PierFranco Conte

Dipartimento di Oncologia e EmatologiaUniversità di Modena e Reggio Emilia

Highlights in the management of breast cancer: Lapatinib Rome, november 17, 2006

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA

HER2: beyond Herceptin

1985: human cDNA cloning

1987: disease validation

1990: MAb 4D5

1998: Herceptin® approved by FDA for metastatic breast cancer

2005: Herceptin® becomes an essential

component of the adjuvant treatment of HER2 + early breast cancer

2007: New HER2 targeted agents are available

“Non esiste vento favorevole per il marinaio che non sa dove andare”

(there is no favourable wind for a sailor who does not know where to go)

Seneca (5 aC-65 dC)

Why targeting HER2 beyond Trastuzumab in Breast Cancer?

• Efficacy

• Primary resistance

• Secondary resistance

• Cardiac safety

• HER2 + molecular subtypes

FIRST-LINE SINGLE-AGENT TRIAL RESPONSE ACCORDING TO HER2 STATUS

Adapted from Vogel C, et al. J Clin Oncol 2002;20:719–26

Pat

ien

ts (

%)

35

0

5

10

15

20

25

30

35

40

45

ICH < 2+ IHC 3+

Efficacy data from Phase II and III trials of trastuzumab combined with chemotherapy

Author Regimen # patients

Response Rate %

Median TTP (mos)

Median OS

(mos)

Slamon Chemo + H

Chemo

235

234

50*

32

7.4*

4.6

25.1*

20.3

Marty Doc + H

Doc

92

94

61*

34

10.6*

5.7

30.5*

22.1

Seidman Pw + H 88 61 7.0 NR

Burstein VNB + H 54 70 5.6 NR

* P = < 0.05

Relationship of HER2 Status on Site of First Relapse

  HER-2/neu not overexpressed

HER-2/neu overexpressed

No relapse 44.5% 31.9%

Locoregional 17.8% 18.8%

Bone 16.1% 5.8%

Lung 7.6% 21.7%

Liver 1.7% 5.8%

Brain 0.4% 4.3%

Kallioniemi et al., Int J Cancer 1991

High incidence of CNS metastases among women treated with trastuzumab

Study Incidence

Bendell et al ASCO 2002 34%

Weitzen et al ASCO 2002 29%

Heinrich et al ASCO 2003 43%

Clayton et al Br J Cancer 2004 39%

Altaha et al ASCO 2004 33%

Stemmler et al SABCS 2004 31%

HER2+ Advanced Breast Cancer

• ~ 60 – 70% of patients exhibit a primary resistance to Trastuzumab monotherapy

• ~ 30 – 50% of patients show a primary resistance to Trastuzumab plus chemotherapy

• Eventually, all the patients become resistant to

Trastuzumab within months or years

• CNS MTS are frequent

• Trastuzumab is ineffective for CNS MTS ( CSF levels 300-fold lower than in the serum)

1703 1591 1434 1127 742 383 140

100

80

60

40

20

0

Patients(%)

Months from randomisation

Observation

No. at risk 1698 1533 1301 930 606 322 114

Disease-free survival (censored)- Median FU 2 yrs

1 year trastuzumab

218316

Events HR 95% CI p value

0.63 0.53, 0.75 <0.0001

3-yearDFS

80.674.0

12 360 186 24 30

19.4% Not effective

74% Not necessary

6.6% Necessary & effective

Higher Incidence of Isolated CNS RelapseAs 1st Event in Patients on Adjuvant Trials

Romond et al, NEJM 2005

H vs Ctr

NSABP B-31 21 11N9831 12 4

Total 33 15

“Brain metastases as first or subsequent event were diagnosed in 28 patients in the trastuzumab group, compared to 35 patients in the control group (HR 0.79, p=0.35) The imbalance in brain metastases as first events can be attributed to earlier failures at other distant sites among patients in the control group”

