Oltre la chemioterapiaOltre la chemioterapia

prof. Giuseppe Naso

ONCOLOGIA MEDICA

POLICLINICO UMBERTO I

prof. Giuseppe Naso

ONCOLOGIA MEDICA

POLICLINICO UMBERTO I

Recent gene-profiling studies

have nicely confirmed that ER-

positive and ER- negative breast

cancer are essentially two

different disease

M.J.Piccart-Gebhart: JCO vol.21, 8: 2003

ER+ ER-

HER-2+ ?

Expression of growth factor receptors in breast cancer

% expression Receptor in breast cancer

KIT 80%

PDGFR 50%-90%

EGFR 14%-91%

EGFR vIII 20%-78%

HER2 20%-25%

HER3 20%-70%

HER4 7%-18%

IGF-IR Induced by estrogen

EGFTGF

Amphiregulin-cellulinHB-EGF

Epiregulin Heregulins

NRG2NRG3

Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

ErbB-1Her1

EGFR

ErbB-2Her2neu

ErbB-3Her3

ErbB-4Her4

C-terminus

100

100

100

44

82

33

36

59

24

48

79

28

The EGFR (ErbB) family and ligands

R

K

R

K

Cell surface

R

K

R

K

Cell surface

R

K

R

K

Cell surface

PI3K

Shc

Grb2 Ras Sos

Raf

MEK1/2

Akt

MAPK

PTEN

GSK-3mTOR FKHR BadIntra-CellularSignaling

NF-

[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]

R

K

R

K

Cell surface

PI3K

Shc

Grb2 Ras Sos

Raf

MEK1/2

Akt

MAPK

PTEN

GSK-3mTOR FKHR BadIntra-CellularSignaling

NF-

[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]

p27

Gene Transcription/Cell Cycle Progression

R

K

R

K

Cell surface

Survival Proliferation Angiogenesis MetastasisCellular Responses

PI3K

Shc

Grb2 Ras Sos

Raf

MEK1/2

Akt

MAPK

PTEN

GSK-3mTOR FKHR BadIntra-CellularSignaling

NF-

[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]

p27

Gene Transcription/Cell Cycle Progression

rho

rac

1 2

K KSHC

PI3KGRB2

SOS

AKT

RAS

PTEN

mTOR FKHR GSK-3 BAD

Cell cicle

progression

Survival

RAF

MEK 1/2

MAP

Anti ErbB1-2 receptors Mabs(Trastuzumab, 2C4, C225)

HER1,HER2,HER4, Tyrosine Kinase Inhibitors (ZD 1839, OSI 774, EKB 559,

GW 2016, CI 1033)

Ras farnesyl transferase Inhibitors (BMS 214662, R115777)

RAF inhibithorsmTOR inhibitors (CCI 779)

Mek inhibitors (CI 1040)

ERAF1

AF2

ESTRADIOLO

ERE

ERE

ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE

ERTAMOXIFENAF1

AF2

ERE ATTIVAZIONE PARZIALEDELLA TRASCRIZIONE

(solo AF1)

Meccanismo d’azione di Estradiolo e Tam a confronto

ERAF1

AF2

ESTRADIOLO

ERE

ERE

ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE

ERAF1

AF2

BLOCCO COMPLETODELLA TRASCRIZIONEEs

A.I.FASLODEX

In most cases AF-1/AF-2 are present in resistant tumours,

and in many of these its activity continues to regulate

tumour growth

TyrosineKinase

GRB2

SOSras-GDP ras-GTP

raf

MEK

MAPK

ATP

ATP

ATP

forma inattiva Forma attivata

fosmycjun

MAP

La cascata delle chinasi della via rasLa cascata delle chinasi della via ras

TyrosineKinase

GRB2

SOSras-GDP ras-GTP

raf

MEK

MAPK

ATP

ATP

ATP

forma inattiva Forma attivata

fosmycjun

MAP

La cascata delle chinasi della via rasLa cascata delle chinasi della via ras

AKT

AF

1

COREPRESSORE

COATTIVATORE MAPATP

Hormone-dependent growth

Che succede se si utilizzano contemporaneamente

un antiestrogeno e un inibitore della TK attivata dagli EGFRs ?

