Download ppt - USING PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCER

Fatima Cardoso, MDFatima Cardoso, MD

Jules Bordet Institute & TRANSBIGJules Bordet Institute & TRANSBIG

2006 European Breast Cancer Meeting Stockholm, Sweden

20–21 May 2006

USING PROGNOSTIC & PREDICTIVE FACTORS

IN BREAST CANCER

PROGNOSTIC FACTOR

%% Treat. ATreat. A

Treat. BTreat. B

++ -

PREDICTIVE FACTOR

Case 1Case 1 Case 2Case 2

%% %%

++ ++-- --

Treat. BTreat. B

Treat. ATreat. A

Treat. BTreat. B

Treat. ATreat. A

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

Who needs a treatment?Who needs a treatment?

PREDICTIVE FACTORSPREDICTIVE FACTORS

Which treatment is best?Which treatment is best?

THERAPEUTIC CHOICES

AVOID UNDER AND OVER TREATMENTAVOID UNDER AND OVER TREATMENT INDIVIDUALIZE TREATMENTINDIVIDUALIZE TREATMENT

WHY DO WE NEED PROGNOSTIC AND PREDICTIVE FACTORSWHY DO WE NEED PROGNOSTIC AND PREDICTIVE FACTORS

ER- ER+

RFS

Basal-likeBasal-like11

HER-2-likeHER-2-like LuminalLuminal11

LuminalLuminal22

LuminalLuminal33

Basal-likeBasal-like22

Adapted from Sotiriou et al, PNAS, 2003Adapted from Sotiriou et al, PNAS, 2003

BC GENE EXPRESSION PATTERNS and OUTCOMEBC GENE EXPRESSION PATTERNS and OUTCOMEMolecular (re-)classification of BCMolecular (re-)classification of BC

PROGRESS IN ADJUVANT CHEMOTHERAPY FOR PROGRESS IN ADJUVANT CHEMOTHERAPY FOR BREAST CANCERBREAST CANCER

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 Average treatment effecttreatment effect

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 with permission from G. HortobagyiAdapted with permission 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 TRASTUZUMAB +++

• New prognostic factors accepted: HER-2, vascular invasion

• Node+ 1-3: in average risk group, if HER-2– and no vascular invasion

St Gallen 2005 Consensus: What’s new?

Beyond St Gallen 2005 …

uPA, PAI-1uPA, PAI-1

Cyclin ECyclin E

Genomic signatures

Genomic signatures

Oncotype DX*(predictive & Px)

Oncotype DX*(predictive & Px)

Topo-II-Topo-II-*Genomic Health

uPA-PAI-1uPA-PAI-1

CLINICAL RELEVANCE OF uPA & PAI-1 IN PRIMARY BREAST CANCER

uPA and PAI-1: first novel tumor biological factors in breast cancer with clinical relevance validated at highest level of evidence (LOE I)

Standardized quality assured ELISA tests: Sweep et al, Br J Cancer 78: 1434-41, 1998

Prospective multi-center therapy trial („Chemo N0“): Jänicke et al, JNCI 93: 913-20, 2001

EORTC RBG meta analysis (n=8,377): Look et al, JNCI 94:116-28, 2002

Recommended for clinical risk assessment:AGO Therapy Guidelines „breast cancer“ (since 2002):www.ago-online.de

N. Harbeck – used with permission

uPA AND PAI-1

FIRST NOVEL TUMOR BIOLOGICAL FACTORS IN BC WITH

LEVEL 1 OF EVIDENCE

WHY ARE THEY NOT WIDELY USED?

1. ELISA not commonly used in pathological practice

a. Biochemistry lab required

b. Further personnel training required

c. €€££$$ required

2. Frozen tumor specimen required

3. Large quantity (100 µg) required

Target population = small tumors – feasible ?

4. Population used in validation studies: Interaction with ER status not well defined (?)

HOW CAN THEY BECOME WIDELY USED?

