Dr Antonio C. Buzaid
Chefe Geral
Centro Avançado de Oncologia
Hospital São José
Os Trabalhos/Abstracts
mais Relevantes em Terapia
Neoadjuvante de Cancer de Mama
Dr Antonio C. Buzaid
Chefe Geral
Centro Avançado de Oncologia
Hospital São José
Índice
Pathologic response according to the molecular subtype and
genetic signature (70 gene assay)
Pathologic response according to the molecular subtype vs the
histologic type
Influence of neoadjuvant chemotherapy on HER2/new status in
invasive breast cancer
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab
in women with locally advanced, Inflammatory, or early HER2positive breast cancer (NeoSphere): a randomised multicentre,
open-label, phase 2 trial
A randomized phase II trial of platinum salts in basal-like breast
cancer patients in the neoadjuvant setting. Results from the
GEICAM/2006-03, multicenter study
Resposta patológica de acordo com o
subtipo molecular e assinatura
genética (70 genes)
Esserman et al. Breast Cancer Res Treat 132:1049, 2012
I SPY-1 Trial
Molecular Subtype
% pCR (n=116)
Luminal A
3
Luminal B
16
HER enriched
50
Basal
33
Normal like
33
Esserman et al. Breast Cancer Res Treat 132:1049, 2012
I SPY-1 Trial
70 gene signature
% pCR (n=116)
Low risk
0
High risk
24%
Esserman et al. Breast Cancer Res Treat 132:1049, 2012
Take home message
• A resposta patológica
completa é muito baixa em
tumores tipo luminal A ou
com assinatura genética (70
genes) de baixo risco
Resposta patológica de acordo com o
subtipo molecular vs histológico
(lobular ou ductal)
Lips et al. Breast Cancer Res Treat 136:35, 2012
I SPY-1 Trial
pCR Rate % (n)
Molecular Subtype
ILC
IDC
Luminal A
0 (1/29)
4 (4/101)
Luminal B
0 (0/2)
10 (8/79)
Basal
0 (0/4)
41 (39/96)
HER-2 enriched
50 (1/2)
49 (31/63)
Normal like
0 (0/4)
28 (8/29)
Lips et al. Breast Cancer Res Treat 136:35, 2012
Take home message
• A resposta patológica
completa é muito baixa em
tumores tipo luminal A
independentemente do tipo
histológico lobular ou ductal
Influence of Neoadjuvant Chemotherapy on
HER2/neu Status in Invasive Breast Cancer
Li et al. Clin Breast Cancer in press
Li et al. Clin Breast Cancer in press
To evaluate the impact of the neoadjuvant
chemotherapy on the expression of the HER-2
gene by FISH and immunohistochemistry
N=124
After neoadjuvant chemotherapy, HER-2
expression was downregulated in 23,4% but no
alteração in gene amplification by FISH was
observed
Li et al. Clin Breast Cancer in press
Take home message
• A expressão do HER-2 por IH
não é confiável após QT e
deve-se realizar FISH nesta
situação
Efficacy and safety of neoadjuvant
pertuzumab and trastuzumab in
women with locally advanced,
Inflammatory, or early HER2-positive
breast cancer (NeoSphere):
a randomised multicentre, openlabel, phase 2 trial
Gianni et al. Lancet Oncol 13:25, 2012
HER2:HER3 dimers have the strongest
mitogenic signaling
Homodimers
HER3:HER3
Heterodimers
HER4:HER4
HER1:HER2 HER1:HER3 HER1:HER4
HER2:HER3
HER2:HER2
HER2:HER4
HER1:HER1
HER3:HER4
Signaling activity
Tzahar et al. Mol Cell Biol 1996;16:5276–5287
15
HER2 dimerization is key to signaling activity
HER2
Ligand-activatedHER2:HER3 dimer
HER3
P
P
P
P
Phosphorylation of the tyrosine
kinase domain by HER2 initiates intracellular signaling
Ferguson et al. Mol Cell 2003;11:507–517. Olayioye et al. EMBO J 2000;19:3159–3167. Hynes et al. Nat Rev Cancer
2005;5:341–354. Rowinsky. Annu Rev Med 2004;55:433–457
16
NeoSphere Study Design
Patients with
operable or
locally advanced/
inflammatory
HER2-positive
breast cancer
Chemo-naive
and primary
tumors >2 cm
(N = 417)
TH (n = 107)
docetaxel +
trastuzumab
THP (n = 107)
docetaxel +
trastuzumab +
pertuzumab
HP (n = 107)
trastuzumab +
pertuzumab
TP (n = 96)
docetaxel +
pertuzumab
S
U
R
G
E
R
Y
FEC q3w x 3
Trastuzumab q3w cycles
FEC q3w x 3
Trastuzumab q3w cycles
Docetaxel q3w X 3 –
FEC q3w X 3
Trastuzumab q3w cycles
FEC q3w x 3
Trastuzumab q3w cycles
Gianni et al. Lancet Oncol 13:25, 2012
NeoSphere: pCR Rates (ITT population)
pCR, % ± 95% CI
50
45
TH vs THP: P = .0141
THP vs TP: P = .003
TH vs HP: P = .0198
40
35
30
25
20
15
10
5
0
29.0
45.8
16.8
24.0
TH
THP
HP
TP
Gianni et al. Lancet Oncol 13:25, 2012
NeoSphere: pCR and HR Status
70
pCR, % ± 95% CI
60
ER or PR+
ER and PR-
50
40
30
20
10
0
20.0 36.8
26.0 63.2
TH
THP
5.9 29.1
HP
17.4 30.0
TP
Gianni et al. Lancet Oncol 13:25, 2012
Take home message
• A combinação de
Trastuzumab + Pertuzumab
+ Docetaxel aumenta
significativamente a taxa de
resposta patológica,
especialmente em tumores
com RH negativos
A randomized phase II trial of platinum salts in
basal-like breast cancer patients in the
neoadjuvant setting. Results from the
GEICAM/2006-03, multicenter study
Alba et al. Breast Cancer Res Treat 136:487, 2012
Study Design
EC seguido de D
Localized disease
Basal subtype
pCR endpoint
N=91
Carbo + Docetaxel
Alba et al. Breast Cancer Res Treat 136:487, 2012
GEICAM/2006-03
Type of Carbo/Doc
Response
%pCR
30%
%ORR
77%
EC-D
pValue
35%
0,61
70%
Alba et al. Breast Cancer Res Treat 136:487, 2012
Take home message
• O esquema com platinante
(carboplatina + docetaxel)
resulta em taxa de resposta
patológica semelhante a EC
seguido de Docetaxel em
tumor com subtipo basal
Take home message
Resposta patológica de acordo com o subtipo molecular e assinatura genética
Luminal A ou assinatura genética com risco baixo tem baixa taxa de pCR
Resposta patológica de acordo com o subtipo molecular vs histológico
Luminal A, independentemente de ser ductal ou lobular, tem baixa taxa de
pCR
Influencia da QT neo na expressão do HER-2
QT regula para baixo a expressão do HER-2 por IH mas não altera a
amplificação do gene (por FISH)
Estudo NeosPhere com bloquei duplo com pertuzumab + trastuzumab
Bloqueio duplo com pertuzumab + trastuzumab aumenta muito a pCR,
principalmente no HER-2 enriched
Uso de platinante em tumor basal (GEICAM/2006-03)
Esquema com Carbo/Docetaxel tem atividade semelhante a EC-D
Obrigado