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Terapia NeoadiuvanteRevisione delle evidenze scientifiche
Valentina GuarneriNonantola, 19 Novembre 2011
The Cochrane Library, Issue 3, 2008
DDFS o OS???
Preoperative vs postoperative, Overall Survival
The Cochrane Library, Issue 3, 2008
pCR vs residual disease, Overall Survival
T-FEC 19 pts
T-FEC + H
23 pts
pCR 26.3 % 65.2 %
pCR ER pos 27 % 61 %
pCR ER neg 25 % 70 %
pN0 78.9 % 86.9 %
Buzdar, J Clin Oncol 2005
NEOADJUVANT P-FEC TRASTUZUMAB IN HER2+ OPERABLE BREAST CANCER
Buzdar AU, Clin Cancer Res 2007
CMFq4w x 3 cycles
NOAH
HER2-positive LABC(IHC 3+ or FISH+)
ATq3w x 3 cycles
Tq3w x 4 cycles
H + ATq3w x 3 cycles
H + T q3w x 4 cycles
H q3w x 4 cycles+ CMF q4w x 3 cycles
H continued q3wto week 52
(n=115) (n=113)
ATq3w x 3 cycles
Tq3w x 4 cycles
CMFq4w x 3 cycles
HER2-negative LABC(IHC 0/1+)
Surgery followed byradiotherapya
(n=99)
Surgery followed byradiotherapya
Surgery followed byradiotherapya
19 crossed over to H
Gianni L, Lancet 2010
HR negative, or HR+ with cN+
GEPAR-QUATTRO: EFFICACY OUTCOMES
0
10
20
30
40
50
60
70
80
ypT0 ypTis ypT0/is, N0 ypN0
Untch M, J Clin Oncol 2010
Untch M et al, J Clin Oncol 2011
Stratification:• T ≤ 5 cm vs. T > 5 cm•ER or PgR + vs. ER & PgR –• N 0-1 vs. N ≥ 2•Conservative surgery or not
Invasive operableHER2+ BCT > 2 cm (inflammatory BC excluded)LVEF 50%N=450
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
lapatinibtrastuzumab
FEC
X
3
SURGERY
RANDOMIZE
lapatinib
trastuzumab
lapatinibtrastuzumab
paclitaxel
paclitaxel
paclitaxel
+ 12 wks6 wks
NEO-ALTTO STUDY DESIGN
Baselga J et al. SABCS 2010
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response
Neo-ALLTO: PATHOLOGIC RESPONSE
Baselga J et al. SABCS 2010
RANDOMIZATION Lapatinib 1000 mg/daily
Lapatinib 1500 mg/daily
CORE
BIOPSY
SURGERY
Chemotherapy
A
B
C
TXL 80 mg/m2
Trastuzumab 2 mg/kg
5 FU 600 mg/m2
Epi 75 mg/m2
CTX 600 mg/m2
CHER LOB Trial: study plan
Guarneri V, ASCO 2011
pCR (breast & axilla) Node negativity Breast conservation
0
10
20
30
40
50
60
70
80
90
Arm A:CT +trastuzumab
Arm B: CT +lapatinib
Arm C: CT +trastuzumab/lapatinib
CHER-LOB: EFFICACY OUTCOMES
Guarneri V, ASCO 2011
THP (n=107)docetaxel + trastuzumab +pertuzumab
HP (n=107)trastuzumab + pertuzumab
TP (n=96)docetaxel + pertuzumab
S
U
R
G
E
R
Y
docetaxel q3w x 4→FEC q3w x 3 trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–17
FEC q3w x 3trastuzumab q3w cycles 5–21
Study dosing: q3w x 4
TH (n=107)docetaxel + trastuzumab
Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumors >2cm (N=417)
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, M0H, trastuzumab; P, pertuzumab; T, docetaxel
NEOSPHERE: STUDY DESIGN
Gianni L et al. SABCS 2010
H, trastuzumab; P, pertuzumab; T, docetaxel
NEOSPHERE: pCR RATES
p = 0.014150
40
30
20
10
0TH THP HP TP
pC
R, %
9
5%
CI
p = 0.0198p = 0.0198
p = 0.003
29.0
45.8
16.8
24.0
6Gianni L et al. SABCS 2010
Trial/author pts # Regimen HR + %
% pCR
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/ViFuP
68 33.3 7.6
HORMONE RECEPTOR STATUS AND pCR
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response HR: hormone receptors
pCR BY HORMONE RECEPTOR STATUS
Baselga J et al. SABCS 2010
T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib
CHER-LOB: pCR rate by HR
25%22.7%
0
10
20
30
40
50
60
Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L)
26.6%
35.7%
56.2%
35.7%
HR+ HR+HR+HR- HR-HR-
0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR posER and PR neg
20.026.0
17.4
36.8
29.1 30.0
63.2
5.9
pC
R, %
9
5%
C
I
H, trastuzumab; P, pertuzumab; T, docetaxelGianni L et al. SABCS 2010
NEOSPHERE: pCR AND HORMONE RECEPTORS STATUS
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”
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