1. Refining ELISA test– less tissue

2. Alternative techniques– other protein assays– gene expression

3. Further validation according to ER status

ALL ONGOING

uPA AND PAI-1

FIRST NOVEL TUMOR BIOLOGICAL FACTORS IN BC WITH

LEVEL 1 OF EVIDENCE

GENOMIC SIGNATURESGENOMIC SIGNATURES

BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission

IMPROVED RISK ASSESSMENT OF EARLY BREAST IMPROVED RISK ASSESSMENT OF EARLY BREAST CANCER THROUGH GENE EXPRESSION PROFILINGCANCER THROUGH GENE EXPRESSION PROFILING

microarraymicroarrayGene-expression profileGene-expression profile

Good signature

Poor signature

N Engl J Med, Vol 347 (25), Dec. 2002N Engl J Med, Vol 347 (25), Dec. 2002

~4% die of breast cancer~96% survive breast cancer

~50% die of breast cancer~50% survive breast cancer

TRANSLATING TRANSLATING MOLECULAR MOLECULAR KNOWLEDGEKNOWLEDGEINTO EARLY INTO EARLY

BREAST CANCER BREAST CANCER MANAGEMENTMANAGEMENT


Audited Audited clinical clinical

datadata

INDEPENDENT VALIDATION : DESIGNINDEPENDENT VALIDATION : DESIGN

RNA

Achieved Achieved n = 307n = 307

Target Target n = 400n = 400

AmsterdamAmsterdam

Gene expression Gene expression profilingprofiling

• Agilent platformAgilent platform• 70-gene prognostic 70-gene prognostic custom designed custom designed chipchip

High or low gene signature

risk

Clinical dataClinical data

« Local » pathological data« Local » pathological data

BrusselsBrusselsComparison of Comparison of clinical vs gene clinical vs gene

signaturesignatureassessment of assessment of prognostic riskprognostic risk

EndpointsEndpoints1. TDM1. TDM2. OS 2. OS 3. DMFS, DFS3. DMFS, DFS

Tissue samplesTissue samples UK (Guy’s, Oxford) : UK (Guy’s, Oxford) :

1984 => 19961984 => 1996 France (IGR, CRH) : France (IGR, CRH) :

1978 => 19981978 => 1998 Sweden (Karolinska) : Sweden (Karolinska) :

1980 => 19901980 => 1990

• Node negative, untreatedNode negative, untreated• < 60 years old< 60 years old• > 5 years follow-up> 5 years follow-up• T1, T2T1, T2• Tumor cell % > 50%Tumor cell % > 50%

Centrally Centrally reviewed reviewed path data path data

(Milan)(Milan)


OVERALL SURVIVAL by GENE SIGNATURE RISKOVERALL SURVIVAL by GENE SIGNATURE RISKAmsterdam/Agendia SignatureAmsterdam/Agendia Signature

Year

Pro

babili

ty0

.00

.20

.40

.60

.81

.0

0 2 4 6 8 10 12 14

Patients Events Risk group

113 16 Genetic low risk194 66 Genetic high risk

113 112 105 101 98 82 69 45 38 CLR194 185 168 147 130 110 90 53 39 CHR

Number at risk

10-year OS89% (81%-94%)

10-year OS70% (62%-76%)

Average Survival HR Average Survival HR 2.66 2.66M. Buyse et al. JNCI 2006. In pressM. Buyse et al. JNCI 2006. In press


TRANSBIG INDEPENDENT VALIDATION The best signature?

Amsterdam’s Signature70 genes

Rotterdam’s Signature76 genes

TEST ALL IN VALIDATION SERIES & DECIDE

Only few genes in common …Only few genes in common …But similar biological pathwaysBut similar biological pathways

Brussels’ GGI signature


OVERALL SURVIVAL by GENE SIGNATURE RISKOVERALL SURVIVAL by GENE SIGNATURE RISKRotterdam/Veridex SignatureRotterdam/Veridex Signature

Year

Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

PatientsEvents Risk group

55 6 Good signature143 39 Poor signature

Logrank P= 0.0126

55 55 52 51 46 38Good signature143 138 124 106 98 89Poor signature

Number at risk

HR (95% CI): 2.87 (1.21-6.82)

5-year survival:

low risk group: 0.98 (0.88-1.00)

high risk group: 0.84 (0.77-0.89)

