P. Neven

GYN ONCOL & MBC, UZ-KULeuven

OngoingClinical Research & Trials

Multidisciplinary Breast Centre

May 2007

Ten most frequently occuring tumours in Flanders, 2000 - 2001

Source: Vlaams Kankerregistratienetwerk, VLK

Age-specific incidence of breast cancer in women,

Flanders, 1997-2001

Source: Vlaams Kankerregistratienetwerk, VLKSABCS 2006 2003: A decrease in breast cancer incidence

May be the incidence will come down?

I. OngoingClinical Trials

May 2007

II. Ongoing MBC Research Projects

Prevention, Adjuvant, Metastatic

I. Clinical Trials

May 2007

Completed, Recruiting, Future Trials

Endocrine Therapy, Chemotherapy, Targeted Therapy

Recently Closed Clinical Trials

May 2007

Adjuvant: BIG-1-98, TEAM, (E-)ZOFASTTACT, FEC-TXT (dd), Caelyx-EndoxanHERA, AC-AT,

Metastatic: Lapatinib trials, Tam + Iressa,EFECT, Lapatinib + Zarnestra, …

Radiotherapy: MSP-trial

Recruiting Clinical Trials

May 2007

Prevention: IBIS-2 DCIS/High Risk

Neo- Adjuvant: Taxotere-Xeloda-Herceptin

Adjuvant: SOFT, TEXT, TAGAS,Pregnancy (pharmacokinetics & outcome)

Metastatic: MoAb IGF-1R, FINDER-2, Vinflunin, Oral Navelbine,Xeloda +/- Sutent, BIBW, HKIEye trial (Maxidex vs Lacrystat Taxotere related dacrocystostenosis)

Future Clinical Trials

May 2007

Neo- Adjuvant: Neo-AlltoNeoadjuvant Paclitaxel + Herceptin +/- Pertuzumab

Adjuvant: Fertility trial, SOLE, ALTTOMINDACT, CASA

Metastatic: Lapatanib +/- Pazopanib

Recruiting Clinical Trials

IBIS-2 DCIS (tamoxifen standard)High Risk (placebo standard)

0

10

20

30

40

50

21

T(n=3116)

A (n=3125)

48

Number ofcases

12

T(n=2372)

E(n=2352)

26

T(n=2575)

L(n=2582)

26

14

ATAC IES MA17 BIG 1-98

T(n=4007)

L (n=4003)

28

16

Incidence of Contralateral Breast Cancers

Aromatase Inhibitors versus Tamoxifen

Why IBIS-II?Prevention

Breast Cancer Prevention

Postmenopausal Women

OngoingClinical Trials

May 2007

IBIS-2: 20 countries recruiting

Prevention: Placebo vs Anastrozole 36/1516ER+ DCIS: Tamoxifen vs Anastrozole 63/1014

Late age 1st pregnancy, parity, age menopause, breast density, familial history, LCIS, ADHSubprotocol: Bone, Lipid, Cognitive function

IBIS-2Recruiting Centres

St.Luc Brussel St.Pierre Brussel VUB Brussel Virga Jesse Hasselt St.Elisabeth Namen St.Augustinus Wilrijk Erasmus Brussel Bordet Brussel Heilig Hart Leuven OLVrouwZH Aalst ZOL Genk Clinique St.Pierre Ottignies CHR Citadelle Luik Brugmann Brussel Centre Hospitalier de l’Ardenne

If you have small cell LCIS,NSABP-P1 included 850 such patients7-years of follow-upTamoxifen versus PlaceboEvents13 (Tam) vs 38 (Placebo)If placebo: incidence of event is 1-2%

Recruiting Clinical Trials

FINDER-II

2nd line Metastatic Endocrine

First Line: TTP Benefit of Fulvestrant over Tamoifenin ER+ & PgR+ Patients*

Howell et al. JCO 2004; 22: 1605-13

Proportionnotprogressed

1.0

0.8

0.6

0.4

0.2

0.00

TTP (days)

100 200 300 600400 500 700 800

Hazard ratio = 0.85 CI (0.63–1.15); p=0.31

Median TTP: Fulvestrant: 11.4 monthsTamoxifen: 8.5 months

FulvestrantTamoxifen

*Retrospective analysis

ORR F 44.3% vs T 29.8%; p=0.02

Fulvestrant 250 mg/month Provides Long-term Downregulation of ER Levels

Gutteridge et al. SABCS 2004

Mean ERH-score

Time on treatment

Pre-treatment

(n=29)

300

250

200

150

100

50

04-6

weeks (n=26)

6months (n=20)

