HER-2/neu:Predictive Marker for Response to Breast Cancer

Therapy

Mark Pegram, M.D.

Associate Professor of Medicine

Director, Women’s Cancer Program

UCLA/Jonsson Comprehensive Cancer Center

UCLA School of Medicine

Progress in breast cancer molecular biology-based therapies

Targetfor therapy

PredictiveValue*

Prognosticvalue

HER2neu

c-erbB-2

Estrogenreceptor

* Trastuzumab* Hormonal Therapy* CMF* Anthracyclines* Taxanes

Number of Patients

FISH+ FISH-

Total patients evaluable 82 29

CR 7 0

PR 21 2

CR + PRCR + PR 28 (34%)28 (34%) 2 (7%)2 (7%)

(95% CI: 24%–45%) (95% CI: 1%–23%)

CR + PR + SD > 6 mo 39 (48%) 3 (10%)CR + PR + SD > 6 mo 39 (48%) 3 (10%)

FISH/Clinical Outcome Analysis1st Line, Single Agent Trastuzumab

(H0650g)-Response RateIHC 2+/3+ combined IHC 2+/3+ combined

Vogel et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 86; & JCO 2002

Metastatic breast cancer HER2 overexpression No prior CT for MBC Measurable disease KPS 60%

Eligible patients (n=469)

Chemotherapy Alone(AC or Paclitaxel)

Chemotherapy + Herceptin

Pivotal Trastuzumab combination therapy trial(H0648g)

Design and enrolment

AC = doxorubicin/epirubicin + cyclophosphamide Slamon et al., NEJM 344: 783-792 (2001)

H0648g Survival for 2+/3+ vs FISH+ Population

Survival (months)

0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

Median Duration of Survival, mo

Herceptin + Chemo (n = 125)

Chemo Alone (n = 116)

Herceptin + Chemo (n = 235)

Chemo Alone (n = 234)

FISH+

IHC 2/3+

27*

18

25*

20

9 months 50%

5 months 25%

*P < 0.05

Slamon et al., NEJM 344: 783-792 (2001)

Mass et al. Proc Am Soc Clin Oncol. 200120:22a. Abstract 85.

MonthsMonths

0.20

0.40.60.81.0

Herceptin + CT (n = 50)Herceptin + CT (n = 50)CT (n = 56)CT (n = 56)P

rob

abili

ty A

live

Pro

bab

ility

Aliv

e

RR = 1.11RR = 1.11p = NSp = NS

0 10 20 30 40 50

19.8 19.8 momo

24.0 24.0 momo

FISH - Negative Subset

FISH- Positive

FISH- Negative

0 2 4 6 8 10 12 14 16 18 20Time to Disease Progression (months)

Number at Risk38 37 32 26 19 15 12 10 8 4 019 17 15 13 8 6 5 3 1 1 0

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rog

ress

ion

-Fre

eTCarboH – Time to ProgressionFirst-Line Patients by FISH Result

•[9.1-NE*]

•17.0

•38

•FISH+ •FISH-

•[6.7-12.0]•95% CI

•7.4•Median TTP (mos)

•19•Patients

NE* = Not estimable

•7/17 (41%)• [19-67]

•23/36 (64%)• [46-79]

• FISH- negative

•FISH- positive

Popular Dogma:

HER2 associated with resistance to CMF

HER2 causes sensitivity to anthracyclines

HER2 is associated with resistance to hormonal therapy

HER2 causes resistance to taxol

Low Risk (N = 267)

High Risk, Treated (N = 120)*

High Risk, Untreated (N = 111)*

HER-2/neu Negative HER-2/neu Positive

High Risk, Treated (N = 40)*

High Risk, Untreated (N = 35)*

Low Risk (N = 40)

DF

S, P

rob

abil

ity

DF

S, P

rob

abil

ity

*P = 0.0003 *P = NS

Time (years) Time (years)0 1 2 3 4 5 6 0 1 2 3 4 5 6

100100

-50-50

HER-2/neu and Prognosis in LN(-) Breast CancerIntergroup Study 0011 (adjuvant CMFP)

Allred DC, Clark GM, Tandon AK, et al., HER-2/neu in node-negativebreast cancer: prognostic significance of overexpression influenced by thepresence of in situ carcinoma. J Clin Oncol 10: 599-605, 1992.

