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Is there still a place for chemotherapy in the HER -2 positive breast cancer?
Joelle COLLIGNON
Guy JERUSALEMGuy JERUSALEM
HER2: role in breast cancer
Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein
Overexpression of HER2 occurs in 15% of breast canc ers
HER2 positivity is associated with
- aggressive disease
- a high risk of relapse
- poor survival
50%
25,1
20,3
60
80
100
20
30
Chemotherapy +/- Trastuzumabin Metastatic Breast Cancer
Months (T
TP, survival)
OR
R (
%)
Trastuzumab + Chemotherapy (n=235)
Chemotherapy (n=234)
50%
32%7,4
4,6
0
20
40
60
0
10
ORRP<0.001
MedianTTPP<0.001
MediansurvivalP=0.046
Months (T
TP, survival)
OR
R (
%)
Slamon D et al, N Eng J Med 2001
4 years follow -up joint analysisNCCTG N9831 and NSABP B -31
Kaplan-Meier estimates of overall survival
Perez E A et al. JCO 2011;29:3366-3373
Human Epidermal Growth Factor Receptor (HER) Family of Receptors and Therapeutic Agents Currently Available or in Development.
Gradishar WJ. N Engl J Med 2012;366:176-178 .
C Inhibition of tyrosine kinase activity
A Inhibition through direct antibody binding
B Inhibition throughdimerisation inhibition
ANTI-HER2 THERAPIES
Lapatinib
J. Baselga and S. Swain, Nature Reviews Cancer,2009
NEOADJUVANT TREATMENT:pCR is predictive of outcome
in HER positive disease
Loibl S, et al, SABCS, 2011
N = 66
NEOADJUVANT TREATMENT WITHOUT CHEMOTHERAPY
Chang J et al, ASCO, 2011
NEOADJUVANT TREATMENT Pathologic response
Chang J et al, ASCO, 2011
DUAL Blockade with Taxanes:NeoALLTO and NeoSphere: Study Design
EFFICACY – pCR and tpCR
Baselga J et al, SABCS, 2010
NeoSphere: Primary endpointPathologic complete response
Adjuvant anti-HER2 therapies will be compared in the ALTTO trial
8000 women with HER2-positive breast cancer
CTx
Herceptin®
x 1 year
Lapatinib
x 1 year
Herceptin®
lapatinib
Herceptin®
+ lapatinib
• Includes translational research, eg tumour and bloo d collection
Trastuzumab and pertuzumab in the adjuvant setting: the APHINITY trial
CLEOPATRA trial: Primary endpoint Independently assessed PFS (n = 433 PFS events)
50
60
70
80
90
100 Ptz + T + D: median 18.5 months
Pla + T + D: median 12.4 months∆ = 6.1 months
free
sur
viva
l (%
)
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
n at risk
402 345 267 139 83 32 10 0 0Ptz + T + D
406 311 209 93 42 17 7 0 0Pla + T + D
Time (months)
HR = 0.6295% CI 0.51‒0.75
p<0.0001
Pro
gres
sion
-fr
ee s
urvi
val (
%)
Baselga et al, SABCS, 2011
TAnDEM study: Anastrazole +/- trastuzumab
Kaufman B,J Clin Oncol , 2009, 27:5529-5537
EGF 30008:Letrozole +/- lapatinib
Johnston,J Clin Oncol 2009; 27(33):5538-5546.
HER2+/ ER+ metastatic breast cancerfirst-line treatment
Combination with
Combination with
chemotherapy
HO648g M77001Combination with
aromatase inhibitors
TAnDEMEGF30008 eLEcTRA
Cortes et al. Nat. Rev. Clin. Oncol. 2011;8:307-11
T-DM1: A HER2-Targeted Antibody-Drug Conjugate
Humanized HER2 mAb: trastuzumab
T-DM1 retains antitumor activities of trastuzumab
Cytotoxic drug: DM1
Systemically stable
Nonreducible thioether linker: SMCC T-DM1
Potent cytotoxic agent (inhibitor of tubulin polymerization and
microtubule dynamics)
Progression -Free Survival by InvestigatorP
ropo
rtio
n pr
ogre
ssio
n-fr
ee
1.0
0.8
0.6
MedianPFS, mos
Hazard ratio 95% CI
Log-rank P value
9.214.2
0.5940.364–0.968
0.0353
Time (months)
Pro
port
ion
prog
ress
ion
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0T-DM1 67 60 51 46 42 35 22 15 6 3 0
Hazard ratio and log-rank P value were from stratified analysis.
Trastuzumab+ docetaxel (n=70)T-DM1 (n=67)
Hurwitz SA et al. ESMO 2011 Abstr 5001
Adverse Event Summary
Safety Evaluable Patients
T-DM1(n=67)
Trastuzumab+Docetaxel(n=68)
Any AE, n (%) 63 (94.0) 68 (100.0)
Grade ≥3 AE 25 (37.3) 51 (75.0)
Serious AE* 13 (19.4) 15 (22.1)Serious AE* 13 (19.4) 15 (22.1)
Three most common AEs (any grade) in T-DM1 armNauseaFatiguePyrexia
32 (47.8)31 (46.3)24 (35.8)
27 (39.7)29 (46.2)14 (20.6)
Three most common AEs (any grade) in trastuzumab + docetaxel arm
AlopeciaNeutropeniaDiarrhea
1 (1.5)5 (7.5)7 (10.4)
45 (66.2)39 (57.4)31 (45.6)
Perez EA, et al. Abstr LBA3. ESMO 2010
First-line HER2-positive mBC
MARIANNE trial
Is there still a place for chemotherapy in the HER2 positive breast cancer?
Chemotherapy should be given to all patients in the adjuvant setting
A high pCR rate is observed with dual HER2 blocade in the neoadjuvant setting. We don’t have predictive facto rs allowing to identify patients who don’t need chemot herapy
Chemotherapy is also indicated for endocrine sensit ive tumors overexpressing HER2
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