HER2+ Early Breast Cancer

• > 50% of patients do not need HER2 targeted therapy

• > 50% of patients show a primary resistance to Trastuzumab plus chemotherapy

• CNS relapse as 1st event is more frequent in patients on adjuvant trastuzumab

Management of trastuzumab resistanceLesson # 1

• Check HER2 positivity on original tumor blocks

• Whenever possible, test HER2 status on recurrent disease

• Trastuzumab and chemotherapy can act synergically on apoptotic pathway

• Other proteins in the EFGR-mediated signalling pathways are important

• Other EGFRs (i.e.HER1) can be important

Trastuzumab resistance

• Trastuzumab can induce apoptosis through inhibition of PI3K/Akt pathway

• PTEN normally opposes PI3K/Akt signaling

• trastuzumab stabilizes PTEN and downregulates Akt signaling

• loss of PTEN can induce trastuzumab resistance

ER+

61%

ER–

39%

ErbB1+

3%

ErbB1+

38%

ErbB2+

11%

ErbB2+

41%

ErbB3+

11%

ErbB3+

27%

Witton et al. J Pathol 2003; 200:290-7.Witton et al. J Pathol 2003; 200:290-7.(n = 220)(n = 220)

ErbB2/ErbB3 Expression and Estrogen Receptor Status in Breast Carcinomas

Reproduced with permission from Witton et al. Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200:290-7.Reproduced with permission from Witton et al. Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003; 200:290-7.

Survival Interrelationship Between ER/PR Status and ErbB Expression

Effect on survival of the expression of other EGF-r family members

Robinson, ASCO 2005

Lapatinib Mechanism of Action

• Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation

• Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)

• Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab

1+1 2+2 1+2

Lapatinib

Downstream signaling cascade

Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;Konecny et al. Cancer Res. 2006;66:1630-1639

Dual kinase inhibitor lapatinib against HER-2 overexpressing and trastuzumab-treated breast cancer cell lines

Konecny GE et al.: Cancer Res, 2006

Combined effect of Trastuzumab and Lapatinib

Phase Ib Trial: EGF10004Overview

• Study objectives:– Determine a dose or range of biologically active doses– Evaluate safety and tolerability– Examine dose pharmacokinetics and pharmacodynamics

• Study design:– Patients randomized to doses of 500, 650, 900, 1200, or

1600 mg/day– Clinical response evaluated every 8 weeks– Biological effects examined by comparing biomarker results

from biopsy samples obtained pretreatment and following 21 days of therapy

Burris et al. Breast Cancer Res Treat 2003; 82(suppl 1):S18 (abstract 39).Burris et al. Breast Cancer Res Treat 2003; 82(suppl 1):S18 (abstract 39).

Burris et al. Breast Cancer Res Treat 2003; 82(suppl 1):S18 (abstract 39).Burris et al. Breast Cancer Res Treat 2003; 82(suppl 1):S18 (abstract 39).

EGF10004 Results: Frequency of Achieving ≥ 75% Inhibition of p-EGFR, p-ErbB2, p-ERK1/2, or

p-AKT Expression in Tumors at Day 21

Dose (mg/day)Dose (mg/day)

Fre

qu

en

cy o

f In

hib

itio

n

(%)

Fre

qu

en

cy o

f In

hib

itio

n

(%)

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

500 mg500 mg650 mg650 mg900 mg900 mg1200 mg1200 mg1600 mg1600 mg

EGF10004: Clinical Characteristics of Responders––

Breast Cancer SubsetEfficacy Data

Number of Patients

Partial Response 4

650 mg/day 1

900 mg/day 1

1200 mg/day 2

Response Duration

Median 5.5 months

Range 3-8 months

Patient Characteristics

Number of Patients

ErbB2+ 4

ErbB1+ 3

Prior Treatment

Trastuzumab 4

Taxane 3

Anthracycline 3

Burris H et al. Burris H et al. J Clin OncolJ Clin Oncol 2005; 23:1-9. 2005; 23:1-9.

Four of 59 evaluable patients achieved a PR with single-agent lapatinib:–All had ErbB2+ breast cancer –All were trastuzumab pretreated

Four of 59 evaluable patients achieved a PR with single-agent lapatinib:–All had ErbB2+ breast cancer –All were trastuzumab pretreated

EGF20009:A Phase II, Randomized Trial Using the Small

Molecule Tyrosine Kinase Inhibitor Lapatinib as a First-Line Treatment in Patients with FISH Positive

Advanced or Metastatic Breast Cancer

H. L. Gomez, M. A. Chavez, D. C. Doval, L. W. Chow, B. Newstat, S. H. Stein,

M. S. Berger, G. W. Sledge

ASCO 2005

Arm 1Arm 1LapatinibLapatinib 1500 mg/day p.o. 1500 mg/day p.o. ×× 12 weeks* 12 weeks*

Arm 1Arm 1LapatinibLapatinib 1500 mg/day p.o. 1500 mg/day p.o. ×× 12 weeks* 12 weeks*