PD(n=8)

p=0.01

p=0.001

Fulvestrant induces dose-related ER downregulation(PgR and Ki67)*

Robertson et al. Cancer Res 2001; 61: 6739–6746

-60

-50

-40

-30

-20

-10

0

Placebo(n=29)

Fulvestrant50 mg (n=31)

Fulvestrant 125 mg (n=32)

Fulvestrant250 mg (n=32)

–13%

–39%

–50%

–59%

Changefrom baseline(%)

125 136 124 113Pre-treatmentmean H-score

*Data not shown

Finder-II

Fulvestrant HD

135 postmenopausal women with HR+ ABC after failure on one prior endocrine therapy

Progression

3-monthly follow-up

Endpoints

TTP (primary)

ORR

CB

Safety

Fulvestrant LD

HD, high-dose (500 mg IM on Day 0, 500 mg on Days 14 and 28 and 500 mg every 28 3 days thereafter)LD, high-dose (500 mg IM on Day 0, 250 mg on Days 14 and 28 and every 28 3 days thereafter)AD, approved dose (250 mg IM every 28 3 days)

Randomisation 1:1

Fulvestrant AD

Finder II Finder II Overview of EligibilityOverview of Eligibility(2nd line Breast Cancer Treatment)(2nd line Breast Cancer Treatment)

12 Month 12 Month gapgap

YesYes

YesYes

NoNo

KEYKEY

Adjuvant TreatmentAdjuvant Treatment

Eligible (randomised into Eligible (randomised into study)study)

Not EligibleNot Eligible

First Line TreatmentFirst Line Treatment

R = RecurrenceR = Recurrence

P = ProgressionP = Progression

Patients who previously received adjuvant treatmentPatients who previously received adjuvant treatment

YesYes

Patients who were diagnosed with Advanced Breast CancerPatients who were diagnosed with Advanced Breast Cancer

Eligible?Eligible?

R

R

R

R PYesYes

P

EBCEBC ABCABC

Regulatory Definition of 2Regulatory Definition of 2ndnd line Breast Cancer line Breast Cancer

Current & Future Clinical TrialsTargeted Therapies

ALTTO

Adjuvant

Two Targets, One DrugLapatinib Profile

Lapatinib is a novel oral dual-tyrosine kinase inhibitor with specificity for the ErbB-1 andErbB-2 receptors

Belongs to the 4-anilinoquinazoline class of tyrosine kinase inhibitors

Binds reversibly to the cytoplasmic ATP-binding site of the kinase, thereby preventing receptor phosphorylation and activation

GW572016

2

N

N

NH

O

O

NH

SO

O

CH3

Cl

F

S

CH3

OHO

O

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine

Lapatinib

ALTTO STUDY DESIGN

Four-arm, randomised, open-label and multicentre study in women with primary breast cancer that over expresses or amplifies HER2.

Sample Size 8000 patients Primary Endpoint: DFS Secondary Endpoints

OS TTR (time to recurrence) TTDR (Time to distant recurrence) Safety and tolerability

Proposed start 2Q07 Study duration: 5 years (4 years for enrolment and 1 year as follow-

up) 2 Interim analyses (at 600 and 1000 DFS events, approximately)

ALTTO STUDY DESIGN

4 Arms: Trastuzumab for 52 wks Lapatinib for 52 wks Trastuzumab + Lapatinib for 52 wks Trastuzumab for 12 wks, 6 wk washout, Lapatinib for 34

wks

Treatment Schema 1 - all (neo-)adjuvant chemotherapy completed prior to administering targeted therapy

Treatment Schema 2 - targeted therapy is initiated after (neo)adjuvant anthracycline-based chemotherapy and given concurrently with weekly paclitaxel

BASE LINE

Lapatinib 1500 mg/day(+ radiotherapy when indicated)

Trastuzumab 3- weekly8mg/kg then 6mg/kg

(+ radiotherapy when indicated)

Lapatinib 1500mg/day for 34 wks

Trastuzumab 4mg/kg then 2mg/kg weekly for

12 wks

52 Weeks

Central Determined

HER 2positive

Lapatinib 1000mg/day + Trastuzumab

3- weekly8mg/kg then 6mg/kg

(+ radiotherapy when indicated)

6 weeksWashout

RANDOMISATION

Surgery, complete

Neo-adjuvantChemotherapy

LVEF 50%

Patients with ER or PgR-positive tumours receive endocrine therapy selected according to menopausal status: endocrine therapy will be started after the end of the chemotherapy, will be administered concurrently with targeted

therapies and will be planned for at least 5 years

(+ radiotherapy when indicated)

