1. Terapia Neoadiuvante Revisione delle evidenze scientifiche
Valentina Guarneri
Nonantola, 19 Novembre 2011

2. Preoperative vs postoperative, Overall Survival
DDFS o OS???
The Cochrane Library, Issue 3, 2008

3. pCR vs residual disease, Overall Survival
The Cochrane Library, Issue 3, 2008

4. Buzdar AU, Clin Cancer Res 2007
NEOADJUVANT P-FEC TRASTUZUMAB IN HER2+ OPERABLE BREAST CANCER
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 %
In particular,
the DMC requested that they be presented with a
calculation of the probability of eventually (ie, after the full
sample size of 164 patients), showing statistical significance
in pCR rates favoring the trastuzumab plus chemotherapy
arm, based on the currently available information. This
probability was 95%. TheDMCfound this to be compelling
evidence that the study had reached its primary objective
and recommended that accrual be suspended.
The pCR data for the first 34 patients, as reviewed
Buzdar, J Clin Oncol 2005
Buzdar AU, Clin Cancer Res 2007 4

5. NOAH HER2-positive LABC (IHC 3+ or FISH+)
AT q3w x 3 cycles
T q3w x 4 cycles
CMF q4w x 3 cycles
HER2-negative LABC (IHC 0/1+)
Surgery followed by radiotherapya
(n=99)
(n=115)
(n=113)
H + AT q3w x 3 cycles
AT q3w x 3 cycles
H + 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
Surgery followed by radiotherapya
Surgery followed by radiotherapya
H continued q3w to week 52
19 crossed over to H 5 5 5

6. Gianni L, Lancet 2010

7. HR negative, or HR+ with cN+

8. GEPAR-QUATTRO: EFFICACY OUTCOMES80 70 60 50 40 30 20 10
ypT0
ypTis
ypT0/is, N0
ypN0
Untch M, J Clin Oncol 2010

9. Untch M et al, J Clin Oncol 2011

14. NEO-ALTTO STUDY DESIGNR
G E Y A N D O M I Z E
lapatinib
trastuzumab
paclitaxel
+ 12 wks
6 wks
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 operable
HER2+ BC
T > 2 cm
(inflammatory BC
excluded)
LVEF  50%
N=450
lapatinib
FEC X 3
trastuzumab
lapatinib
trastuzumab
34 weeks
52 weeks of anti-HER2 therapy
Baselga J et al. SABCS 2010 14

15. Neo-ALLTO: PATHOLOGIC RESPONSE
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab
pCR pathologic complete response
Baselga J et al. SABCS 2010 15

16. CHER LOB Trial: study plan
RANDOMI
ZATI ON
Lapatinib 1000 mg/daily
Lapatinib 1500 mg/daily
CORE BI
OPSY S
URGE RY 
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
Guarneri V, ASCO 2011

17. CHER-LOB: EFFICACY OUTCOMES10 20 30 40 50 60 70 80 90
Arm A:CT +
trastuzumab
Arm B: CT +
lapatinib
Arm C: CT +
trastuzumab/lapatinib
pCR (breast & axilla)
Node negativity
Breast conservation
Guarneri V, ASCO 2011

18. NEOSPHERE: STUDY DESIGN
TH (n=107) docetaxel + trastuzumab S U R G E Y
FEC q3w x 3
trastuzumab q3w cycles 5–17
trastuzumab q3w cycles 5–21
Patients with operable or locally advanced /inflammatory* HER2-positive BC
Chemo-naïve & primary tumors >2cm (N=417)
THP (n=107) docetaxel + trastuzumab + pertuzumab
HP (n=107) trastuzumab + pertuzumab
docetaxel q3w x 4→FEC q3w x 3
trastuzumab q3w cycles 5–17
TP (n=96) docetaxel + pertuzumab
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 18

19. NEOSPHERE: pCR RATES pCR, %  95% CI 45.8 29.0 24.0 16.8 50 40 30 20
The main therapeutic result showed a very high rate of tumor eradication in th breast when pertuzumab was added to the conventional trastuzumab and docetaxel combination: 46.8 % for the triplet regimen and 29 % for the comparator arm. pCR accounted for 16.8% in women receiving the two monoclonals without chemotherapy, and 24% when pertuzumab and docetaxel were used 20
29.0
24.0 10
16.8
H, trastuzumab; P, pertuzumab; T, docetaxel TH
THP HP TP
Gianni L et al. SABCS 2010 6 19

20. HORMONE RECEPTOR STATUS AND pCR
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
565
AC+T 57
22.8
14.1
GEPARDO
250
ddAD+/-T 56
15.4
1.1
GEPARDUO
913
ddAD/CA-D 74
6.2
GEPARTRIO
286
TAC/TAC-NX 68
36.6
10.1
Guarneri
1731
FAC+/-P
23.8
7.8
Gianni
438
A+/P/CMF 63
42.2
11.6
201
FEC/ET/GET
16.6
3.5
Colleoni
399
ECF/EC/ET/ViFuP
33.3
7.6 20

21. 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 21

22. CHER-LOB: pCR rate by HR
25%
22.7% 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%
HR+
HR-
T: trastuzumab; L: lapatinib; T+L: trastuzumab plus lapatinib 22

23. NEOSPHERE: pCR AND HORMONE RECEPTORS STATUS70 60
ER or PR pos
ER and PR neg 50
63.2 40
pCR, %  95% CI 30 . 20
36.8
30.0 10
29.1
26.0
20.0
5.9
17.4
H, trastuzumab; P, pertuzumab; T, docetaxel TH
THP HP TP
Gianni L et al. SABCS 2010 23

24. Chang, ASCO 2011

25. Chang, ASCO 2011

26. 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”