tailored therapies: prognostic & predictive factors f. cardoso, md jules bordet institute,...
TRANSCRIPT
TAILORED THERAPIES:TAILORED THERAPIES:PROGNOSTIC & PREDICTIVE FACTORSPROGNOSTIC & PREDICTIVE FACTORS
F. Cardoso, MDF. Cardoso, MDJules Bordet Institute, Brussels, BelgiumJules Bordet Institute, Brussels, Belgium
BELGIAN BREAST MEETING 2008
October 4-5, 2008
THE GOALS OF TREATMENT TAILORING
AVOID UNDER- AND OVER-TREATMENTAVOID UNDER- AND OVER-TREATMENT INDIVIDUALIZE TREATMENTINDIVIDUALIZE TREATMENT
New/better PROGNOSTIC New/better PROGNOSTIC FACTORSFACTORS
New/better PREDICTIVE New/better PREDICTIVE FACTORSFACTORS
MULTI-GENE TOOLS
MammaPrint™ (70-gene signature)MammaPrint™ (70-gene signature)
Genomic signatures
Genomic signatures
Oncotype DX(predictive & Px)
Oncotype DX(predictive & Px)
76-gene signature76-gene signature
Genomic gradingGenomic grading
uPA, PAI-1uPA, PAI-1
UNI-GENE TOOLS
NEW PROGNOSTIC BIOMARKERSNEW PROGNOSTIC BIOMARKERS
Tumorspecimen
SignatureDevelopm
ent Approache
s
Candidate Genes = Breast CancerBiology
Clinicaloutcome
Q-RT-PCR
“Candidate gene” approach
Signature
Clinicaloutcome
“Top-down” approach
Signature
Microarray
Biological
Hypothesis
ClinicalOutco
me
“Bottom-up” approach
Signature
Microarray
C Sotiriou – used with permission
4 assays commercially available…
Mammaprint 70-gene assay
OncotypeDX 21-gene Recurrence
Score
AviaraDx 2-gene H/I Ratio
MapQuant Dx™ Genomic Grade
Provider Agendia, Inc. Genomic Health, Inc. AviaraDx, Inc. Ipsogen SA.
Type of tissue sample
Fresh/Frozen FFPE FFPE Fresh/Frozen
Technology DNA Microarrays Q-RT-PCR Q-RT-PCR DNA Microarrays
Centrally certified laboratory (CLIA or ISO)
YES YES YES YES
Indication Stage I-II disease
tumor size 5 cm
node-negative +
Node positiveER+ & ER-
< 61 years of age
ER-positive
Treated with tamoxifen
node-negative & node positive
Stratify ER-positive
patients into groups with low or high risk of recurrence and good or poor response to endocrine therapy
Resolves grade 2 tumors into low-risk grade 1 or
high risk grade 3 tumors.