Arm 2Arm 2LapatinibLapatinib 500 mg p.o. b.i.d. 500 mg p.o. b.i.d. ×× 12 weeks* 12 weeks*

Arm 2Arm 2LapatinibLapatinib 500 mg p.o. b.i.d. 500 mg p.o. b.i.d. ×× 12 weeks* 12 weeks*

Eligibility criteria:Eligibility criteria:• Advanced or Advanced or

metastatic breast metastatic breast cancer cancer

• No prior therapy for No prior therapy for advanced or advanced or metastatic diseasemetastatic disease

• ERBB2ERBB2 amplification amplification by FISHby FISH

Eligibility criteria:Eligibility criteria:• Advanced or Advanced or

metastatic breast metastatic breast cancer cancer

• No prior therapy for No prior therapy for advanced or advanced or metastatic diseasemetastatic disease

• ERBB2ERBB2 amplification amplification by FISHby FISH

First efficacy assessment at 8 weeksFirst efficacy assessment at 8 weeks

Second efficacy assessment at 12 weeksSecond efficacy assessment at 12 weeks

First efficacy assessment at 8 weeksFirst efficacy assessment at 8 weeks

Second efficacy assessment at 12 weeksSecond efficacy assessment at 12 weeks

EGF20009: Phase II Randomized Trial of Lapatinib as First-line Treatment in FISH-Positive

Metastatic Breast Cancer

Stratification:Stratification:• Visceral or nonvisceral Visceral or nonvisceral

diseasedisease• Hormone receptor Hormone receptor

statusstatus

Stratification:Stratification:• Visceral or nonvisceral Visceral or nonvisceral

diseasedisease• Hormone receptor Hormone receptor

statusstatus * Patients with clinical benefit may continue * Patients with clinical benefit may continue on lapatinibon lapatinib* Patients with clinical benefit may continue * Patients with clinical benefit may continue on lapatinibon lapatinib

(n = 130)(n = 130)(n = 130)(n = 130)

RRAANNDDOOMMIIZZEE

RRAANNDDOOMMIIZZEE

Primary endpoint:: Objective response ratePrimary endpoint:: Objective response rate

Secondary endpoints: clinical benefit rate, time to response, Secondary endpoints: clinical benefit rate, time to response, duration of response, TTFduration of response, TTF

Primary endpoint:: Objective response ratePrimary endpoint:: Objective response rate

Secondary endpoints: clinical benefit rate, time to response, Secondary endpoints: clinical benefit rate, time to response, duration of response, TTFduration of response, TTF

Efficacy in All PatientsResponse Investigator Review

N=40 Independent Review

N=40

CR 0 0

PR 12 (30%) 14 (35%)

Unconfirmed PR* 3 (7.5%) 2 (5%)

SD 13 (32.5%) 14 (35%)

PD 10 (25%) 5 (12.5%)

Unknown 2 (5%)**, † 5 (12.5%) **, †

*Two subjects considered to have a PR by investigator had <28 day confirmation scans.** One subject not evaluated due to death from multiple injuries prior to tumor assessment.† 1 subject by the investigator review and 4 subjects by independent review had only one timepoint and that timepoint did not meet the criteria for SD per the protocol (8 weeks).

EGF20009: Lapatinib Monotherapy for First-line

FISH-Positive Metastatic Breast CancerSafety

1500 mg q.d. 500 mg b.i.d.

Pruritis 40% 27%

Rash 23% 17%

Diarrhea 23% 16%

Dry Skin 3% 17%

• One grade 3 event (nausea)One grade 3 event (nausea)• One treatment-related serious adverse event, gastritis/esophagitisOne treatment-related serious adverse event, gastritis/esophagitis• No serious decrease in LVEF (> 20% decrease from baselineNo serious decrease in LVEF (> 20% decrease from baseline and below lower limit of normal)and below lower limit of normal)

Grade 1/2 Adverse EventsGrade 1/2 Adverse Events

Gomez et al. SABCS 2005 (abstract 1071).Gomez et al. SABCS 2005 (abstract 1071).

Patient C: Brain Lesion Baseline

Patient C: Brain Lesion Week 12

Lapatinib + Trastuzumab in Advanced Pretreated Metastatic Breast Cancer

Phase I Study: EGF10023• Study objectives:

– Safety of lapatinib in combination with trastuzumab

– Optimally tolerated regimen of combination

– Pharmacokinetic parameters

– Clinical activity

• Eligibility criteria:– Advanced ErbB2+ MBC

– Prior treatment with trastuzumab allowed but not required

• Treatment consisted of escalating doses of lapatinib 750, 1000, 1250, or 1500 mg/day with trastuzumab (4-mg/kg loading dose; 2 mg/kg/week)

Storniolo et al. ECCO 2005 (abstract 278); SABCS 2005 (abstract 1075).Storniolo et al. ECCO 2005 (abstract 278); SABCS 2005 (abstract 1075).