Effects of ER and EGFR blockade are:

•Reproducible:

Total cell kill has been achieved in 5/6 experiments by 4 months using Tamoxifen and Iressa

•Seen with other anti-hormonal drugs:

Faslodex plus Iressa achieved a total cell kill by 3 months

•Observed in other cell lines:

T47D cells show equivalent early responses

Role of HER2 in breast cancer

• HER2 gene amplification or receptor overexpression occurs in approximately 25 % of breast cancers

• HER2-positive tumours are associated with poor prognosis

HER2 status as a prognostic indicator

Univariate Multivariate

Factor Survival Relapse Survival Relapse

No. positivenodes 0.0001 0.0002 0.0003 0.001

HER2 0.0011 <0.0001 0.02 0.001

Log (PR) 0.05 0.05 N/A N/A

Tumour size 0.06 0.06 N/A N/A

Log (ER) 0.15 0.10 0.03 N/A

n=86 node-positive patients/Southern blot assay/median follow-up 46 monthsER = oestrogen receptorPR = progesterone receptor

Slamon DJ et al. Science 1987; 235: 177–182

HER2 status as a prognostic indicator:Disease-free survival of node-positive breast cancer

patients related to HER2 status

100

80

60

40

20

00 12 24 36 48 60 72

Dis

ease

-fre

e su

rviv

al p

rob

abil

ity

Time (months)

HER2 gene <3 copies

HER2 gene 3 copies

Log rank p=0.001

Seshadri R et al. J Clin Oncol 1993; 11: 1936–1942

HER2 status as a prognostic indicator:Survival of node-negative breast cancer patients

related to HER2 status

1.00

0.75

0.50

0.25

0

Cu

mu

lati

ve p

rob

abil

ity

0 24 48 72 96 120 144

Not amplified

Amplified

Amplified: >10 copies/nucleusNot amplified: <3 copies/nucleusBorderline: excluded

Time to death (months)

Log rank p<0.001

Ross JS, Fletcher JA. Stem Cells 1998; 16: 413–428

Expression of growth factor receptors in breast cancer

% expression Receptor in breast cancer

KIT 80%

PDGFR 50%-90%

EGFR 14%-91%

EGFR vIII 20%-78%

HER2 20%-25%

HER3 20%-70%

HER4 7%-18%

IGF-IR Induced by estrogen

HER hierarchy

Bivalence of EGF-like ligands

Relative potency of HER dimers

HER2-promoted recycling of HER1

cbl

Eligible patients (n=469)

No prior anthracyclines

Prior anthracyclines

Paclitaxel(n=96)

Trastuzumab + Paclitaxel(n=92)

AC(n=138)

Trastuzumab + AC(n=143)

• Metastatic breast cancer• erbB2 overexpression• No prior chemotherapy for MBC• Measurable disease• KPS ≥60%

Slamon et Al N Engl J Med, March 2001

Herceptin® in breast cancer:what evidence do we have?

Herceptin® in combinationSummary of benefits

Herceptin® +AC (n=143)

AC alone(n=138)

Herceptin®

+ paclitaxel(n=92)

Paclitaxelalone (n=96)

Herceptin® +chemotherapy

(n=235)Chemotherapyalone (n=234)

Median TTP (months) 8.1 6.1 6.9 3.0 7.6 4.6(p=0.0003) (p=0.0001) (p=0.0001)

Response rate (%) 52 43 42 16 49 32(p=0.1038) (p<0.0001) (p=0.0002)

Median duration of 9.1 6.5 11.0 4.4 9.3 5.9response (months) (p=0.0025) (p=0.0001) (p=0.0001)

Median TTF (months) 7.2 5.6 5.8 2.9 6.9 4.5(p=0.0009) (p=0.0001) (p=0.0001)

1-year survival (%) 83 72 72 60 78 67(p=0.0415) (p=0.0975) (p=0.0080)

TTP = time to disease progressionTTF = time to treatment failure

Slamon DJ at al. 2001os = p 0.05

Herceptin + Taxani (+/- Platino)TTP (3 studi randomizzati)

3

76,1

10,6

7,2

13,5

0

4

8

12

16

Mes

i

Taxol H+Taxol Taxotere H +Taxotere H+Taxol H+Taxol+Carboplatino

Slamon NEJM 2001 Robert SABCS 2002Marty ECCO 2003

p=0.001

p=0.001p=0.001

Herceptin + Taxani (+/- Platino)OS (3 studi randomizzati)

Slamon NEJM 2001 Robert SABCS 2002

18

25

18

2830

?