Specifically indicated for
invasive primary ER+ grade 2
tumors
Level of Evidence (I-V)
III II III III
FDA clearance YES NO NO NO
Availability EUROPE/USA USA USA EUROPE
Cost ~$3,200 ~$3,500 ~$3,000 ~$3,000C Sotiriou – adapted with permission
Several signatures shown to outperform current clinico-pathological parameters for treatment decision making
C Fan et al., N Engl J Med 355:560, 2006
21 genes
200+ genes
70 genes
500+ genes
DESPITE < 5% OVERLAP IN GENES, THERE WAS CLOSE TO 80% CONCORDANCE IN
PROGNOSTIC PREDICTION
CONCORDANCE OF PREDICTION RESULTS OF 5 DIFFERENT
PREDICTORS APPLIED TO THE SAME 295 CASES
DISSECTING GENE EXPRESSION SIGNATURES
AmsterdamNo (%)
70 genes
(Van de Vijver et al. NEJM, 2002)
35 (50)
6 (9)
34 (49)
10 (14)
4 (6)
7 (10)
9 (9)
ESR1 = luminal/basal
ERBB2 = Her2-neu
STK6 = proliferation/GGI
PLAU = stroma/invasion
STAT1 = immune response
VEGF = angiogenesis
NA = undetermined
RotterdamNo (%)
76 genes
(Wang et al. The Lancet, 2005)
17 (18)
2 (3)
30 (39)
1 (1)
6 (8)
4 (5)
30 (39)
Microarray Indices
C. Sotiriou – used with permission
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permissionApril April 2007 - Confidential2007 - Confidential
HR all endpoints strongest in the first 5 years after diagnosis
Time to distant metastasis
WITH ALL GENE SIGNATURES HR VARIES WITH TIME
ONCOTYPE DXONCOTYPE DX
Ready for use routine use in the clinic? Ready for use routine use in the clinic? NONO
CLINICALCLINICALVALIDATIONVALIDATION
The test identifies subsets The test identifies subsets with significantly differentwith significantly different
* risks of relapse * risks of relapse * chances of response* chances of response
The test is The test is * sensitive* sensitive* specific* specific* reproducible* reproducible
TECHNICALTECHNICALVALIDATIONVALIDATION
EXCEPT Interlaboratory variability NO (only level 2-3)
7070--GENE SIGNATURE (MAMMAPRINTGENE SIGNATURE (MAMMAPRINT))
Ready for use routine use in the clinic? Ready for use routine use in the clinic? NONO
CLINICALCLINICALVALIDATIONVALIDATION
The test identifies subsets The test identifies subsets with significantly differentwith significantly different
* risks of relapse * risks of relapse * chances of response* chances of response
The test is The test is * sensitive* sensitive* specific* specific* reproducible* reproducible
TECHNICALTECHNICALVALIDATIONVALIDATION
YES, but only in experienced labsNO (only level 3)
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
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%
R-T
Chemotherapy
N=3300 N=780
Endocrine therapy
EORTC 10041 BIG 3-04 trial MINDACT TRIAL DESIGN6,000 Node - & 1-3 N+ women
N=1920
Potential CT sparing in 10-15% pts
BIG-TRANSBIG Secretariat– Used with permissionBIG-TRANSBIG Secretariat– Used with permission
MINDACT ACCRUAL STATUSFirst patient screened February 2007 & First patient enrolled March 2007First patient screened February 2007 & First patient enrolled March 2007
As of 1/10/08: 1530 screened pts & 625 enrolled (first 800 – pilot phase As of 1/10/08: 1530 screened pts & 625 enrolled (first 800 – pilot phase – estimated in December)– estimated in December)
49 centers are open in 8 countries49 centers are open in 8 countries
Overall:Overall:– 44% of screened patients are enrolled– 79% of screened patients have a sample shipped
38%: N+38%: N+32%: less than 50% tumor cells 32%: less than 50% tumor cells 30%: late enrollment30%: late enrollment
AMENDEMENT: extended timelines, N+ eligible, and decrease of needed AMENDEMENT: extended timelines, N+ eligible, and decrease of needed % of tumor cells % of tumor cells will increase the ratio enrolled/screened will increase the ratio enrolled/screened
TAILORxTAILORxStudy DesignStudy Design
ARM AHormonal Therapy
A lone
Secondary S tudy Group 1RS < 11
