Transcript Triple-Negative Breast Cancers: The Search for Targets

Triple negative breast cancer
19th Annual NOCR meeting
Las Vegas, March 15th 2013
Ruth M. O’Regan, MD
Professor and Vice-Chair for
Educational Affairs, Department of
Hematology and Medical Oncology,
Emory University,
Chief of Hematology and Medical
Oncology, Georgia Cancer Center for
Excellence, Grady Memorial Hospital
Natural history of “triple negative” breast
cancers
Basal/TN
Basal/TN
Copyright ©2003 by the National Academy of Sciences
Sorlie et al PNAS 2003
Triple negative breast cancers
 High grade aggressive cancers with a
high propensity to distant metastases in
short-term
 Poor outcome is multi-factorial but is
associated with
 Chemo-resistance (only about one-third
respond to chemotherapy)
 Lack of molecular targets towards which
novel agents can be developed
Topics to be covered
 Triple negative subtyping
 Use of pre-operative chemotherapy
 Activity of chemo-therapeutics in TNBC
from pre-operative and metastatic
trials
 Clinical data on potential targets in
TNBC
 Chemo-resistant TNBC
Iniparib does not improve outcome in unselected
metastatic triple negative breast cancer
GC
(N=258)
PFS
Median PFS, mos
(95% CI)
HR (95% CI)
p-value
0.9
OS
4.1
5.1
(3.1, 4.6)
(4.2, 5.8)
0.79 (0.65, 0.98)
0.027
0.9
Pre-specified alpha = 0.01
0.8
GC
GCI
(N=258) (N=261)
11.1
11.8
(9.2, 12.1) (10.6, 12.9)
0.88 (0.69, 1.12)
0.28
Pre-specified alpha = 0.04
0.8
0.7
0.6
0.5
0.4
0.3
0.7
0.6
0.5
0.4
0.3
0.2
0.2
0.1
0.1
0
Median OS, mos
(95% CI)
HR (95% CI)
p-value
1.0
Probability of Survival
Probability of Progression Free Survival
1.0
GCI
(N=261)
0
2
4
6
8
10
12
14
Months Since Study Entry
No. at risk
0
16
0
2
4
6
8
10
12
14
16
Months
No. at risk
GC
258
171
116
63
38
18
6
1
0
GC
258
239
214
181
151
99
38
11
0
GCI
261
187
138
83
53
11
2
0
0
GCI
261
248
230
204
169
111
52
15
0
O’Shaughnessy PASCO 2011
Sub-types of triple negative
breast cancer
• Evaluated gene expression profiles from
21 breast cancer data sets (14 training
and 7 validation = 587 cases of TNBC)
• Used cluster analysis to sub-divide
TNBC into 6 sub-types displaying unique
gene expression and ontologies
• Identified breast cancer cells lines
representative of each subtype
Lehmann et al JCI 2011
Basal-like 1: cell cycle,
DNA repair and
proliferation genes
Basal-like 2: Growth factor
signaling (EGFR, MET, Wnt,
IGF1R)
IM: immune cell
processes (medullary
breast cancer)
M: Cell motility and
differentiation, EMT
processes
MSL: similar to M but
growth factor signaling, low
levels of proliferation genes
(metaplastic cancers)
Lehmann et al JCI 2011
LAR: Androgen receptor
and downstream genes,
luminal features
Sub-types demonstrate differential response to therapies in vivo
Vehicle
Cisplatin
Anti-androgen
P13K/mTOR
inhibitor
Lehmann et al JCI 2011
Importance of Pathologic CR
Overall Survival
Liedtke et al. JCO 2008; 26(8): 1275-81
Among Basal-like Tumors
RCB I (n = 2)
RCB 0 (n = 16)
RCB II (n = 17)
RCB III (n= 9)
Log-rank P = 5.5 x 10-7
Incidence of pCR by Breast
Cancer Subtype
• 107 patients treated with neoadjuvant AC and
hormone therapy if HR+.
Response
Type
All
Patients
N=107
(%)
Basal Like
N=34
(%)
HER2
N=11
(%)
Luminal B
N=26
(%)
Luminal A
N=36
(%)
CR
14
29
10
8
6
PR
47
56
60
50
33
SD
38
15
30
42
58
PD
1
0
0
0
3
pCR
16
27
36
15
0
Carey et al; Clin Cancer Res 2007; 13(8)
Neoadjuvant Cisplatin in BRCA1-deficient and Triple
Negative Breast Cancer
Patient Population
Stage
Regimen
Pathological Complete
Response, n (%)
BRCA1 mutation
(n = 25)
I – III*
Cisplatin 75 mg/m2 q3w
X4
18 (72%)
Triple negative
(n = 28)
II - III
Cisplatin 75 mg/m2 q3w
X4
6 (22%)**
Triple negative
(n = 51)
II - III
Cisplatin 75 mg/m2 q3w
X4 + bevacizumab 15
mg/kg q3w X3
8 (16%)
Triple negative
(n = 78)
II - III
Multiple cisplatin based***
NA (32%)
Bottom line: Activity of platinums in TNBC appears similar to other
agents but appear particularly active in cancers with mutations of
BRCA (and maybe in cancers with other defects in DNA repair)
Gronwald et al. J Clin Oncol 2009
Ryan et al. J Clin Oncol 2009
Garber et al. Breast Cancer Res Treat 2006
Leone et al. J Clin Oncol 2009
GEICAM Phase II Study
Stratification
criteria:
•Tumor size (<1 cm vs.