0

12

24

36

Mes

i

Taxol H+Taxol Taxotere H +Taxotere H+Taxol H+Taxol+Carboplatino

Marty ECCO 2003

p=0.5 p=0.001 p=NR

Goal of the second-generation HER2 programme

For example

Better response rate

Longer duration of response

More clinical benefit in tumours that express intermediate (2+ or 1+) or even low levels (0) of HER2

Develop an agent with clinical activity superior to Herceptin®

Pertuximab

(2C4)

Anti-HER2 epitope mapExtracellular domain

CRD-2

Intracellular domain

TK

CT

CRD-1

Bald L, Fendly B

7C2(aa 23–53)

Herceptin®

(aa 529–625)

2C4 Pertuximab(aa 22–584)

Inhibition of heregulin binding by 2C4, a monoclonal antibody to HER2

Bo

un

d/t

ota

l

2C4 (nM)

0.10

0.08

0.06

0.04

0.02

0.000.1 1 10 100

HER2:HER3

HER3

Inhibition of ligand binding by 2C4 to HER2-containing receptor complexes

EGFR/HER2 HER3/HER2 HER4/HER2Receptor combination

EGF

HRG HRGRel

ativ

e li

gan

d b

ind

ing

(%

)

100

80

60

40

20

0

Control

2C4

Effect of Herceptin® or 2C4 on ligand-mediated MAP kinase activation

EGF – + + + – – – – – –

TGF – – – – + + + – – –

HRG – – – – – – – + + +

2C4 – – + – – + – – + –

Herceptin® – – – + – – + – – +

Summary

In contrast to Herceptin®, 2C4 is very effective in

Blocking HER2 association with other HER family members

Inhibiting HER2 activation and subsequent downstream signalling

suppressing the growth of tumours with ligand-activated HER2

TC

neo-ANGIOGENESIS

NC

CELL GROWTH

HYPOSSIA(HIF-1 HIF-2)

CELL GROWTH(Apoptotic blockade)

neo-LYNPHOGENESIS

VEGF-A

VEGF-B

VEGF-C

VEGF-D

ONCOGENES ACTIVATION

ONCO-SUPPRESSOR GENES INACTIVATION

MSR – NER – BER - OSR

The switch to an angiogenic phenotype represent a pivotal step in the multistage process toward malignancy (Folkman 1996)

For solid tumors to grow beyond 1-2 mm3 they require increased access to oxygen and nutrients from the blood supply (Folkman 1971)

1-2 mm3

INTRODUCTION INTRODUCTION

Angiogenesis is required for solid tumor growthAngiogenesis is required for solid tumor growth

Tumor angiogenesis begins when growing tumors, in response to hypoxia or other stimuli, secrete angiogenic factors

Vascular endotelial growth factor is one of the most potent promoters of angiogenesis and has been identified as a fundamental regulator of tumor neovascolarizzazion

INTRODUCTION INTRODUCTION

Solid tumors stimulate angiogenesis by secreting Solid tumors stimulate angiogenesis by secreting angiogenic factorsangiogenic factors

INTRODUCTION Tumor angiogenesis promotes tumor growth

and metastasis The creation of new

blood vessels and lymphatic tissue by solid tumors allows them to enlarge and to metastasize to distal sites

Inhibition of tumor angiogenesis, therefore, has the potential to inhibit tumor growth and spread

VEGF levels apper to have prognostic significance in human VEGF levels apper to have prognostic significance in human tumors ( LAM, breast cancer, colon cancer,hepatocellular tumors ( LAM, breast cancer, colon cancer,hepatocellular cancer, NSCLC and ovariancancer, NSCLC and ovarian cancer)cancer)

The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis

There are five members of the VEGF family (VEGF-A, placental growth

factor, VEGF-B, VEGF-C,

VEGF-D, VEGF-E) VEGF is a diffusabile

endothelian cell-specific

mitogen pro-angiogenic factor

that increases vascular permeability

VEGF-B

VEGF-A

VEGF-E

VEGF-C

VEGF-D

INTRODUCTIONINTRODUCTION

The VEGF family are critical tumor-secreted The VEGF family are critical tumor-secreted angiogenic factorsangiogenic factors

VEGFR-1 is activated by VEGF-A and VEGF-B

VEGFR-2 is activated by VEGF-A, VEGF-C, VEGF-D, and VEGF-E

VEGFR-3 is activated by VEGF-C and VEGF-D

Different VEGF family members bind and activate different VEGF receptors on endothelial cells