ARM BHormonal Therapy
A lone
ARM CChemotherapy P lusHormonal Therapy
RANDOMIZEStratification Factors :
Tumor S ize , Menopausal S tatus ,P lanned Chemo, P lanned Radiation
Primary S tudy GroupRS 11-25
ARM DChemotherapy P lusHormonal Therapy
Secondary S tudy Group 2RS > 25
REGISTERSpecimen Banking
ONCOTYPE DX ASSAY
Pre-REGISTER Key Eligibility:Key Eligibility:
•Node-negative
•HR-positive
•Her2-negative
•Age < 75 years
•Candidate for chemo
Key Eligibility:Key Eligibility:
•Node-negative
•HR-positive
•Her2-negative
•Age < 75 years
•Candidate for chemo
Accrual: 2834 / 4,400 pts with RS 11-25
Non-inferiority design for RS 11-25
Courtesy J. Sparano
COMPARISON OF TAILORX AND MINDACT TRIALS
TAILORx MINDACT
Groups TBCI BIG
Population Node-neg, ER+ Node-neg (&+), ER+/-
Assay 21 gene ODX™ 70 gene Mammaprint®
Utility Scale &
Level of Evidence
+ or ++
II
+ or ++
III
Tissue FPET FPET, Fresh frozen, blood
No. ~7000 ~6,000
No. randomized 4,400 1,920
Randomized group RS 11-25 (40%) Discordant risk (32%)
Randomization Treat with HT +/- CT Treat according to
clinical vs. genomic risk
Non-randomized groups RS < 11: HT only
RS > 25: CT & HT
Both low risk (13%): HT only
Both high risk (55%): CT HT
Courtesy & adapted from M. Piccart
BEYOND FIRST PROJECTS…Node positive disease
GOOD PROFILE: SUFFICIENTLY LOW RISK
Courtesy of S. Mook; SABC 2007
34% ADJUVANT! HIGH RISK PATIENTS ARE LOW RISK BY THE 70-GENE PROFILE
0.00
0.25
0.50
0.75
1.00
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=55, 15 events)CAF-T (n=91, 26 events)
Stratified log-rank p = 0.97 at 10 years
Low risk (RS < 18)
Disease-Free Survival by Treatment
No benefit to CAF over time if low RS
0.0
00
.25
0.5
00
.75
1.0
0
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=47, 26 events)CAF-T (n=71, 28 events)
Stratified log-rank p = 0.033 at 10 years
High risk (RS ≥31)
Disease-Free Survival by Treatment
0.0
00
.25
0.5
00
.75
1.0
0
Dis
ease
-fre
e su
rviv
al
0 2 4 6 8 10
Years since registration
Tamoxifen (n=46, 22 events)CAF-T (n=57, 20 events)
Stratified log-rank p = 0.48 at 10 years
Intermediate risk (RS 18-30)
Disease-Free Survival by Treatment
Courtesy K. Albain
SABCS 2007, #10
Strong benefit if high RS
Predictive value of 21-Gene RS
SWOG 8814/TBCI 0100 Ten-Year DFS Point Estimates (95% CI)
Recurrence Score
Risk Category
Tamoxifen
Alone
CAF followed by tamoxifen
Low (< 18) * 60%
(40%, 76%)
64%
(50%, 75%)
Intermediate (18-30) 49%
(32%, 63%)
63%
(48%, 74%)
High (≥ 31) 43%
(28%, 57%)
55%
(40%, 67%)
*40% event rate over 10 years and resistance to CAF Courtesy K. Albain
SABCS 2007, #10
BEYOND FIRST PROJECTS…Predictive of response to CT
Mamma-Print Risk
Predicted
Chemo Response
Predicted Sensitivity to Endocrine Treatment (SET)
Low
(SET-1)
Intermediate
(SET-2)
High
(SET-3)Total (N)
Low (N=64)
RCB-0/I 6% 1.5% 5.5% 8
RCB-II/III 50% 11% 26% 56
Total (N) 36 8 20 64 (100%)
High (N=134)
RCB-0/I 47% 3% 1% 69
RCB-II/III 37% 6% 6% 65
Total (N) 112 13 9 134 (100%)
Low risk but still …might opt for chemotherapy
Predicted not to be sensitiveeither to T/FAC or Tamoxifen
Suggest Clinical Trial
May do well with current best chemoand endocrine therapies
L Pusztai & al; ASCO 2008
Four different genomic outcome predictors applied to the 198 cases from the TRANSBIG data: (i) 70-gene MammaPrintTM prognostic signature, the Genomic Grade Index prognostic index (GGI) (iii) a 200-gene endocrine sensitivity index (SET) and (iv) a second generation phenotype-specific Paclitaxel-FAC chemotherapy response predictor
CONCLUSIONS
• Patients predicted to be at low risk for recurrence are predicted to be mainly sensitive to HT. However, 6% of these low risk by MammaPrint pts were also predicted to achieve excellent pathologic response to CT, and thus might consider adjuvant CT as a reasonable option.