Patient Characteristics of Responders

*PK patient**Prior lapatinib monotherapy (EGF10004)

† Lapatinib dose (mg/day)

ResponseTreatment Duration (Months)

Dose (mg/day)†

ER/PR Status

Prior MBC Treatment

Chemo HormoneTrastuzumab ±

Chemo

CR 11+ 1500, 1000 - 2 0 1

PR 10 1000 + 2 0 5

PR 6 1000 - 1 0 2

PR 5+ 1250, 750 - 1 0 1

PR 4 1000, 750 + 4 2 4

PR 4 1000 - 1 1 6

PR* 4+ 1000 - 3 0 3

PR* 2+ 1000 - 0 0 4

SD 7 750 - 3 0 2

SD 6 1000 + 4 3 0

SD** 5 750 - 7 1 3

Lapatinib + Trastuzumab in Advanced Pretreated Metastatic Breast Cancer:

Results

• Optimally tolerated dose and dose-limiting toxicities:– Lapatinib 1000 mg/day with standard trastuzumab was

defined as optimally tolerated regimen (OTR).– The most frequent adverse at OTR were diarrhea, rash,

fatigue, nausea, anorexia, and vomiting.

• Pharmacokinetics:– No effect on PK of lapatinib or trastuzumab was observed

during coadministration. – Synergism of action of lapatinib and trastuzumab similar to

preclinical studies reported.

Storniolo et al. ECCO 2005 (abstract 278); SABCS 2005 (abstract 1075).Storniolo et al. ECCO 2005 (abstract 278); SABCS 2005 (abstract 1075).

Management of trastuzumab resistanceLesson # 2

• Combining two MoAbs binding at different epitopes of HER2 receptor can inhibit more efficiently HER2-driven signalling (trastuzumab+Pertuzumab)

Combining an anti-ErbB2 antibody with small molecule

tyrosine kinase inhibitor, that act at different sites of the receptor with distinct mechanisms of action, might enhance the efficacy of both drugs (trastuzumab +Lapatinib)

• Inhibition of multiple EGFR-family receptors can be important (lapatinib)

A Phase III Randomized, Open-Label, International Study Comparing

Lapatinib and Capecitabine vs. Capecitabine in Women with Refractory Advanced or Metastatic Breast Cancer

(EGF100151)

C.E. Geyer, D. Cameron, D. Lindquist, S. Chan, T. Pienkowski, C.G. Romieu, A. Jagiello-Gruszfeld,

J. Crown, B. Kaufman, A. Chan, J.K. Forster

Allegheny General Hospital, Pittsburgh, PA; Western General Hospital, Edinburgh, UK; US Oncolgy Research Network, Houston,TX; Nottingham

City Hospital, Nottingham, UK; Cancer Center, Warsaw, Poland; CRCC Val d’Aurelle Paul Lamarque, Montpellier, France; ZOZ MSWiA, Olsztyn,

Poland; St. Vincent’s University Hospital, Dublin, Ireland; Sheba Medical Center, Tel Hashomer, Israel; Mount Medical Centre, Perth, Australia;

GlaxoSmithKline, Greenford, UK

Study Design

• Progressive, HER2+ MBC or LABC

• Previously treated with anthracycline, taxane and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

*Trastuzumab must have been administered for metastatic disease

N=528

EGF 100151 - Study Objectives

• Primary– TTP

• Secondary– Overall survival– Progression free survival – 6-month progression free survival– Overall tumor response rate– Clinical benefit (complete, partial response or stable

disease for at least 6 months)– Time to response– Duration of response

Prior TherapyLapatinib +

Capecitabine(n=160)

Capecitabine(n=161)

Anthracyclines 156 (98%) 156 (97%)

Taxanes 157 (98%) 159 (99%)

Trastuzumab 156 (97%) 156 (97%)

Metastatic 149 (93%) 146 (91%)

Adjuvant 7 (4%) 10 (6%)

Prior Trastuzumab for Metastatic Disease

Interval from last dose prior to randomization*

Progressed on trastuzumab*

42 (29%) 48 (33%) 54 (37%)

2 ( 1%)

< 4 wks4 - 8 wks> 8 wks Unknown

51 (34%) 42 (28%)56 (38%)

Yes 142 (97%)147 (99%)

Capecitabine (n=146)Lapatinib + Capecitabine (n=149)

* Based on those who received treatment for MBC only.

