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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