TAILORED THERAPIES: PROGNOSTIC & PREDICTIVE FACTORS F. Cardoso, MD Jules Bordet Institute,...

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