Median duration of trastuzumab (range)

44.1 wk (5-329)42.3 wk (3-296)

Issued – Monday 3 April 2006, London, UK & Philadelphia, US -LSE Announcement

GlaxoSmithKline Receives Positive Data and Halts Enrolment in Phase III Trial of Tykerb® (Lapatinib) in Advanced Breast Cancer

First Regulatory Filings now Planned for 2nd Half of 2006Based on the unanimous recommendation of an Independent Data Monitoring Committee (IDMC), GlaxoSmithKline (GSK) announced today that it has halted enrolment in its Phase III clinical trial evaluating the combination of Tykerb (lapatinib ditosylate) and capecitabine (Xeloda®) versus capecitabine alone. The trial evaluated women with refractory advanced or metastatic breast cancer who have documented ErbB2 (HER2) overexpression and whose disease progressed following treatment with trastuzumab (Herceptin) as well as other cancer therapies. A pre-planned interim analysis of 321 patients in the study yielded statistically significant results, exceeding the primary endpoint.

EGF100151: Phase III Trial of Capecitabine ± Lapatinib in Advanced or

Metastatic Breast Cancer Efficacy

EGF100151: Phase III Trial of Capecitabine ± Lapatinib in Advanced or

Metastatic Breast Cancer Efficacy

Capecitabine

Capecitabine Plus

Lapatinib

P Value

Median TTP 19.7 weeks 36.9 weeks .00016

Median PFS 17.9 weeks 36.9 weeks .000045

Median OS Not reached Not reached .800

Overall RR 14.3% 22.5% .113

CR 0 (0%) 1 (1<%) –

PR 23 (14%) 35 (22%) –Geyer ASCO 2006 Special Session

Time to Progession – ITT Population

70

10

20

30

40

50

60

70

80

90

0

100

* Censors 4 patients who died due to causes other than breast cancer

10 20 30 40 50 600Time (weeks)

CapecitabineLapatinib +

Capecitabine

0.00016P-value (log-rank, 1-sided)

69 (43%)45 (28%)Progressed or died*

19.736.9Median TTP, wk

161160No. of pts

0.51 (0.35, 0.74)Hazard ratio (95% CI)

% o

f p

atie

nts

fre

e fr

om

pro

gre

ssio

n*

EGF100151: Phase III Trial of Capecitabine ± Lapatinib in Advanced or Metastatic Breast CancerBrain Metastases as Site of Progression

EGF100151: Phase III Trial of Capecitabine ± Lapatinib in Advanced or Metastatic Breast CancerBrain Metastases as Site of Progression

Capecitabine

(n = 161)

Capecitabine Plus

Lapatinib

(n = 160)

Patients With CNS Metastases at Baseline

2 2

Patients With CNS Relapse*

11 4

Patients With CNS as Only Site of Relapse

10 3

* P =.110

Geyer ASCO 2006 Special Session

EGF 100151-Most Frequent Adverse Events

All Grades

Gr 3

Gr 2

Severity

Gr 4

Gr 1

Diarrhea Rash and/or Skin Reaction

% o

f P

atie

nts

PPE

L+C

L+C

L+CCC

C

10

20

30

40

50

60

70

80

90

100

0

26

19

121

13

15

11

9

28

6

9

20

5

19

13

2.5

12

11

7

L = lapatinib; C = capecitabine.

EGF 100151-Mean LVEF at Scheduled Assessments

Week 12 Week 18 Week 24 Week 36 Week 48Week 6Screening

Assessment

Lapatinib + Capecitabine

Capecitabine

Mea

n L

VE

F (

%)

80

75

70

65

60

55

50

n=160 n=160

n=108

n=92

n=84 n=67

n=63n=37

n=37 n=26

n=15n=9

n=7n=1

Conclusions

Lapatinib with capecitabine is an effective new

regimen for advanced HER2+ breast cancer

and should be considered a new standard of

care for women meeting eligibility criteria of

this trial

Summary: Cardiac Effects Associated with Lapatinib Therapy (n = 3558)

• 1097 pts with > 6 mo exposure to lapatinib• In 598 patients pre-treated with A but no H

