1. OPEN ISSUES IN MULTIDISCIPLINARY BREAST CANCER MANAGEMENT
Mediterranean School of Oncology
Rome, March 30, 2012
NEOADJUVANT THERAPY
Lucia Mentuccia
Oncologia Medica, Sora

2. Goals of Neoadjuvant Theapy in Breast Cancer
To improve surgical outcomes and options
For operable breast cancer, the aim is to increase the chance of breast conserving surgery in patients who would otherwise require mastectomy
For inoperable locally advanced breast cancers, the aim is to achieve operability
To gain information on tumor response
To define short-term surrogate markers of response

3. 1523 pts with clinical T1-3, N0-N1 breast cancer
NSABP B-18
1523 pts with clinical T1-3, N0-N1 breast cancer
Stratification
• Age
• Clinical Tumor Size
• Clinical Nodal Status
Operation
AC x 4
AC x 4
Operation
Wolmark N t al; J Natl Cancer Inst Monogr. 2001 3

4. Clinical and Pathologic Breast Tumor Response
NSABP B-18:
Clinical and Pathologic Breast Tumor Response
pCR
(63 pts) 9%
36%
cCR
(249 pts) 4%
pNon-Inv
(26 pts)
23%
cPR
(296 pts)
43%
pInv
(160 pts)
cSD + cPD
(140 pts)
20%
Wolmark N t al; J Natl Cancer Inst Monogr. 2001 4

5. NSABP B-18: Surgery Performed
100 40 32 80
Mast
Lump 60 % 40 60 68
P < 0.01 20
Postop-Chemo
Preop- Chemo
Wolmark N t al; J Natl Cancer Inst Monogr. 2001

6. Wolmark N t al; J Natl Cancer Inst Monogr. 2001

7. 7

10. Pts with T1c-3 N0 or T1-3N1 breast cancer
NSABP B-27
2411 pts
Pts with T1c-3 N0 or T1-3N1 breast cancer
Randomization
AC x 4
Tam X 5 Yrs
AC x 4
Tam X 5 Yrs
AC x 4
Tam X 5 Yrs
Surgery
Taxotere x 4
Surgery
Surgery
Taxotere x 4
Bear HD, et al. J ClinOncol. 2006;24(13):

11. Complete Response in Breast
NSABP B-27
Pathologic
Complete Response in Breast
Bear HD, et al. J ClinOncol. 2006;24(13):

12. Disease free-survival
pCR to Neoadjuvant Chemotherapy is correlated with improved DFS & OS (NSABP B-27)
Disease free-survival
Overall Survival
Bear HD, et al. J ClinOncol. 2006;24(13):

13. NSABP B-27: Overall Survival Nodal Status
Pts with pCR
Pts without pCR

14. NSABP B-27: OS, DFS, RFS

15. Preoperative vs postoperative, Overall Survival
The Cochrane Library, Issue 3, 2008

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

18. Intrinsic sub-types have different prognosis and different response to primary CT

19. Response Rates with Neoadjuvant Trastuzumab
Study
Pernas et al 2006, n=16
T → FEC + H
Buzdar et al 2007, n=64
T → FEC + H
Coudert et al 2005, n=33
D + H
Lybaert et al 2006, n=89
X + D + H
Gianni et al 2007, n=115
AT → T → CMF + H
Limentani et al 2007, n=31
D + V + T (including IBC)
Trastuzumab
Griggs et al 2005, n=18
D + H
NOAH, all patients
Hurley et al 2002, n=48
D + cisplatin + H (including IBC)
NOAH, IBC only
Harris et al 2003, n=40
V + H (including IBC)
Lapatinib
Kelly et al 2006, n=37
AC → T + H (including IBC)
Burstein et al 2003, n=40
T + H (including IBC)
Bines et al 2003, n=32
D + H
Baselga et al 2007, n=31
AT → T → CMF + H (IBC only)
Christofanilli et al 2006, n=30
T + L (IBC only) 10 20 30 40 50 60 70 80 90
100
pCR (%)
L, lapatinib; V, vinorelbine; X, capecitabine; FEC, 5-fluorouracil, epirubicin, cyclophosphamide 19

