1. Neo-­‐adjuvant
Treatment
in
Breast
Cancer
Past,
Present
and
Future
Noa
Efrat
Ben-­‐Baruch
Kaplan
Medical
Center
Rehovot,
Israel

2. Past,
Present
and
Future
• Inoperable
breast
cancer
– Haagensen
grave
signs
• Operable
Breast
cancer
– One
size
fits
all
– Is
it
beGer
than
adjuvant
therapy?
– Treat
by
biological
subtypes
– Use
for
rapid
approval
of
new
drugs
– Use
for
screening
of
molecularly
targeted
drugs

3. • 1.Skin
ulceraPon
• 2.FixaPon
of
tumor
to
the
chest
wall
• 3.Axillary
nodes
>
2.5
cm
in
diameter
• 4.Edema
of
<
1/3rd
of
the
skin
of
breast
• 5.Presence
of
fixed
axillary
nodes

4. Relation Between Clinical Presentation and Outcomes:
LABC, IBC, and Non-LABC/IBC
Hance et al. JNCI 2005; 97: 966

9. Past,
Present
and
Future
• Inoperable
breast
cancer
– Haagensen
grave
signs
• Operable
Breast
cancer
– One
size
fits
all?
– Is
it
be3er
than
adjuvant
therapy?
– Treat
by
biological
subtypes
– Use
for
rapid
approval
of
new
drugs
– Use
for
screening
of
molecularly
targeted
drugs

10. Operation
Operation
AC X4
+ TAM if >50 years
AC X4
+ TAM if >50 years
NSABP Protocol B-18
Operable Breast Cancer
Stratification
Age
Clinical Tumor Size
Clinical Nodal Status

11. 79
36
0%
40%
20%
Tumor Response (685pts.)
100%
80%
60%
PR cCR
13
pCR
*25% pCR w DCIS

12. NSABP B-18:Neoadjuvant Chemotherapy
Increases the Likelihood of BCT for
Operable Breast Cancer
40
60
32
68
0
80
60
40
20
100
Postop Preop
%
P<.01
For >5 cm tumors,
22% BCT versus 8%
Mastectomy
Lumpectomy
Fisher B, et al. J Clin Oncol. 1997;15(7): 2483-2493.

13. 90
80
70
60
50
40
30
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Survival
N Ev HR P
Post 751 311
Pre 742 308 .99 0.90

14. 40
30
50
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
N Ev HR
No pCR
pCR
599 344
86 29 .47
No pCR
NSABP B-18: DFS and pCR
P<.0001
75
pCR
52
100
90
80
70
% 60
Years
Wolmark N. Presented at: National Cancer Institute State of the Science Conference on Preoperative Therapy
in Invasive Breast Cancer; March 26-27, 2007; Bethesda, Maryland.

15. B-27
OPERABLE BREAST CANCER
Age, T, cN
AC
OPERATION
AC→Txt*
OPERATION
*100mg/m² x 4; Tam for all
AC
OPERATION
Txt

26. Past, Present and Future
• Inoperable breast cancer
– Haagensen grave signs
• Operable Breast cancer
– One size fits all
– Is it better than adjuvant therapy?
– Treat by biological subtypes
– Use for rapid approval of new drugs
– Use for screening of molecularly targeted drugs

27. HER
Family
Signaling
Hudis
C.
N
Engl
J
Med
2007

28. 0 10 20 30 40 50 60 70 80 90 100
Christofanilli et al 2006, n=30
Bines et al 2003, n=32
Burstein et al 2003, n=40
Kelly et al 2006, n=37
Harris et al 2003, n=40
Hurley et al 2002, n=48
Griggs et al 2005, n=18
Limentani et al 2007, n=31
Gianni et al 2007, n=115
Lybaert et al 2006, n=89
Coudert et al 2005, n=33
Buzdar et al 2007, n=64
Pernas et al 2006, n=16
Response Rates with Neoadjuvant Trastuzumab
pCR (%)
T + L (IBC only)
D + H
T + H (including IBC)
AC → T + H (including IBC)
V + H (including IBC)
D + cisplatin + H (including IBC)
D + H
D + V + T (including IBC)
X + D + H
AT → T → CMF + H
D + H
T → FEC + H
T → FEC + H
Study
L, lapatinib; V, vinorelbine; X, capecitabine;
FEC, 5-fluorouracil, epirubicin, cyclophosphamide
AT → T → CMF + H (IBC only)Baselga et al 2007, n=31
Trastuzumab
NOAH, IBC only
Lapatinib
NOAH, all patients