– 1.2% LVEF decrease; 0.3% symptomatic

• In 759 patients pre-treated with H and chemotherapy – 1.7% LVEF decrease; 0.1% symptomatic

• In 2201 A and H naïve patients– 1.7% LVEF decrease; 0.2% symptomatic

Perez EA, ESMO 2006

Effect of tumor selection and treatment selection on response

T-FEC T-FEC + H

pCR 26.3 % 66.7 %

pCR ER pos 27 % 61 %

pCR ER neg 25 % 70 %

pN0 78.9 % 90.3 %

Buzdar, JCO 2005

Early closure of the Study due to the strong advantage for H combination, after first 42 pts

EGF109085/CHERLOBSTUDY DESIGN

Tumor biopsy for histological diagnosis and IHC evaluation of tissue biomarkers

Stage II-IIIA, HER2 +

A: CT + Trastuzumab

Random

Surgery within 5 weeks from the last administration of CT and after at least 1 week from the last administration of lapatinib

and/or trastuzumab

B: CT + LAPATINIB C: CT + LAPATINIB + Trastuzumab

DOSES AND TREATMENT REGIMENS

Arm A: Paclitaxel 80 mg/m2 weekly for 12 weeks → FE75C q 21 X 4 courses plus trastuzumab 4 mg/kg loading dose followed by 2mg/kg weekly

Arm B: Paclitaxel 80 mg/m2 weekly for 12 weeks → FE75C q 21 X 4 courses plus Lapatinib 1500 mg po daily

Arm C: Paclitaxel 80 mg/m2 weekly for 12 weeks → FE75C q 21 X 4 courses plus trastuzumab 4 mg/kg loading dose followed by 2mg/kg weekly plus Lapatinib 1000 mg po daily

Lapatinib and trastuzumab administration will start on the same day of the 1st infusion of CT, will continue throughout all the duration of the

treatment and will be discontinued 1 week before surgery

5FU 600 mg/m2, Epirubicin 75 mg/m2, Cyclophosphamide 600 mg/m2

EGF109077/LET-LOBSTUDY DESIGN

Tumor biopsy for histological diagnosis and IHC evaluation of tissue biomarkers

Stage II-IIIA, HR +, HER2 -

A: LETROZOLE + PLACEBO

x 6 mos

Random

B: LETROZOLE + LAPATINIB1500mg/die

x 6 mos

Surgery within 2 weeks after the last administration of study drug

BIOMARKER EVALUATIONThe following biomarkers will be evaluated, to define the inhibition of the down-stream pathways of EGFR-family:

- EGFR, HER2- pTEN, pAKT, pMAPK- Apoptosis with TUNEL Test- Ki 67

These parameters will be evaluated by IHC, on paraffin-embedded specimens obtained from diagnostic core biopsy of the primary lesion and from surgical specimens.

Fresh tumor tissue from core-biopsy must be snap frozen, to perform a microarray analysis of the gene expression profile before treatment and to evaluate its correlation with response.

PI Center

Prof PF Conte Modena

Dr L. Cavanna Piacenza

Dr L. Crinò Perugia

Prof D. Amadori Forlì

Prof S. Cascinu Ancona

Dr A. Ardizzoni Parma

Prof M. Aglietta Candiolo

Dr K. Cagossi Carpi

Dr C. Boni Reggio Emilia

Dr A. Michelotti Pisa

Dr S. Crispino Siena

Dr S. Barni Treviglio

Dr A. Bottini Cremona

PI Center

Dr G. Giardina Varese

Prof S. Iacobelli Chieti

Dr. M.Danova Pavia

Prof A. Llombart Lérida (Spain)

Dr. M. Margelí Badalona (Spain)

Dr. A. Guerreo Valencia (Spain)

Prof J. Jassem Gdansk (Poland)

Prof M. Untch Berlin (Germany)

Prof H. Cortes-Funes Madrid (Spain)

Prof M Verrill Newcastle, ( UK )

Prof. C. Szczylik Warsaw, (Poland)

Prof. C. Jackisch Offenbach, (Germany)

LOB TRIALS (EGF109085-EGF109077): Participating Centers

Molecular subtypes of breast cancer and clinical management

• Her2+ represents a distinct molecular subtype

• Her2+ tumors have a unique clinical behaviour (shorter DFI, more visceral and CNS metastases)

• Her2 + tumors exhibit a peculiar pattern of sensitivity to chemo and hormonal therapy

• Her2 targeting agents have dramatically changed the course of this disease and represent now the foundation of treatment in early and advanced disease