20. Buzdar AU, Clin Cancer Res 2007
The MD Anderson Study
Paclitaxel q3wk x 4
N=19
FEC x 4
BC pts
M0, T1-3, No-1,
HER2+
(FISH or ICH 3+)
N=42 R
Paclitaxel q3wk x 4 + H x 12
N=23
FEC x 4 + H x 12
FEC, 5-fluorouracil, epirubicin, cyclophosphamide
H, trastuzumab
Additional 22 pts
Buzdar AU, Clin Cancer Res 2007

21. pCR with CT  Trastuzumab75
66% 50
% of patients
26% 20
T-FEC
T-FEC + Tras
Buzdar AU, Clin Cancer Res 2007 21 21

22. MD Anderson Neoadjuvant Trial DFS at 72 months FU
Buzdar AU, Clin Cancer Res 2007
Buzdar A et al ASCO Breast 2009 22 22

23. 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
Gianni L et al. Lancet 2010; 375: 377–84 23 23 23 23

24. pCR rates in the NOAH trial: intent-to-treat population
Patients (%) 50
p=0.002 40
39% 30 20
pCR and tpCR
20% 10
With H
Without H
HER2 positive
Gianni L et al. Lancet 2010; 375: 377–84 24 24

25. EFS: HER2-positive population
L. Gianni et al., The Lancet, 2010 25

26. … Future Clinical Practice….

27. Anti-HER2 Treatment: mechanisms of action

28. Three Neoadjuvant Trials Using Targeted Therapies for HER-2 Positive BC

29. San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8-12, 2010
Lapatinib vs trastuzumab in Combination with Neoadjuvant Anthracycline-Taxane-Based CHEMOTHERAPY: Primary Efficacy Endpoint Analysis of The GEPARQUINTO study (GBG 44) Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching P, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G for the GBG /AGO study group
This presentation is the intellectual property of the author/presenter  Contact them for permission to reprint and/or distribute.
Materiale di training ad escliusivo uso interno

33. Conclusions from Run-in Phase (N=60)
Neutropenia Grade III/ IV in 82%
G-CSF made mandatory together with L
Treatment discontinuations in 34.5%
L dose reduced from 1250 to 1000 mg/ d
Diarrhea Grade III/ IV in 6.9%
Loperamide given as stand-by medication for L
* von Minckwitz, M. Untch et al, Ann Oncol 2010
Materiale di training ad escliusivo uso interno

34. Breast Conservation Rate

35. Conclusions
Anthracycline-taxane based CT + T achieved a pCR (ypT0/is ypN-/+) rate of 50% in HER2-positive patients, confirming our previous findings (TECHNO, GeparQuattro)
CT + L (1250/ 1000 mg) resulted in a significantly lower pCR rate of 35% (Caveat: 10% more discontinuations with L).
Compliance of L with EC and Docetaxel was lower than with T.
Results should be seen in the context of other studies like Neo-ALTTO, which uses a higher dose of L (1500 mg/d) but a shorter pre- operative treatment duration.
Materiale di training ad escliusivo uso interno

36. on behalf of the Neo-ALTTO Study Team
First results of the Neo-ALTTO trial (BIG / EGF ): A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer
José Baselga, Ian Bradbury, Holger Eidtmann, Serena Di Cosimo, Claudia Aura, Evandro de Azambuja, Henry Gomez, Phuong Dinh, Karine Fauria, Veerle Van Dooren, Paolo Paoletti, Aron Goldhirsch, Tsai-Wang Chang, Istvan Lang, Michael Untch, Richard D. Gelber and Martine Piccart-Gebhart
on behalf of the Neo-ALTTO Study Team
December 10, 2010 36

37. 52 weeks of anti-HER2 therapy
Study Design S U R
G E Y A N D O M I Z E
lapatinib
trastuzumab
paclitaxel
+ 12 wks
6 wks
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
FEC X 3
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 37 37

38. Efficacy – pCR and tpCR

39. Efficacy – Overall (Clinical) Response at 6 weeks (w/o chemo) and at surgery
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