• 40-50% of high risk patients are predicted to be refractory to existing therapies & need clinical trials of new agents.
• Simultaneous prediction of risk of recurrence and sensitivity to endocrine- and chemo-therapies is currently possible and could allow more personalized treatment decisions in the future.
L Pusztai & al; ASCO 2008
Higher RS predictive of chemotherapy (ie, CMF/MF) benefit (Paik et al. JCO 2006)(Paik et al. JCO 2006)
LowRS<18
InterRS 18-30
HighRS≥31
1.31 (0.46-3.78)
0.61 (0.24-1.59)
0.26 (0.13-0.53)
1.0 1.50.5
Interaction p = 0.0368Interaction p = 0.0368
B20: Relative Risk of Chemotherapy by RS Group (Cox model)
MULTI-GENES TOOLS
MammaPrint™ (70-gene signature)MammaPrint™ (70-gene signature)
Genomic signatures
Genomic signatures
Oncotype DX(predictive & Px)
Oncotype DX(predictive & Px)
76-gene signature76-gene signature
Genomic gradingGenomic grading
uPA, PAI-1uPA, PAI-1
UNI-GENES TOOLS
PATIENT RISK PROFILESPrognostic BIOMARKERSPrognostic BIOMARKERS
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
Recommended for clinical use by ASCO Guidelines in 2007Harris et al, JCO 25 (33), 2007
Adapted from N. Harbeck with permission
Chemo NChemo N00 : Prospective multicenter therapy trial in : Prospective multicenter therapy trial in node-negative breast cancernode-negative breast cancer
Jänicke et al, JNCI 2001; Harbeck et al, Breast Cancer Res Treat 2001Jänicke et al, JNCI 2001; Harbeck et al, Breast Cancer Res Treat 2001
1.01.0
.9.9
.8.8
.7.7
.6.6
.5.5848472726060484836362424121200
Prob
abili
ty O
SPr
obab
ility
OS
Time (months)Time (months)
p = 0.003p = 0.003
uPA uPA andand PAI-1 low PAI-1 low
uPA / PAI-1 highuPA / PAI-1 high
n = 245, 7 deceasedn = 245, 7 deceasedn = 164, 17 deceasedn = 164, 17 deceased
PrognosisPrognosis: Patient survival: Patient survival
Chemo NChemo N00: no adjuvant systemic therapy: no adjuvant systemic therapy
Benefit from chemotherapyBenefit from chemotherapy
Time (months)Time (months)
CMFCMF
observationobservation
p = 0.019; RR = 0.42 (0.20 – 0.87)p = 0.019; RR = 0.42 (0.20 – 0.87)
848472726060484836362424121200
.5.5
.4.4
.3.3
.2.2
.1.1
0.00.0
58 %58 %
n = 91, 12 relapsesn = 91, 12 relapsesn = 90, 20 relapsesn = 90, 20 relapses
Chemo NChemo N00: uPA / PAI-1 high (per protocol) : uPA / PAI-1 high (per protocol)
N. Harbeck – used with permission
UPA-PAI-1UPA-PAI-1
Ready for use routine use in the clinic? Ready for use routine use in the clinic? YESYES
CLINICALCLINICALVALIDATIONVALIDATION
The test identifies subsets The test identifies subsets with significantly differentwith significantly different * risks of relapse * risks of relapse * chances of response* chances of response
The test is The test is * sensitive* sensitive * specific* specific * reproducible* reproducible
TECHNICALTECHNICALVALIDATIONVALIDATION
YES YES (level 1)
WX/60-006 – study scheme
Patients with HER2-negative MBC
appropriate for first-line mono
chemotherapy with Capecitabine