LocalDetermined

HER 2positive

T 2 mg/kg weekly+

paclitaxel 80 mg/m2 weekly

L 1500 mg/day L 1500 mg/day + +

paclitaxel 80 mg/mpaclitaxel 80 mg/m22 weekly weekly

Su

rgery

Lapatinib (L)1500 mg/day

Trastuzumab (T)

4 mg/kg, then 2 mg/kg weekly

L 1000 mg/day +

T 4 mg/kg, then 2 mg/kg weekly

L 1000 mg/day +

T 2 mg/kg weekly+

paclitaxel 80 mg/m2 weekly

FE

C x 3 cou

rses

L 1500 mg/dayL 1500 mg/day

T 6 mg/kg at 3 week intervals

L 1000 mg/day +

T 6 mg/kg at 3 week intervals

NEO - ALTTO STUDY DESIGNNEO - ALTTO STUDY DESIGN(T>2 cm, Nx, M0, FISH +, IHC 3+)(T>2 cm, Nx, M0, FISH +, IHC 3+)

6 weeks 12 weeks 9 weeks 34 weeks

Tumor biopsyPET

Tumor biopsy

New drugs for targetting HER-1 / HER-2 / …Dual-Target HER-1 Drugs in the Pipeline

Lapatinib HER-1, HER-2 GSK Phase III breast

HKI-272 HER-1, HER-2 Wyeth Phase II breast BIBW-2992 HER-1, HER-2 Boehringer Phase II breast AEE788 HER-1, HER-2, VEGF Novartis Solid tumours BMS-599626HER-1, HER-2 BMS Solid Tumours CI-1033 HER-1, HER-2, HER-4 Pfizer Phase II breast …

Metastatic

Recruiting Clinical Trials

Exemestane +/-IGF-1R

1st Line Metastatic Endocrine

Targetted Therapies

IGF and its receptorImportant mediators of cell growth

Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer

IGF regulates the malignant phenotypeIGF is a strong breast cancer mitogenThere is cross talk between ER and IGF signalling

Non-genomic or genomic ERIGF is a regulator of estrogen-mediated growthIGF induces proliferation of ER+ breast cancer cellsUpregulation in tamoxifen-resistant breast cancer cells

Combining Endocrine and Biological Agents in M+ Breast Cancer

IGF

Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer

IGFR is Tyrosine Kinase type 1 receptorSmall molecules and MoAbMonoclonal AB

IGF-1R

Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer

Exemestane + MoAb/IGF-1R vs Exemestane

ER+ First Line Measurable MetastaticRandomized (1:1) and Open Label150 patients

PFS

CB, Safety, PK parameters, CTC markers for expression of IGF-1R, HRQoL

CP 751,871 // 20mg/kg // q3wArm A Exemestane 2.5mg + CP Fulvestrant + CP q4wArm B Exemestane 2.5mg CP

Pfizer

Prophylactic mastectomy and subclinical breast pathologies

HER-2 expression by body weight

Arthralgia and AIs

The prognostic value of PR in breast cancer

LHRH-agonists to protect ovarian function in ER-pos BrCa

The continuous importance of tamoxifen as an adjuvant therapy

Endometrial thickness on AI-switch

MMP in breast cancer

Associations between ER/ PR/ HER2 expression in operable BrCa

II. Own Clin. And Basic ResearchRecently Published …(leaving out clin. trials)

May 2007

Early relapse by ER/ PR/ HER2 expression: “Improving NPI”

HER-1 / uPAR in triple negative and other breast cancers

PET-CT in staging large and locally advanced breast cancer

Correlations LN-status - ER/PR/HER-2, LN-status - age

Correlations Age - ER/PR/HER-2 expressionRetrospective and prospective registration study: Breast cancers & Mirena

Postmenopausal breast cancer characteristics by use of HRT

Paloprai, ER-PR+ breast cancers, Fulvestrant and uterine volume

OngoingClinical & Basic Research

May 2007

Molecular genetic analysis as an addition to the morphologic classification of breast cancersThe clinical relevance of protease in breast cancer: matrix metalloproteinasen and cathepsines Menopausal symptoms of breast cancer therapiesProteonomics in breast cancerGenetics in breast and ovarian cancer

PhD topics

Breast Cancer Prognosis

Global molecular genetic approachER - ER +

basal-like HER-2 + luminal type (subtype A, B/C)

?