•Monoclonal antibody, specific for VEGF A

•Derived from the murine antibody A4.6.1, comprises 93% human antibody and 7% murine derived antigen-binding-protein, the humanization proving a longer half-life and less immunogenicity

•Able to neutralize the biological properties of human VEGF, including endothelian cell mitogenic activity, vascular permeability-enhancing activity and angiogenic properties( Kim K.1992)

•The antibody did not recognize the other growth factor tested including FGF, EGF, PDGF

BEVACIZUMAB (avastin; Genentech)BEVACIZUMAB (avastin; Genentech)

BEVACIZUMAB: Preclinical StudiesBEVACIZUMAB: Preclinical Studies

Extensive preclinical studies have demonstrated the efficacy in different cell lines subcutaneously injcect into nude mice ( Kim KJ 1993) while did not reveal a direct effect on the growth of tumor cells (Warren RS 1995)

TUMOR SUPPRESSION IS MEDIATED THROUGH INHIBITION OF NEOVASCULARIZZATION

Warren and coworkers demonstrated that treatment with anti-VEGF ab was effective in suppressing primary tumor growth as well liver metastatis growth in a murine model of Colorectal cancer

BEVACIZUMAB: Clinical StudiesBEVACIZUMAB: Clinical Studies

More than 30 clinical trials with Bevacizumab in solid tumors and More than 30 clinical trials with Bevacizumab in solid tumors and hematologic malignancies are planned, ongoing or recenttly hematologic malignancies are planned, ongoing or recenttly completedcompleted

In general, the therapeutic strategies being evaluated can be In general, the therapeutic strategies being evaluated can be diveded into the following categories:diveded into the following categories:

•Bevacizumab monotherapyBevacizumab monotherapy

•Bevacizumab in combination with chemotherapy or radiotherapyBevacizumab in combination with chemotherapy or radiotherapy

•Bevacizumab in combination with other putative anti-angiogenic Bevacizumab in combination with other putative anti-angiogenic strategies ( low-dose INF, thalidomide..)strategies ( low-dose INF, thalidomide..)

•Bevacizumab in combination with tumor-target therapies ( erlotinib, Bevacizumab in combination with tumor-target therapies ( erlotinib, trastuzumab, imatinib)trastuzumab, imatinib)

•Bevacizumab in combination with immunotherapyBevacizumab in combination with immunotherapy

Bevacizumab phase I-II clinical trial efficacy results in breast cancer

3mg/kg 10mg/Kg 20mg/Kg Total

N° of Pts 18 41 16 75

Objective Response Rate (n/%) 1 (5.6%) 3 (7.3%) 1 (6.3%) 5 (6.7)

Median Response Duration (months) 3.1 5.6 8.0 5.6

Stable disease at 154 days 2 (11%) 7 (17%) 3 (19%) 12 (16%)

Median Survaival (months) 14.0 12.8 7.6 10.2

Sledge GW et al. JCO 2003

BEVACIZUMAB:Summary of trials in solid tumorBEVACIZUMAB:Summary of trials in solid tumor

Inhibition of Ubiquitin-Proteasome pathway

Bortezomib

L’emivita di una proteina è determinata in gran parte dal suo residuo terminale

Residui altamente stabilizzanti(t1/2 >20 ore)

Ala Cys Gly Met Pro Ser Thr Val

Residui intrinsecamente destabilizzanti(t1/2= da 2 a 390 min.)

Arg His He Leu Lys Phe Trp Tyr

Residui destabilizzanti solo dopo modificazione chimica

Asn Asp Gln Glu

The Proteasome: Enzyme with Important Impact on Multiple Regulatory Pathways

•Is found in all eukariotic cells, from yeast to man

•Is present in the cytoplasm and nucleus

•Degrades more than 80% proteins

Tumor microenvironmentExtracellular matrix

Inibitori di traduzione del segnale:Inibitori di traduzione del segnale:Ras e FT-IRas e FT-I

NeoplasticTransformation

Inactivation of Rb and p53Immortalization

telomerase activation

Activation of ras-pathway

Weinberg, A. 2003

Farnesyl-transferase inhibitors

The ras gene is mutated in one fifth of all human cancers.

