Terapia Neoadiuvante Revisione delle evidenze scientifiche Valentina Guarneri Nonantola, 19 Novembre 2011
Dec 14, 2015
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”