DFS in 1962 operable breast cancersSubgroup Analysis by ER/PR/HER-2

Mean

subgroup

AllNNN NNP PNN PNP PPN PPP

Numbers173 91 191 31 1361 115 1962

Age at diagnosis55,65 56,37 60,53 58,68 57,72 51,70 57,41

NPI4,95 5,04 4,33 4,61 4,11 4,98 4,30

DFS at 3.5 yrs of FU (%)84.40 75.81 89,49 80,42 93,76 81,47 90,16

Thesis Lic Biomed. Sc. (S. Pintens) and Project Co-Assist. (O. Brouckaert)

Early breast cancer relapse by ER/PR/HER-2 – n=1962

UZ Leuven 2000 - 2005

O Brouckaert & S Pintens DFS by ER/PR/HER-2

Annual incidence of relapseNNN Early relapse

Can we improve NPI?

Subgroup DFS (%)NPI <3,4 96,18

NPI 3,4-5,4 91,81

NPI > 5,4 80,69

NPI <3.4 HER-2- 96,45

NPI <3,4 HER-2+ 90,62

NPI 3,4- 5,4 HER-2- 93,24

NPI 3.4- 5,4 HER-2+ 82,84

NPI > 5,4 HER-2- 83,37

NPI > 5,4 HER-2+ 68,08

The futureCyclin E as a prognostic factor

Stage I-II breast cancer: Total cyclin E predicts Survival

Interaction ER-status and age by HER-2 status

N = 2227

ER

+ P

robabilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

HER-2 status Negative (N = 1971)Positive (N = 256)

ER

+ P

robabilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

HER-2 negative

HER-2 positive

The interaction between ER and age is HER-2 dependentThe negative association between ER and HER-2 is age dependent

ER/PR and HER-2

Interaction PR-status and age by HER-2 status

The interaction between PR and age is HER-2 dependentThe negative association between PR and HER-2 is age dependent

ER/PR and HER-2

HER-2 status Negative (N = 1971)Positive (N = 256)

PR

+ P

robabilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

HER-2 negative

HER-2 positive

N = 2227

PR

+ P

robabilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

Interaction HER-status and age by ER/PR

The interaction between HER-2 and age is ER/PR dependentThe older one is the less likely HER-2 positive is only if the tumour is ER-positive

ER/PR and HER-2

N = 2227

HER

-2+

Pro

babilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

ER/PR status ER-/PR- (N = 281)ER+/PR- (N = 230)ER+/PR+ (N = 1716)

HER

-2+

Pro

babilit

y

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Age (years)

20 30 40 50 60 70 80 90 100

Breast Cancer: Adjuvant TherapyTreatment Side Effects

Quality of Life

Adjuvant Therapy

Lani Morales

PROGRESS IN BREAST CANCER ADJUVANT THERAPYPROGRESS IN BREAST CANCER ADJUVANT THERAPY

L-PAM, MFL-PAM, MF

CMF x 6CMF x 6AC x 4AC x 4

FAC FAC FEC x 6 FEC x 6A(E) A(E) CMF CMF

AC x 4 AC x 4 Paclitaxel x 4 Paclitaxel x 4

TAC x 6TAC x 6FEC FEC docetaxel docetaxel

AC AC paclitaxel dose-dense paclitaxel dose-dense

±±

++

++++

++++++

++++

++++++

±±

++

Average treatment Average treatment effecteffect

Financial Financial toxicitytoxicity

1970’s1970’s 1980’s1980’s 1990’s1990’s 2000’s2000’s

Successive generations of adjuvant CT regimensSuccessive generations of adjuvant CT regimens

Adapted from G. HortobagyiAdapted from G. Hortobagyi

d) d) 20.000 $ 20.000 $c) c) 13.800 $13.800 $b) b) 7.400 $ 7.400 $a) a) 800 $ 800 $

++ ADJUVANT AIs ++

+ Herceptin: 40.000 euro

Multidisciplinary Breast Centre- UZLeuvenMay 2007

Coordinator: MR Christiaens Radiology: A Van Steen, C Van Ongeval Pathology: M Drijkoningen Surgery: MR Christiaens, A Smeets Gynaecology: P Neven, K Leunen, F Amant, P Berteloot Plastic Surgery: M Vandevoort, G Fabre Med Oncology: R Paridaens, H Wildiers Radiotherapy: W Van den Bogaert, E Van Limbergen, C Weltens Human Genetics: E Legius KanActief: L Serrien Data Manager: W Hendrickx Breast “nurses”, Physiotherapists, Trial “nurses” PhD: I Van den Bempt, A Smeets, J De Cock Assistents

Centrum VergaderingMedical DirectorHead of departments

PathologyRadiologySurgeryMed OncolRadiotherapyObstet & Gyn

I hope I gave you a touch of ourongoing

Clinical Research & Trial Activities

Multidisciplinary Breast Centre