RAS

ras (p21) G-Protein (intrinseca attività GTP-asica)

ras agisce come un interruttore molecolare che sialterna da una forma inattiva (ras-GDP) ad una forma attiva (ras-GTP)

The switch function of RAS

TyrosineKinase

GRB2

SOSras-GDP ras-GTP

raf

MEK

MAPK

ATP

ATP

ATP

forma inattiva Forma attivata

fosmycjun

MAP

La cascata delle chinasi della via rasLa cascata delle chinasi della via ras

Prenilazione

Carbossi-terminale (C-terminale)

CAAX CC – CXC - CCXX

Farnesilazione es.: ras,rho Geranil-geranilazione es.:rab

C=cisteinaA=residui alifaticiX=qualunque aminoacido

Gruppo Farnesile (C15) Gruppo Geranilgeranile (C20)

C15

Classes of FTase inhibitors

Peptide CAAX peptidomimetics : L-778,123

Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat

Bisubstrate Inhibitors : BMS-214662

Inhibitors classes I

Inhibitors classes II

Peptide CAAX peptidomimetics : L-778,123

Nonpeptide CAAX peptidomimetics : Tipifarnib, Sarosat

Bisubstrate Inhibitors : BMS-214662

Phase I-II studies with farnesyl-trasferase inhibitors in clinical development

Drug Company Route RD DLT Activity

R115777 Janssen/ oral 300 mg bid, 7-14 Myelosuppression, 1 PR NSCLCZarnestra Ortho-Biotech fatigue, Tipifarnib neurotoxicity,skin

SCH66336 Schering – Plough oral 350 mg bid, 7-14 Nausea, vomiting, 1 PR NSCLCSarosar diarrhea, fatigue

BMS-214662 Bristol Meyer iv 300 mg/m2 24 h liver, neuropathy -Squibb c.i weekly

L-778,123 Merck iv 560 mg/m2 c.i. 7-14 Myelosuppression, sonnolence, fatigue -

Tipifarnib (R115777): Phase II clinical trials

Johnston SR.: SABCS 2000

Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach

Combination of 2 selective Combination of 2 selective inhibitors approachinhibitors approach

EGFR

VEGF

Endothelial cells

Cancer cells

Angiogenesis

Cell Proliferation

Tortora 2004

ErlotinibCetuximab, etc

Bevacizumab etc.

Combined blockade of EGFR and VEGF

Combined blockade of EGFR and VEGFCombined blockade of EGFR and VEGF

Jung YD et al, Eur J Cancer 2002; 38: 1133-40. Ciardiello F et al. Clin Cancer Res 2000; 6: 3739-3747

EGFR

VEGF

Endothelial cells Cancer cells

TGF

KDR

Angiogenesis

Cell Proliferation

ZD6474

Tortora & Ciardiello, 2002

ZD6474 Inhibits KDR and EGFR

ZD6474 is a potent orally-active inhibitor of VEGF-signalling

Inhibits VEGF-induced hypotension, vascular permeability and angiogenesis in vivo

Broad-spectrum anti-tumour activity in mouse models consistent with an anti-angiogenic mechanism

Dosing for > 100 days has been feasible in man

Phase I adverse events generally mild

Anti-VEGF activity suggested by hypertension and delay in dermal wound angiogenesis

ZD6474: Phase I Studies

0

0,5

1

1,5

2

2,5

3

3,5

0 21 42 63 84 105 126

Giorni

Volu

me

tum

oral

e

0

0,5

1

1,5

2

2,5

3

3,5

0 21 42 63 84 105 126

Giorni

Vo

lum

e tu

mo

ralecontrollo

Gefitinib

Gefitinib >ZD6474

controllo

Cetuximab

Cetuximab > ZD6474

ZD6474 inibisce la crescita di tumori divenuti resistenti a Gefitinib o Cetuximab

Ciardiello et al., 2004

AZD2171

Enzastaurin

Agents affecting all VEGFRs

AZD2171

AZD2171 is an oral therapy with potential application in multiple tumor types

AZD2171 has activity against VEGF receptors 1, 2 & 3- No activity on EGFR

Phase I clinical studies in refractory solid tumors underway

Manageable toxicity in early phase I

AZD2171

VEGFR3 (Flt-4)

VEGFR1(Flt-1)

VEGFR2 (KDR)

Company ConfidentialCopyright © 2004 Eli Lilly and Company

Lilly Research LaboratoriesNot for Promotional USE

NN

NO O

H

Me

N

N

H

Cl-+

MW = 552.08

• Potent oral selective inhibitor of PKC (IC50 = 0.006 M)

• Is an acyclic indolylmaleimide that competes with the ATP binding site preventing substrate phosphorylation

• Inactive against other kinases

• Antiangiogenic activity in preclinical models.