10 year survival:

low risk group: 0.87 (0.73-0.94)

high risk group: 0.72 (0.63-0.78)

C. Desmedt et al. Presentated at: EBCC 2006C. Desmedt et al. Presentated at: EBCC 2006

CONCLUSIONS VALIDATION PHASECONCLUSIONS VALIDATION PHASE

• The Amsterdam 70-gene signature has been independently The Amsterdam 70-gene signature has been independently validated validated

• The Rotterdam 76-gene & Genomic Grade signatures have been The Rotterdam 76-gene & Genomic Grade signatures have been independently validated using the same TRANSBIG validation independently validated using the same TRANSBIG validation seriesseries

• The performances of the signatures are similarThe performances of the signatures are similar

• There is a strong time dependency of all signatures (better There is a strong time dependency of all signatures (better predictors of predictors of EARLY RELAPSEEARLY RELAPSE), which was not seen for the ), which was not seen for the clinical riskclinical risk

• The Amsterdam 70-gene test is robust (laboratory reproducibility) The Amsterdam 70-gene test is robust (laboratory reproducibility) and available for patient diagnostic testingand available for patient diagnostic testing

• GREEN LIGHT FOR MINDACT TRIAL!GREEN LIGHT FOR MINDACT TRIAL!

Evaluate Clinical-Pathological risk and 70-gene signature risk

Clinical-pathological and 70-gene both

HIGH risk

Discordant casesClin-Path HIGH70-gene LOW

Clin-Path LOW70-gene HIGH

Clinical-pathological and 70-gene both LOW

risk

Use Clin-Path risk to decide Chemo or not

Use 70-gene risk to decide Chemo or not

55% 32% 13%

R1

Chemotherapy

N=3300 N=780

Endocrine therapy

EORTC-BIG MINDACT TRIAL DESIGN6,000 Node negative women

N=1920

Potential CT sparing in 10-15% pts

GENOMIC GRADEGENOMIC GRADE

Histologic Grade

G1

G2

G3

Genomic Grade

GG1

GG2

GG3

Sotiriou et al., ASCO 2005

• Poor inter observer reproducibility• G2: difficult treatment decision making, under- or over treatment likely

• Findings consistent across multiple data sets and microarray platforms• More objective assessment• Easier treatment decision-making• High proportion of genes involved in cell proliferation !

C. Sotiriou – used with permission

HistologicalHistological Grade 3Grade 3

HG3

GENOMIC GRADE IN EACH OF THE GENOMIC GRADE IN EACH OF THE HISTOLOGIC GRADE SUBGROUPSHISTOLOGIC GRADE SUBGROUPS

Genomic Grade 1 Genomic Grade 3

Histological Grade 2Histological Grade 2

HG2

Histological Grade 1Histological Grade 1

HG1

C. Sotiriou – used with permissionC. Sotiriou et al. JNCI 2006

Oncotype DXOncotype DX

NSABP & NSABP & Genomic HealthGenomic Health

MULTI GENE RT-PCR ASSAY FOR PREDICTING RECURRENCE IN NODE NEGATIVE BC PATIENTS

250 candidategenes

Tested usingRT-PCR

Three studies

21 GENE PREDICTORRecurrence score

low intermediate high

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENER

PGRBcl2

SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

GSTM1

REFERENCEREFERENCEBeta-actinBeta-actin

GAPDHGAPDHRPLPORPLPO

GUSGUSTFRCTFRCBest RT-PCR performance Best RT-PCR performance

and most robust predictorsand most robust predictors

CD68

BAG1

Paik et al, N Engl J Med 2004Paik et al, N Engl J Med 2004

THREE BREAST CANCER STUDIES USED TO SELECT THREE BREAST CANCER STUDIES USED TO SELECT CANDIDATE GENES FOR A RECURRENCE SCORE CANDIDATE GENES FOR A RECURRENCE SCORE UNDER UNDER

TAMOXIFEN TREATMENTTAMOXIFEN TREATMENT

Recurrence score for TAM-treated pts Recurrence score for TAM-treated pts established and subsequently validatedestablished and subsequently validated