40. Safety Number (%) of patients with AEs at Grade ≥ 3 L (N= 154)
T (N= 149)
L+T (N= 152)
Diarrhea
36 (23%)
3 (2%)
32 (21%)
Hepatic *
20 (13%)
2 (1%)
13 ( 9%)
Neutropenia
24 (16%)
4 (3%)
Skin disorders
10 (7%)
* Includes 2 patients with Hy’s Law criteria in T, and one patient in L
No major cardiac dysfunction
One death in L+T immediately after end of treatment
L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

41. 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
121 paz
Guarneri V, ASCO 2011 41

42. 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 42

43. 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 43

44. NeoSphere pCR rates: ITT population summary50
p = 0.003 40
pCR, %  95% CI
45.8 30 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 44

45. 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 45 45

46. 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 46 46

47. 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 47 47

48. 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 48 48

49. Neoadjuvant therapy 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
The preoperative setting is ideal to test new combinations through the “window of opportunity model”

50. Neo Adjuvant Systemic Therapy
Should neoadjuvant regimens for HER2-positive disease always contain anti-HER2 drug?
87.2%
8.5%
4.3%
Yes No A
Is dual HER2-targeting a reasonable option for the preoperative setting for HER2 disease?
21.7%
67.4%
10.9%
Yes No A
St Gallen 2011 50 50

51. Von Minckwitz G, SABCS 2010

52. Von Minckwitz G, SABCS 2010

53. Von Minckwitz G, SABCS 2010 53

54. OBJECTIVES
Von Minckwitz G, SABCS 2010

55. Von Minckwitz G, SABCS 2010

56. CHARACTERISTICS OF PATIENTS

57. Von Minckwitz G, SABCS 2010

58. Neoadjuvant Bevacizumab and Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast Cancers: Secondary Endpoint Analysis of the GEPARQUINTO Study (GBG 44)
Gerber B et al.
Proc ASCO 2011;Abstract 1006.
Gerber B et al. Proc ASCO 2011;Abstract 1006.
Gerber B et al. Proc ASCO 2011;Abstract 1006.

59. Benefit of bev limited to TNBC subgroup
GEPARQUINTO: Benefit of Bevacizumab Added to Neoadjuvant Chemotherapy in TNBC Subgroup
Benefit of bev limited to TNBC subgroup
pCRbreast (with bev vs without bev)*
TNBC patients: 36.4 vs 27.8% (p = 0.021)
All patients: 15.0 vs 17.5% (p = NS)
* pCRbreast = no inv/non-inv in breast and nodes
Gerber B et al. Proc ASCO 2011;Abstract 1006.
Gerber B et al. Proc ASCO 2011;Abstract 1006. 59 59 59 59

60. The Effect of pCR of Bevacizumab and/or Antimetabolites Added to Standard Neoadjuvant Chemotherapy: NSABP Protocol B-40
Bear HD et al.
Proc ASCO 2011;Abstract LBA1005.
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.

61. Operable Breast Cancer
NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable HER2-Negative Breast Cancer
Tissue for Biomarkers
Tissue for Biomarkers
SURGERY
Operable Breast Cancer R
+/-
X10
T docetaxel X capecitabine G gemcitabine B bevacizumab
+/-

62. NSABP B-40: Benefit of Adding Bevacizumab to Standard Chemotherapy
Benefit of bev predominant in HR+ and not TNBC patient subgroup
pCRbreast (with bev vs without bev):
HR+ patients: 23.3 vs 15.2% (p = 0.008)
TNBC patients: 51.3 vs 47.3% (p = 0.44)
Bear HD et al. Proc ASCO 2011;Abstract LBA1005. 62 62 62 62

63. Neo Adjuvant Systemic Therapy
Is neodjuvant endocrine therapy alone a reasonable option for postmenopausal pts with highly endocrine-responsive disease?
97.8%
2.2% 0%
Yes No A
If YES, for which duration (choose one)?
15.2%
3-4 months
4-8 months
Maximal response
39.1%
45.7%
St Gallen 2011 63

64. Grazie! 64