N = 100
Combination arm Capecitabine: 2000 mg/m2 Days 1-14 q3ws
WX-671 once daily po
Monotherapy armCapecitabine: 2000 mg/m2 Days 1-14 q3ws
Placebo once daily per os
Staging intervals at baseline and every 6 weeks until progression or toxicity
Efficacy endpoints:- PFS- ORR at week 12 and 24 weeks- Overall survival
Overall survival
WX-671 is the oral pro-drug to the active metabolite WX-UK1WX-UK1 is an uPA inhibitor with broad activity against a number of serine proteases
MULTI-GENE TOOLSGenomic
signatures
Genomic signatures
PgRPgR
UNI-GENE TOOLS
HER-2HER-2
PREDICTIVE FACTORSPREDICTIVE FACTORS
PHARMACOGENOMICS
Ki67Ki67
AIB1AIB1
Oncotype DX(predictive & Px)
Oncotype DX(predictive & Px)
Topo-II-Topo-II-
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
PanelPanel20052005
NIH NIH Consensus Consensus
PanelPanel20002000
ASCOASCOGuidelinesGuidelines
20012001
30%-70% chances of responding to HT (ER) & 40%-50% of responding to
TRASTUZUMAB (HER-2)
• ADVANCES IN ADJUVANT CHEMOTHERAPY
– CAN WE DO SAFELY AVOID ANTHRACYCLINES?
• In HER-2+ pts
• In all pts
or THE TOPO-II SAD STORY!!!!!!!!!!!
Disease Free Survival
% D
isea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
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
BCIRG 006 at SABCS 05 (D. Slamon)BCIRG 006 at SABCS 05 (D. Slamon)
DFS CO-AMPLIFIED TOPO II BY ARM%
Dis
ease
Fre
e
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
% D
isea
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
AC → TH
>>AC → T or TCH
Anthracyclines & trastuzumab are imp
AC → TH & TCH
>>AC → T
Only trastuzumab is imp
UPDATE ON BCIRG 006 at SABCS 06 (D. Slamon)UPDATE ON BCIRG 006 at SABCS 06 (D. Slamon)
AC → TH ≈ TCHAC → TH ≈ TCH
even when TOPO II is co-amplified !!!even when TOPO II is co-amplified !!!
UPDATE ON BCIRG 006 at SABCS 07 (D. Slamon)UPDATE ON BCIRG 006 at SABCS 07 (D. Slamon)
AC-T = AC-TH = TCHAC-T = AC-TH = TCH
when TOPO II is co-amplifiedwhen TOPO II is co-amplified
ONLY POSSIBLE CLINICAL RECOMMENDATION:
TCH is a very good option and should be chosen when cardiac risk factors or c.i. for anthracyclines
are present
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
FIRST RESULTS AT SABCS 2008
TRASTUZUMAB IN THE METASTATIC SETTINGTRASTUZUMAB IN THE METASTATIC SETTING
Highly selected populationHighly selected populationUsing a targeted agentUsing a targeted agent
RESISTANCE TO RESISTANCE TO TRASTUZUMABTRASTUZUMAB
(DE NOVO AND ACQUIRED)(DE NOVO AND ACQUIRED)
Responses in only ± 50% patientsResponses in only ± 50% patientsMedian duration of response: 9 to 12 monthsMedian duration of response: 9 to 12 months
HOWEVERHOWEVER
POTENTIALPOTENTIAL MECHANISMS OF RESISTANCE TO MECHANISMS OF RESISTANCE TO TRASTUZUMABTRASTUZUMAB• IS THE TARGET PRESENT?IS THE TARGET PRESENT?
•HER-2 statusHER-2 status: : Technical limitations Technical limitations (IHC; FISH; central evaluation)(IHC; FISH; central evaluation)
• IS THE TARGET ACTIVE?IS THE TARGET ACTIVE?