29. Phase
3
MDACC
trial
P
q3w
x
4
→
FEC
q3w
x
4
Eligibility
Invasive
operable
HER
2+
breast
cancer
Stage
II
to
IIIA
LVEF
≥
45%
StraRficaRon
Size
(T)
node
status
ER/PR
S
U
R
G
E
R
Y
R
P
q3w
x
4
+
H
qw
→
FEC
q3w
x
4
+
H
qw
C
=
cyclophosphamide,
E
=
epirubicin,
F
=5-­‐fluorouracil,
H
=
HercepPn,
P
=
paclitaxel
n=23 + 22
n=19
Primary objective: pCR rate (ypT0 and ypN0)
The
planed
sample
size
was
164
pts.
A`er
34
pts
had
completed
therapy,
the
trial
was
stopped
b/c
superiority
of
H
+
chemo
J
clin
Oncol.
2005;
23:
3676
Clin
Cancer
Res.
2007;
13:
228

30. 66%
26%
T-FEC T-FEC + Tras
0
20
50
75
%ofpatients
pCR with CT ±Trastuzumab
Buzdar AU, Clin Cancer Res 2007

31. P=0.041
Clin
Cancer
Res.
2007;
13:
228
P
+
FEC
alone
(n=19)
P
+
FEC
+H
(n=45)
pCR,
percentage
(95%CI)
26.3
(9-­‐51)
60
(44.3-­‐74.3)
85.3%

32. CMF
q4w x 3 cycles
NOAH
HER2-positive LABC
(IHC 3+ or FISH+)
AT
q3w x 3 cycles
T
q3w x 4 cycles
H + AT
q3w x 3 cycles
H + T
q3w x 4 cycles
H q3w x 4 cycles
+ CMF q4w x 3 cycles
H continued q3w
to week 52
(n=115) (n=113)
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)
Surgery followed by
radiotherapya
Surgery followed by
radiotherapya
19 crossed over to H
Gianni L et al. Lancet 2010; 375: 37

33. Patients
(%)
39%
20%
0
10
20
30
40
50
With H Without H
HER2 positive
p=0.002
pCR rates in the NOAH trial:
intent-to-treat population
Gianni L et al. Lancet 2010; 375: 37

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

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

36. NeoALTO Study Design
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
34 weeks
52 weeks of anti-HER2 therapy
lapatinib
trastuzumab
lapatinib
trastuzumab
F
E
C
X
3
S
U
R
G
E
R
Y
R
A
N
D
O
M
I
Z
E
lapatinib
trastuzumab
lapatinib
trastuzumab
paclitaxel
paclitaxel
paclitaxel
+ 12 wks6 wks

37. Efficacy – pCR and tpCR

38. NeoSphere: study design
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
3
trastuzumab
q3w
cycles
5–17
FEC
q3w
x
3
trastuzumab
q3w
cycles
5–17
FEC
q3w
x
3
trastuzumab
q3w
cycles
5–21
Study
dosing:
q3w
x
4
TH
(n=107)
docetaxel
+
trastuzumab
PaPents
with
operable
or
locally
advanced
/
inflammatory*
HER2-­‐posiPve
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,
M0
H,
trastuzumab;
P,
pertuzumab;
T,
docetaxel
Gianni L et al. SABCS 2010

39.
H,
trastuzumab;
P,
pertuzumab;
T,
docetaxel
NeoSphere pCR rates: ITT population
summary
p
=
0.0141
50
40
30
20
10
0
TH
THP
HP
TP
pCR,
%
±
95%
CI
p
=
0.0198
p
=
0.003
29.0
45.8
16.8
24.0
6
Gianni L et al. SABCS 2010

40. 0
10
20
30
40
50
60
70
TH THP HP TP
ER or PR pos
ER and PR neg
20.0
26.0
17.4
36.8
29.1 30.0
63.2
5.9
pCR,%±95%
CI
H, trastuzumab; P, pertuzumab; T, docetaxel
Gianni L et al. SABCS 2010
NEOSPHERE: pCR and hormone receptors
status

41. Triple
NegaPve
Breast
Cancer
Bevacizumab?

42. Von
Minckwitz
G,
SABCS
2010

43. 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.