Benefit of CMF in Node-positive Breast Cancer Overexpressing HER2

HER2 status DFS (HR) CSS (HR)

Positive (16%) 0.484 0.495

Negative 0.641 0.730

N = 337

Menard, et al., Milano, Italy (Proc. ASCO, 1999)

OS

(%

pat

ien

ts)

Months after enrolmentOS = overall survivalTreatment = high-, moderate- or low-dose chemotherapy

Low HER2 expression (<50%) High HER2 expression (50%)

Muss HB. NEJM 1994;330(18):1260–7

100

80

60

40

20

00 10 20 30 40 50 60 70 80

OS

(%

pat

ien

ts)

100

80

60

40

20

00 10 20 30 40 50 60 70 80

High (n=36)Moderate (n=41)Low (n=36)

OS according to treatment and HER2expression in node-positive breast cancer

High (n=94)Moderate (n=96)Low (n=93)

p=0.96 p<0.001

CALGB 8541

NSABP B-11: 638 LN+/ER- Patients

0

10

20

30

40

50

HER2-Neg PFHER2-Neg PAFHER2-Pos PFHER2-Pos PAF

10

-year

DFS

Esti

mate

HER2-Neg HER2-Pos

PF PAF PF PAF

Paik S, Bryant J, Park C, et al. erbB-2 and Response to Doxorubicin in Patients With Axillary Lymph Node-Positive,Hormone Receptor-Negative Breast Cancer. J Natl Cancer Inst 90: 1361-1370, 1998.

P = 0.02

SWOG/Intergroup Study:Preliminary Results

DFS HER2 (-) HER2 (+)

TAM 81% 41%

TAM + CAF 84% 74%

P-value 0.39 0.01

Ravdin, et al., Proc. ASCO 17: 97a, 1998

DOX IC50 (uM)

MCF7/NEO 0.39 ± 0.03MCF7/HER-2 0.34 ± 0.07

435/NEO 0.6 ± 0.09435/HER-2 0.6 ± 0.07

231/NEO 0.3 ± 0.03231/HER-2 0.2 ± 0.05

BT 20/NEO 0.17 ± 0.03BT 20/HER-2 0.15 ± 0.02

CaOV3/NEO 0.5 ± 0.05CaOV3/HER-2 0.3 ± 0.04

2008/NEO 0.06 ± 0.0072008/HER-2 0.06 ± 0.01

Error = Standard Deviation

Effect of HER-2/neu Overexpression on Sensitivity to Doxorubicin

Pegram, et al., Oncogene 15: 537-547, 1997

HER-2/neu AmpliconB

AF5

7T

opo

2

CD

C 6

MLN

51

WI 1

7575

TRA

H 1

TRA

P 10

0C

SF 3

PSM

OB

EST

EST

HER

-2/n

euG

rb7

CA

B-1

TRA

P 22

0ES

TES

TES

TES

TR

PL 1

9ES

TES

T

RPL

23

MLN

50

EST

PIP

5 K

2

MEL

18

AF-

17

*Coamplification of topo II and HER2 in ~44% ofHER2-amplified breast cancers

Jarvinen TA, et al Am J Pathol 156: 839-47, 2000

* *

In vitro Response to Taxane

Pegram et al.: Oncogene 15:537-547, 1997

NEO NEO NEO NEOHER2 HER2 HER2 HER2

MCF-7 MDA-MB-231 BT20 MDA-MB 435

* *100%

Pac

lita

xel

IC5

0

(rel

ativ

e to

co

ntr

ol)

• Investigate the association between HER2 status and response to paclitaxel

• In a randomized controlled trial

• Fluorescence in Situ Hybridization (FISH)

• Metastatic breast cancer cohort to allow comparison of RR, PFS and OS

Objective

Metastaticbreast cancer

Epirubicin 60 mg/m2 1h

Paclitaxel 175 mg/m2 3h

Epirubicin 60 mg/m2 1h

Cyclophosphamide 600 mg/m2

Randomized Phase III study

Konecny et al. Proc ASCO 2001

Epirubicin Paclitaxel vs Epirubicin Cyclophosphamide

ET vs EC

Response rates by FISH UCLA Analysis

0

10

20

30

40

50

60

70

80

HER2-(n =146)