•Role of truncated HER-2 receptorRole of truncated HER-2 receptor (p95-HER-2)(p95-HER-2)
•Role of activated form of HER-2 Role of activated form of HER-2 (p-HER-2)(p-HER-2)
•Mechanical blockade of the receptorMechanical blockade of the receptor (Mucin 1 or 4 Interference) (Mucin 1 or 4 Interference)
• IS THE TARGET BEHAVING DIFFERENTLY?IS THE TARGET BEHAVING DIFFERENTLY? (HER-2 as transcription (HER-2 as transcription factor)factor)
• ROLE OF POTENTIAL ADDITIONAL TARGETSROLE OF POTENTIAL ADDITIONAL TARGETS
•Other HER family members: Other HER family members: Upregulation of HER1 or HER3Upregulation of HER1 or HER3
• ROLE OF REDUNDANT PATHWAYSROLE OF REDUNDANT PATHWAYS
•PI3K / AKT, IGF-IR pathwaysPI3K / AKT, IGF-IR pathways, , MAP-kinase, ER pathway MAP-kinase, ER pathway
• Role of immune function, Role of immune function, ↑ expression of growth factors (ligands), ↑ expression of growth factors (ligands), etcetc
POTENTIALPOTENTIAL WAYS OF OVERCOMING WAYS OF OVERCOMING RESISTANCE TO RESISTANCE TO TRASTUZUMABTRASTUZUMAB
• OPTIMAL SELECTION OF PATIENTSOPTIMAL SELECTION OF PATIENTS
• Quality of HER-2 testing is essential (high level of discordance between Quality of HER-2 testing is essential (high level of discordance between central & local labs for both IHC & FISH)central & local labs for both IHC & FISH)
• Primary vs. Metastatic sitesPrimary vs. Metastatic sites
• Use of other predictive markers: Use of other predictive markers: c-myc; p95HER2; PTEN; pHER-2; ECD-HER2; c-myc; p95HER2; PTEN; pHER-2; ECD-HER2; survivin; patternssurvivin; patterns of HER-receptors co-expression and/or of functional HER-2 of HER-receptors co-expression and/or of functional HER-2 heterodimersheterodimers; ;
• USE OF OTHER ANTI-HER-2 AGENTSUSE OF OTHER ANTI-HER-2 AGENTS (Lapatinib, HKI-272, Pertuzumab, (Lapatinib, HKI-272, Pertuzumab, Trastuzumab-DM1, HSP-90 inhibitors)Trastuzumab-DM1, HSP-90 inhibitors)
• ““MULTI-TARGETED THERAPY”MULTI-TARGETED THERAPY”
• Simultaneous blockage of same pathway in several sitesSimultaneous blockage of same pathway in several sites (pan-HER inhibitors)(pan-HER inhibitors)
• Simultaneous blockage of redundant pathways: combinations with other Simultaneous blockage of redundant pathways: combinations with other biological agentsbiological agents (IGF-I inhibitors, PI3K inhibitors, AKT or mTOR inhibitors, (IGF-I inhibitors, PI3K inhibitors, AKT or mTOR inhibitors, MAPK inhibitors)MAPK inhibitors)
185kd
p95
serum
Trastuzumab binds to extracellular domain and can not inhibit “free” p95
Saez et al, Clin Can Res 12:424, 2006
ECD/ p95: POTENTIAL DISCRIMINATIVE MARKER BETWEEN T vs L
• P95 is a truncated HER-2 receptor which lacks the external domain (do not bind trastuzumab)
• Approximately 25% of breast cancers express p95, 9% of breast cancers high levels of p95 - it predicts worse outcome
• Truncated receptor demonstrates increased kinase activity and transforming potential
0 1 2 3 4 5
5060
7080
9010
0
MYC+,AC->T
MYC+,AC->TH
MYC-,AC->T
MYC-,AC->TH
P-value for Interaction = 0.007P-value for Interaction = 0.007
Paik et al, SABCS 2005
