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2006 European Breast Cancer Meeting Stockholm, Sweden 20–21 May 2006. USING PROGNOSTIC & PREDICTIVE FACTORS IN BREAST CANCER. Fatima Cardoso, MD Jules Bordet Institute & TRANSBIG. PROGNOSTIC FACTOR. %. Treat. A. Treat. B. +. -. PREDICTIVE FACTOR. Case 1. Case 2. Treat. B. %. %. - PowerPoint PPT Presentation
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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
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
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)
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
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
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
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
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
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
Slamon D., SABCS 2005
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
Slamon D., SABCS 2005
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
Slamon D., SABCS 2005
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