• Well tolerated in preclinical toxicology studies.

• Administered once daily PO. Normal volunteer and Phase I studies completed. Phase II studies ongoing.

Enzastaurin

Company ConfidentialCopyright © 2004 Eli Lilly and Company

Lilly Research LaboratoriesNot for Promotional USE

Receptor

VEGF

DAG

IP3/Ca2+

PKC-

COX2

mRNA

• Tumor invasion• Angiogenesis

ENZASTAURIN

Activation

GSK3

AKT

Caspase 9

Apoptosis

Protein translationIL-6

IL-8

PKC- and the Proposed Action of Enzastaurin on Angiogenesis and

Apoptosis

• Pericytes protects endothelial cells from apoptosis and overexpress PDGF-R• PDGF-R is overexpressed by many tumors• PDGF-R and VEGF cooperate

Blood vessels are not only endothelial cells (L.M. Ellis)

Improving Anti-VEGF therapy by expanding the targets

PTK787

SU11248

Multiple target agents affecting VEGFRs (and PDGF-R)

• Complete inhibitor of the VEGF receptor tyrosine kinases VEGFR1(FLT-1), VEGFR2 (KDR) and VEGFR3 (FLT-4). It also inhibits PDGF-R.

• Well tolerated up to 1250 mg/day (phase III dose, used up to 15 mo)

• Rapidly absorbed (1 to 2.5 hours), T1/2: 3-6 hrs

• Renal metabolism

PTK787/ZK 222584PTK787/ZK 222584

Formula: C24H21N4Cl MW = 346.82

PTK787/ZK 222584PTK787/ZK 222584

Formula: C24H21N4Cl MW = 346.82

PTK/ZK: A multi-VEGF receptor tyrosine kinase inhibitor

SU11248 is an Oral, Multi-targeted, RTK Inhibitor With Selective Activity against PDGFR, VEGFR, KIT, and FLT3

Split Kinase Domain RTKs

FLT1FLK1/KDRFLT4

FGFR1FGFR2FGFR3FGFR4

PDGFR

CSF1RKITFLT3/FLK2

PDGFR

Potent Activity vs. Class III, Class V RTKs:Biochemical Ki values <10nMCellular IC50 values 5-50nM

Weak Activity vs. Class IV RTKs:Biochemical Ki values 1000 nMCellular IC50 values 6000 nM

Highly selective for Class III, Class V RTKs, versus other tyrosine kinases and serine/threonine kinases evaluatedClass III Class V Class IV

• Direct anti-tumor activity via inhibition of target RTKs

- VEGFR in Melanoma, PDGFR in Glioma, KIT in GIST, FLT3 in AML

• Indirect inhibition of tumor growth via inhibition of angiogenesis

- VEGFR and PDGFR

Conclusioni (I)

Genes changing in associationwith response

Genes changing in associationwith response

Good respondersGood responders Poor respondersPoor responders

14 genes 14 genes sharedshared

biologically biologically responsiveresponsive

biologicallbiologically y

refractoryrefractory

256 genes256 genes256 genes256 genes 49 genes49 genes49 genes49 genes

Response in patients treated with FAC/paclitaxel preoperative

chemotherapy

Response in patients treated with FAC/paclitaxel preoperative

chemotherapy

Hortobagyi GN ASCO 2002Hortobagyi GN ASCO 2002

150 Genes150 Genes

pCRpCR NoPCRNoPCR

Conclusioni (II)

“…A targeted therapy only works when the target is present and plays an important role in the cancer…”

IRESSA and NSCLC:a very important lesson

No target 10-12% of Response

Target 100% of Response

Prof. Enrico Cortesidott.ssa A. De Benedetto dott. A. Luginidott. A. Padovani dott.ssa R. Ferraldeschidott.ssa G. D’auria dott. P. Ceratti dott.ssa N. Pizzardi dott.ssa L. Mentucciadott.ssa M. Mazzoli dr. V. Picone

Oncologia Medica B Univ. Di Roma “La Sapienza”