HER2+(n = 88)

33%

48% 47%

71%

ETEC

P=0.092 P=0.031

Konecny, et al., Proc ASCO 2001

SurvivalHER2 negative (n = 170)

ET 82 (95%CI 51-112) EC 90 (95%CI 79-101)

Median Survival in Months

200150100500

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Log rank p = 0.8999

ET 31 / 91events

EC 29 / 79 events

Weeks

Cu

m S

urv

ival

Konecny, et al., Proc ASCO 2001

200150100500

HER2 positive (n =102)

ET 103 (95%CI 64-142) EC 56 (95%CI 41-71)

Median Survival in Months

Survival

ET 14 / 49 events

EC 27 / 53 events

Log rank p = 0.035

Weeks

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Cu

m S

urv

ival

Konecny, et al., Proc ASCO 2001

Multivariate analysis

Survival

Including hormone receptors, grade, site of metastasis, number of sites, prior adjuvant chemotherapy, prior palliative hormone therapy

HER2+ ET vs EC p=0.043 0.48 (0.24, 0.98)HER2- ET vs EC p=0.880 0.96 (0.53, 1.72)

Wald Test* Odds Ratio (95% CI)

* Cox proportional hazard regression model controlling other baseline prognostic factors

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

485 467 433 102 1478 455 402 108 0

40

50

60

70

80

90

100

% A

live

and

Dis

ease

Fre

e

TAC

FAC

0 12 24 36 48Months

N at RiskTACFAC

138 131 118 32 0148 135 107 26 0

40

50

60

70

80

90

100

Disease Free Survival by HER2 status

Negative (FISH) Positive (FISH)

RR = 0.74p = 0.06

RR = 0.59p = 0.02

c-erbB2 Overexpression is an IndependentMarker of Endocrine Resistance in

Advanced Breast CancerHouston, et al., Guy’s Hospital, Br J Cancer 79: 1120, (1999)

Overall Response (CR/PR or SD X 6 mos), N = 241

ER(+) ER(-) TTP

c-erbB2 (+) 15/57 (24%) 1/19 (5%) 4.1c-erbB2 (-) 85/132 (64%) 8/33 (24%) 8.7P-value 0.05 0.29 <0.001

Multivariate Analysis:c-erbB2 status most predictive factor for TTP (P=0.0009)

Elevated Serum HER2 Predicts Responseto Hormone Therapy in MBC

A. Lipton, et al., Penn State/Hershey Med CtrProc. ASCO 2000, #274

N = 566, second line hormonal therapy (2 trials)

Response Rate (CR/PR/SD) = 24% for HER2 (+) = 44% for HER2 (-)

P < 0.0001Response duration/TTP/OS = significantly shorter

in HER2(+), P < 0.0001Multivariate Analysis: HER2 is an independentpredictive factor (adjusting for age, race, DFI, KPS,Visceral vs. non-visceral, ER/PR status)

HER-2/neu concentration in fmol/mg

70006000500040003000200010000

ER

co

nce

ntr

atio

n in

fmo

l/mg

700

600

500

400

300

200

100

0

Relationship between HER2 and ERin Primary Breast Cancer

by Quantitative ELISAG. Konecny, et al., UCLA School of Medicine, Los Angeles, CA

Conclusions:

Relationship between HER2 and drug response:

• HER2 amplification correlates with response to Herceptin

• HER2 positive patients exhibit relative resistance to hormonal therapy

• HER2 positive patients may benefit from CMF

• HER2 positive patients benefit from doxorubicin

• HER2 amplified patients benefit from taxanes

Acknowledgements

UCLA OncologyDennis SlamonJean-Marc NabholtzRichard PietrasGottfried KonecnyMalgorzata BerytSheree HsuCarminda O’Callaghan

University of Southern CaliforniaMichael Press

Roche/Genentech,Inc.

Mark SliwkowskiRobert Mass

AGO Study Group

Jean-Marc Nabholtz