0 2 4 6 8 10 12 14 16

Years

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

DR

FS

Low R isk (R S < 18) Intermediate R isk (R S 18 - 30) H igh R isk (RS 31)

338 pts

149 pts

181 pts

B14-RESULTSB14-RESULTSDRFS—Low, Intermediate, High RS GroupsDRFS—Low, Intermediate, High RS Groups

Paik et al, N Engl J Med 2004Paik et al, N Engl J Med 2004

PREDICTIVE MARKERS

HER-2 neu

95% Negative predictive value

<5% chances of responding to TRASTUZUMAB (HER-2) or to HT (ER)

30-70% Positive predictive value

Accepted Predictive Markers

In Breast Cancer

ER/PgR

Oxford Oxford OverviewOverview

20002000

St Gallen St Gallen Consensus Consensus

PanelPanel20032003

NIH NIH Consensus Consensus

PanelPanel20002000

ASCOASCOGuidelinesGuidelines

20012001

30%-70% chances of responding to HT (ER) & 40%-50% of responding to

TRASTUZUMAB (HER-2)

PREDICTIVE MARKERS FOR CHEMOTHERAPY

Topo II non-amplified

Time (Months)

12 360 24 48

% E

FS

0.4

0.6

0.8

1.0

0.3

0.5

0.7

0.9

Topo II amplified

Time (Months)

12 360 24 48

% E

FS

0.4

0.6

0.8

1.0

0.3

0.5

0.7

0.9

No pts at risk:

Anthra-Based

Anthra-BasedCMF

CMF

15 14 11 911 Anthra 23 21 17 12168 7 4 44 CMF 15 15 12 1112

Time to first event (months)0 12 24 36 48 60 72 84

%

0.0

0.2

0.4

0.6

0.8

1.0

CMF56 51 47 37 23 14HEC64 62 53 41 31 23

CMF

HEC

HR=1.26 (0.63-2.50)p=0.51

Topo II pos.

Time to first event (months)0 12 24 36 48 60 72 84

%

0.0

0.2

0.4

0.6

0.8

1.0

CMF 52 48 39 30 24 19HEC 52 50 47 37 29 24

HEC

CMF

HR=0.66 (0.32-1.36)p=0.25

p-value interaction test: 0.13

Topo II neg.

FISHFISH

IHCIHC

ADJUVANT SETTINGCMF vs. ANTHRA-BASED TOPO II CMF vs. ANTHRA-BASED TOPO II RESULTS RESULTS

Di Leo A et al, Clin Cancer Res, 2002Di Leo A et al, Clin Cancer Res, 2002

All pts with HER-2 amplificationAll pts with HER-2 amplification

Di Leo A et al, Ann Oncol 2001Di Leo A et al, Ann Oncol 2001

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

6 x Docetaxel and Carboplatin75 mg/m2 AUC 6

1 Year Trastuzumab

N=3,222

1 Year Trastuzumab

ACT

ACTH

TCH

Her2+(Central FISH)

N+or high risk N-

4 x AC60/600 mg/m2

4 x Docetaxel100 mg/m2

Slamon D., SABCS 2005

BCIRG 006

Stratified by Nodes and Hormonal Receptor Status

Disease Free Survival%

Dis

ease

Fre

e0.

50.

60.

70.

80.

91.

0

0 1 2 3 4 5

Year from randomization

77%

86%

80%

73%

84%

80%86%

93%

91%

Patients Events

1073 147 AC->T

1074 77 AC->TH

1075 98 TCH

HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001

HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002


AC->TH

AC->T

TCH

DFS CO-AMPLIFIED TOPO II BY ARM%

Dis

ea

se F

ree

Months

0.5

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48 54

Patients Events Treatment

227 23 AC->T

265 13 AC->TH252 21 TCH

Logrank P= 0.24

TCH

AC->TH

AC->T


DFS NON CO-AMPLIFIED TOPO II BY ARM%

Dis

ea

se F

ree

Months

0.0

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48 54

Patients Events Treatment

458 92 AC->T472 45 AC->TH446 54 TCH

Logrank P= <0.001

TCHAC->TH

AC->T


HER-2 AND TOPOISOMERASE-IIHER-2 AND TOPOISOMERASE-II PROMISING POTENTIAL PROMISING POTENTIAL PREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACYPREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACY

