Terapia Neoadiuvante
Revisione delle evidenze scientifiche
Valentina Guarneri
Nonantola, 19 Novembre 2011
Preoperative vs postoperative, Overall Survival
DDFS o OS???
The Cochrane Library, Issue 3, 2008
pCR vs residual disease, Overall Survival
The Cochrane Library, Issue 3, 2008
NEOADJUVANT P-FEC TRASTUZUMAB IN
HER2+ OPERABLE BREAST CANCER
T-FEC
19 pts
T-FEC + H
23 pts
26.3 %
65.2 %
pCR ER pos
27 %
61 %
pCR ER neg
25 %
70 %
78.9 %
86.9 %
pCR
pN0
Buzdar, J Clin Oncol 2005
Buzdar AU, Clin Cancer Res 2007
NOAH
HER2-positive LABC
(IHC 3+ or FISH+)
(n=115)
HER2-negative LABC
(IHC 0/1+)
(n=113)
(n=99)
H + AT
q3w x 3 cycles
AT
q3w x 3 cycles
AT
q3w x 3 cycles
H+T
q3w x 4 cycles
T
q3w x 4 cycles
T
q3w x 4 cycles
H q3w x 4 cycles
+ CMF q4w x 3 cycles
CMF
q4w x 3 cycles
CMF
q4w x 3 cycles
Surgery followed by
radiotherapya
Surgery followed by
radiotherapya
Surgery followed by
radiotherapya
H continued q3w
to week 52
19 crossed over to H
Gianni L, Lancet 2010
HR negative, or
HR+ with cN+
GEPAR-QUATTRO: EFFICACY OUTCOMES
80
70
60
50
40
30
20
10
0
ypT0
ypTis
ypT0/is, N0
ypN0
Untch M, J Clin Oncol 2010
Untch M et al, J Clin Oncol 2011
NEO-ALTTO STUDY DESIGN
Invasive operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450
Stratification:
• T ≤ 5 cm vs. T > 5 cm
•ER or PgR + vs.
ER & PgR –
• N 0-1 vs. N ≥ 2
•Conservative surgery
or not
lapatinib
paclitaxel
R
A
N
D
O
M
I
Z
E
trastuzumab
paclitaxel
lapatinib
trastuzumab
paclitaxel
lapatinib
S
U
R
G
E
R
Y
F
E
C
trastuzumab
X
3
6 wks + 12 wks
lapatinib
trastuzumab
34 weeks
52 weeks of anti-HER2 therapy
Baselga J et al. SABCS 2010
Neo-ALLTO: PATHOLOGIC RESPONSE
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response
Baselga J et al. SABCS 2010
CHER LOB Trial: study plan
C
O
R
E

B
I
O
P
S
Y
R
A
N
D
O
M
I
Z
A
T
I
O
N




A
B
Lapatinib 1500 mg/daily

C

S
U
R
G
E
R
Y
Chemotherapy
5 FU 600 mg/m2
Epi 75 mg/m2
CTX 600 mg/m2
TXL 80 mg/m2
Trastuzumab
2 mg/kg
Lapatinib 1000 mg/daily
Guarneri V, ASCO 2011
CHER-LOB: EFFICACY OUTCOMES
90
80
70
60
50
40
30
20
10
0
Arm A:CT +
trastuzumab
pCR (breast & axilla)
Arm B: CT +
lapatinib
Node negativity
Arm C: CT +
trastuzumab/lapatinib
Breast conservation
Guarneri V, ASCO 2011
NEOSPHERE: STUDY DESIGN
TH (n=107)
docetaxel +
trastuzumab
Patients with
operable or
locally advanced
/inflammatory*
HER2-positive BC
Chemo-naïve &
primary tumors
>2cm (N=417)
S
FEC q3w x 3
trastuzumab q3w cycles 5–17
U
THP (n=107)
docetaxel +
trastuzumab +
pertuzumab
R
G
FEC q3w x 3
trastuzumab q3w cycles 5–17
E
HP (n=107)
trastuzumab +
pertuzumab
TP (n=96)
docetaxel +
pertuzumab
R
docetaxel q3w x 4→FEC q3w x 3
trastuzumab q3w cycles 5–17
Y
FEC q3w x 3
trastuzumab q3w cycles 5–21
Study dosing: q3w x 4
BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide
*Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0
H, trastuzumab; P, pertuzumab; T, docetaxel
Gianni L et al. SABCS 2010
NEOSPHERE: pCR RATES
pCR, %  95% CI
p = 0.0198
p = 0.0141
50
p = 0.003
40
45.8
30
20
29.0
24.0
10
16.8
0
TH
H, trastuzumab; P, pertuzumab; T, docetaxel
THP
HP
TP
Gianni L et al. SABCS 2010
6
HORMONE RECEPTOR STATUS AND pCR
% pCR
Trial/author
pts #
Regimen
HR + %
HR-
HR+
Kemeny
54
FACVb
66
20.0
7.7
Ring
435
CMF, A/E
71
21.6
8.1
Bear
1211
AC
59
13.6
5.7
Bear
565
AC+T
57
22.8
14.1
GEPARDO
250
ddAD+/-T
56
15.4
1.1
GEPARDUO
913
ddAD/CA-D
74
22.8
6.2
GEPARTRIO
286
TAC/TAC-NX
68
36.6
10.1
Guarneri
1731
FAC+/-P
68
23.8
7.8
Gianni
438
A+/P/CMF
63
42.2
11.6
Guarneri
201
FEC/ET/GET
74
16.6
3.5
Colleoni
399
ECF/EC/ET/ViFu
P
68
33.3
7.6
pCR BY HORMONE RECEPTOR STATUS
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response HR: hormone receptors
Baselga J et al. SABCS 2010
CHER-LOB: pCR rate by HR
60
56.2%
50
40
30
25%
35.7%
35.7%
HR-
HR+
26.6%
22.7%
20
10
HR+
HR-
HR+
HR-
0
Arm A (CT + T)
Arm B (CT +L)
Arm C (CT + T + L)
T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib
NEOSPHERE: pCR AND HORMONE
RECEPTORS STATUS
70
pCR, %  95%
CI
60
ER or PR pos
ER and PR neg
50
63.2
40
30
20
36.8
10
0
26.0
5.9
20.0
TH
THP
30.0
29.1
17.4
HP
TP
H, trastuzumab; P, pertuzumab; T, docetaxel
Gianni L et al. SABCS 2010
Chang, ASCO 2011
Chang, ASCO 2011
PST IN HER2+ OPERABLE BREAST
CANCER: KEY FINDINGS
•
•
•
•
•
•
Patient selection is mandatory for the integration of
novel agents in cancer treatment
Chemotherapy + trastuzumab is the gold standard
Double-HER2 blockade increases the pCR rate
Endocrine pathway is still important even in
presence of HER2 co-expression
A dual anti-HER2 blockade + endocrine therapy is
promising
The preoperative setting is ideal to test new
combinations through the “window of opportunity
model”