cMYC and Outcome in NSABP B31 TrialTime to First Recurrence
(N=1549)
PTEN levels predict response to Trastuzumab
PI K3CA mutation also predicts response to Trastuzumab
Low PTEN: 25% of breast cancers
Mutant PI3K: 25% of breast cancers
(mutually exclusive)
Activated PI3K pathway:Low PTEN or mutant PIK3CANon-activated PI3K pathway:
High PTEN and wild type PIK3CA
René Bernards, SABCS 2007
ALTTO:ALTTO:Pre-defined subgroup analysesPre-defined subgroup analyses
Molecular Molecular markermarker
c-Mycc-Myc
PTENPTEN
p95HER2p95HER2
DistributionDistribution HypothesesHypotheses
c-Myc co-amplifiedc-Myc co-amplified30%30%
Loss / reduced Loss / reduced expression in 40%expression in 40%
Seen in 10%Seen in 10%
““Exquisitely sensitive to trastuzumab”Exquisitely sensitive to trastuzumab”
Group where L benefits more likelyGroup where L benefits more likely(80% power for any pair-wise comparison (80% power for any pair-wise comparison
to detect to detect DFS 0.754DFS 0.754))
Group where L benefits more likelyGroup where L benefits more likely(80% power for any pair-wise (80% power for any pair-wise
comparison to detect comparison to detect DFS 0.72DFS 0.72))
Group where L benefits more likelyGroup where L benefits more likely(80% power for any pair-wise(80% power for any pair-wise
comparison to detect comparison to detect DFS 0.638DFS 0.638))
““Resistant to trastuzumab”Resistant to trastuzumab”
““Resistant to trastuzumab”Resistant to trastuzumab”
c-Myc not co-amplifiedc-Myc not co-amplified70%70%
COMBINATION OF TRASTUZUMAB WITH OTHER BIOLOGICAL AGENTS
Gefitinib (4%)
Bevacizumab (55%)
Lapatinib (20%)
Pertuzumab (21%)
Anti-HSP90 (50% CB)
Letrozole (26%)
Anastrozole (20.3%)
Tamoxifen
Adapted with permission from E Azambuja
Name Class Mechanism of action Phase of development
HKI-272 Small molecule Irreversible inhibiton of EGFR and HER-2
Phase II
Pertuzumab Monoclonal antibody
Block HER-2 Phase III
17-AAG Derivate of geldanamycin
Hsp90 inhibitor Phase II
Pazopanib Small molecule multitargeted TK inhibitor
Inhibition of VEGFR/PDGFR and c-Kit
Phase II
Trastuzumab-DM1 Monoclonal antibody-drug conjugated
Selective delivery of CT drug to HER-2 protein
Phase II
NEW ANTI-HER-2 AGENTS
Adapted with permission from E Azambuja
Marker(s) studied (abst)
Key findings Implications for clinical practice
Genetic variations in CYP2 D6 and adjuvant
TAM outcome
(abst 504, 505)
Poor metabolizers (7% of population) show worse outcome
Avoidance of CYP 450 inhibitors such as
haloperidol, amiodarone, cimetidin, fluoxetin,
paroxetine, sertraline !
0
20
40
60
80
100
0 2 4 6 8 10 12
Relapse-Free Survival* According to CYP2D6 MetabolizerStatus in Women Receiving Tamoxifen Adjuvant Therapy
*Breast cancer recurrence or death*Breast cancer recurrence or death
%
Years after randomization
2-year RFSEM 98%IM 92%PM 68%
EM (n=115)EM (n=115)
IM (n=40)IM (n=40)
PM (n=16)PM (n=16)Log rankP=0.009
Knox et al: ASCO abstract #504 June 4, 2006Knox et al: ASCO abstract #504 June 4, 2006E: Extensive, I: Intermediate, P: Poor, M: Metabolizer
ASCO 2006 : CYP2D6 AND THERAPEUTIC INDEX OF TAMOXIFEN