HOW TO OBTAIN LEVEL 1 HOW TO OBTAIN LEVEL 1 EVIDENCEEVIDENCE

LARGE PROSPECTIVE TRIALSMETA-ANALYSIS

HER-2 AND TOPOISOMERASE-IIHER-2 AND TOPOISOMERASE-II AS POTENTIAL PREDICTIVE AS POTENTIAL PREDICTIVE MARKERS OF ANTHRACYCLINE EFFICACY: A META-ANALYSISMARKERS OF ANTHRACYCLINE EFFICACY: A META-ANALYSIS

DANISH TRIALDANISH TRIALFEC vs CMFFEC vs CMF

UK TRIALUK TRIALEECMF vs CMFCMF vs CMF

NCIC-CTG TRIALNCIC-CTG TRIALCEF vs CMFCEF vs CMF

BELGIAN TRIALBELGIAN TRIALEC vs CMFEC vs CMF

Tampere University LaboratoryTampere University LaboratoryCentral evaluation of HER-2/TOPO II Central evaluation of HER-2/TOPO II gene amplification by FISHby FISH

Correlation with outcome of CMF or anthracycline-based therapy with 4,500 tumor samples

TOP TRIAL OR « TRIAL OF PRINCIPLE »Operable tumors, > 2 cm

ER-negative

EPIRUBICIN 100 mg/m² x 4

SURGERYSURGERY

Docetaxel x 4Radiotherapy ± HT

Hypothesis : pCr in HER-2 / Topo2 co-amplified tumors pCr in HER-2 - / basal-like 1 tumors

Incisional biopsy

Snap frozen sample

HER2/Topo2 FISH analysis(Vysis probe)

Genomic signatureof response to anthracyclines

Inflammatory or LABC ER-negative

EPIRUBICIN 100 mg/m² x 6dose dense / 2w + G-CSF

Gene expression

analysis

EORTC-BIG-p53 TRANSLATIONAL RESEARCH TRIAL: STUDY DESIGN

Target accrual= 1300 (872 p53-, 436 p53+)Hypothesis: ↑ DFS at 3 y by 5% in p53- and by 20% in p53+

RAND

Non Taxane armFEC100 or Canadian FEC

Taxane armT-T-T-ET-ET-ET

Sample 1: standard fixationIncisional biopsy

Sample 2: snap frozen

. Loc. adv.

. Infl.

. Large Operable

Local ± TAMtherapy

Local ± TAMtherapy

P53 pathway

P53 analysis

FRAGRANCE trial

4 - 6 months

Letrozole

15 days

MicroarrayAnalysis

MicroarrayAnalysis

Genomic signature of de novo AI resistance

MicroarrayAnalysis

Postmenopausal patients (no age limits)Non-candidates for CTT 2 cmStages I, II & IIIER and/or PgR+

INTEGRATING TRANSLATIONAL RESEARCH IN CLINICAL RESEARCH & PRACTICE

• MultidisciplinarityMultidisciplinarity

• Collaboration (between specialties, between centers…)Collaboration (between specialties, between centers…)

• Bench-to-bedside-to-benchBench-to-bedside-to-bench

• Biological material collectionBiological material collection (unethical not to do it!) (unethical not to do it!)

• Patient Patient selectionselection & treatment & treatment tailoredtailored to the individual to the individual

• New New technologiestechnologies, new , new statisticalstatistical methods… methods…

• Costs ??Costs ??

INDISPENSABLE and already ongoingINDISPENSABLE and already ongoing

EU fundingOther

Total expected costs:

€35, 000,000

EU funding €7,000,000

OTHER:National Funding

Pharmaceutical IndustryBiotechnology companies (Agendia)

Other grants

NATIONAL FUNDING FOR

NATIONAL PATIENTS

(indispensible)

MINDACT & TRANSBIG FUNDING - 1

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

BIG-TRANSBIG Team Bordet Fellows

Translational Research TeamM. Piccart