44. GEPARQUINTO: Benefit of Bevacizumab
Added to Neoadjuvant Chemotherapy in
TNBC Subgroup
Gerber B et al. Proc ASCO 2011;Abstract 1006.
• 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.

45. Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
Operable
Breast
Cancer
R
Tissue for
Biomarkers
S
U
R
G
ER
Y
Tissue for
Biomarkers
+/-
+/-
X10
T docetaxel
X capecitabine
G gemcitabine
B bevacizumab
NSABP B-40: Chemotherapy ±
Bevacizumab in Patients with Operable
HER2-Negative Breast Cancer
Endpoints: pCR, cCR, DFS, gene expression patterns

46. T - AC TX - AC* TG - AC*
pCRbreast (n = 395; 394; 391) 32.7% 29.7% 32.0%
pCRbreast + nodes (n = 393; 390; 388) 26.0% 23.3% 27.3%
* p-value not significant versus T - AC
T = docetaxel; X = capecitabine; G = gemcitabine
NSABP B-40: Effect of
Capecitabine or Gemcitabine Added
to Docetaxel on pCR Rates
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.

47. NSABP B-40: Benefit of Adding Bevacizumab
to Standard Chemotherapy
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
• 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)

48. Past, Present and Future
• Inoperable breast cancer
– Haagensen grave signs
• Operable Breast cancer
– One size fits all
– Is it better than adjuvant therapy?
– Treat by biological subtypes
– Use for rapid approval of new drugs
– Use for screening of molecularly targeted
drugs

49. Background
PI: Laura Esserman M.D. and UCSF
The I-SPY TRIALS
I-SPY 1àI-SPY 2
National trials to integrate imaging and tissue
biomarkers to
Predict response to Rx à Tailor Rx to response

53. clinicaloptions.com/oncology
An Update on Breast Cancer
I-SPY2: Efficacy of Neoadjuvant Veliparib/
Carboplatin + Paclitaxel
Signature, % Estimated pCR Rate
(95% Probability Interval)
Probability Veliparib/
Carboplatin Superior to
Control
Predictive Probability
of Success in
Phase III Trial
HR+ HR-
All HER2- 33 (22-43) 22 (10-35) 92 55
HR+/HER2- 14 (4-27) 19 (6-35) 28 9
HR-/HER2- 52 (35-69) 26 (11-40) 99 90
Rugo HS, et al. SABCS 2013. Abstract S5-02. Reproduced with permission.
Estimated pCR Rate:
All HER2- Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
pCR Rate
Control
V/C
Probability V/C
is superior to
control = 0.92
Estimated pCR Rate:
Triple-Negative Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
pCR Rate
Control
V/C
Probability V/C
is superior to
control = 0.99
Estimated pCR Rate:
HER2-/HR+ Signature
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
pCR Rate
Control
V/C
Probability V/C
is superior to
control = 0.28

54. clinicaloptions.com/oncology
An Update on Breast Cancer
I-SPY2: Conclusions
§ Adaptive trial design found veliparib/carboplatin treatment
efficacious in patients with triple-negative breast cancer
– Trial not designed to evaluate individual contributions of
veliparib and carboplatin
§ Adverse events increased with veliparib/carboplatin
regimen
– Toxicity may be managed with dose reductions and delay
§ I-SPY2 trial design efficiently evaluated treatment regimen
in patient subsets based on biomarker analysis
– Additional response predictors currently under investigation
Rugo HS, et al. SABCS 2013. Abstract S5-02.

55. pCR as Regulatory Endpoint

57. Past, Present and Future
• Inoperable breast cancer
– Haagensen grave signs
• Operable Breast cancer
– One size fits all
– Is it better than adjuvant therapy?
– Treat by biological subtypes
– Use for rapid approval of new drugs
– Use for screening of molecularly targeted drugs