, The Journal of Urology 2005

Soluble HER2 in serum

Confidential

Okegawa et al., Int. J. Urol. 2006

Confidential

- Why HER2-poorly positive tumor cells respond to anti-

HER2 antibodies?


Confidential

HER2 is more expressed on tumor-initiating cells


ConfidentialMolecular Biology Unit, INT, Milan

HER2 is more expressed on tumor-initiating cells

Confidential

Untreated DXR-treated

Trastuzumab-treated

3 cell sospensions

In vitro sphereformation

In vivo serialtransplantation


Confidential

1.6 –

1.4 –

1.2 –

1 –

0.8 –

0.6 –

0.4 –

0.2 –

0Control DXR Herceptin

I I

IControl DXR Herceptin

I I I

HER2-amplified cells

Control cells

% M

amm

osph

ere

form

atio

n

Reduction of tumor-initiating cells after treatment with trastuzumab but not DXR


Confidential

1 –

0.8 –

0.6 –

0.4 –

0.2 –

0Control DXR Herceptin Control DXR Herceptin

Reduction of tumor-initiating cells after treatment with trastuzumab but not DXR

Ser

ial t

rasp

lant

in n

ud

e m

ice

(%)


HER2-amplified cells Control cells

Confidential

Conclusions

§ Prostate cancer do not overexpress HER2 but patients seem to benefit from anti-HER2 therapy

§ Do Tumor-initiating cells from prostate cancer express more HER2?


Confidential

HER2 gene amplification can be acquired during progression of breast cancer – most likely due to selection of HER2

amplified cells among cells in primary tumor(Meng et al., PNAS 101: 9393, 2004)

Index tumor HER2 negative

Recurred (N=24) – 9 cases had CTC with HER2 amplification (37.5%)

4 treated with Herceptin

1 CR and 2 PR

This cells also tend to haveuPAR amplification and

overexpression

Adjuvant trastuzumab mayInhibit selection of

these cells


Confidential


Confidential

5/55/55/5---3/42/43°

5/55/55/50/54/53/52°

5/55/55/53/55/55/51°No. of xeno-transplants

TrastuzumabDXRControl

TrastuzumabDXRControlTreatment

105 HER2 normalcarcinoma

105 HER2-amplifiedcarcinoma

Reduction of tumor-initiating cells after treatment with trastuzumab But not DXR


Confidential


HER 2 nel carcinoma della...

Documents

Transcript of HER 2 nel carcinoma della...