1-2cm vs. 2-5 cm vs.
>5)
•Tumor grade (I vs. II
vs. III)
•Nodal status (N0 vs.
N1/N2).
•Basal-like by IHC
R
A
N
D
O
M
I
Z
A
T
I
O
N
Alba E, et al. Abstract 74933, ASCO 2011
ARM A
ARM B
Epirubicin 90mg/m2 +
Cyclophosphamide 600mg/m2
(q 21 days x 4 courses)
pCR =35%
followed
by
Docetaxel 100mg/m2
(q 21 days x 4 courses)
Epirubicin 90mg/m2 +
Cyclophosphamide 600mg/m2
(q
21 =30%
days x 4 courses)
pCR
followed by
Docetaxel 75mg/m2 +
Carboplatin AUC 6 mg/ml/min
(q 21 days x 4 courses)
Capecitabine ± Ixabepilone in
Triple Negative MBC
Efficacy
Ixa + Cape (n =
191)
Cape
(n =
208)
31%
15%
CR
3%
1%
PR
28%
14%
4.2 mos
1.7 mos
ORR
Median PFS
HR
0.63
P value
Median OS
HR
P value
Rugo et al. SABCS 2008, Abstract 3057
< .0001
10.3 mos
(n = 213)
9.0 mos
(n = 230)
0.87
.18
Pooled triple negative subgroup (n = 443)
Iniparib does not improve outcome in unselected
metastatic triple negative breast cancer
GC
(N=258)
PFS
Median PFS, mos
(95% CI)
HR (95% CI)
p-value
0.9
OS
4.1
5.1
(3.1, 4.6)
(4.2, 5.8)
0.79 (0.65, 0.98)
0.027
0.9
Pre-specified alpha = 0.01
0.8
GC
GCI
(N=258) (N=261)
11.1
11.8
(9.2, 12.1) (10.6, 12.9)
0.88 (0.69, 1.12)
0.28
Pre-specified alpha = 0.04
0.8
0.7
0.6
0.5
0.4
0.3
0.7
0.6
0.5
0.4
0.3
0.2
0.2
0.1
0.1
0
Median OS, mos
(95% CI)
HR (95% CI)
p-value
1.0
Probability of Survival
Probability of Progression Free Survival
1.0
GCI
(N=261)
0
2
4
6
8
10
12
14
Months Since Study Entry
No. at risk
0
16
0
2
4
6
8
10
12
14
16
Months
No. at risk
GC
258
171
116
63
38
18
6
1
0
GC
258
239
214
181
151
99
38
11
0
GCI
261
187
138
83
53
11
2
0
0
GCI
261
248
230
204
169
111
52
15
0
O’Shaughnessy PASCO 2011
PARP Inhibitor Trials – Activity Seen
Only in BRCA1/2 Mutation Carriers
Agent
Author
BRCA1/BRCA2
TNBC
Response
Rate
Olaparib
Fong
60 patients
37% -BRCA1/2
mutations
N/A
63% clinical
benefit rate
(phase I; mixture
tumor types)
(only in BRCA associated
cancers)
Olaparib 400 mg
po BID
Tutt
27 patients
BRCA1 67%
BRCA2 33%
50%
41%
ABT888
+temozolomide
Isakoff
41 patients
BRCA1: 7.3%
BRCA2: 12%
56%
BRCA 1 and 2:
37.5%
No response in
normal BRCA
status
1. Fong PC, et al. N Engl J Med. 2009; 361:123-34; 2. Tutt, et all. Lancet 2010. Vol. 376 No. 9737 pp 235-244; 3. Isakoff et al. J Clin Oncol 28:15s, 2010
(suppl; abstr 1019) ;
Angiogenic inhibitors in triple
negative breast cancer
• Addition of bevacizumab to paclitaxel in
1st line triple negative metastatic breast
cancer significantly improves DFS (HR
0.47)
• Addition of bevacizumab to
chemotherapy significantly improves
DFS in 2nd line triple negative
metastatic breast cancer (HR 0.53
versus HR-positive 0.89 (NS))
Miller at al NEJM, Brufsky el al PASCO 2010
Neoadjuvant Chemo plus Carboplatin +/Bevacizumab in Stage II-III TNBC
(Phase II CALGB 40603)
Paclitaxel 80mg/m2 wkly x4
ddAC x4
Paclitaxel 80mg/m2 wkly x4
ddAC x4
Bevacizumab 10mg/kg q2w x 9
Paclitaxel 80mg/m2 wkly x4
4-8 wks after last
ddAC
ddAC x4
Carboplatin AUC 6 q3w x 4
Paclitaxel 80mg/m2 wkly x4
Surgery
ddAC x4
XRT
No adjuvant chemo
planned
Bevacizumab 10mg/kg q2w x 9
Carboplatin AUC 6 q3w x 4
Sikov WM, et al. J Clin Oncol. 2010;28:15s (Abstract TPS 110).
Phase II Neoadjuvant Trial of Sorafenib in
combination with Cisplatin followed by dose
dense Paclitaxel for ER-, PR-, Her2- (Triple
Negative) Early-stage Breast Cancer
PET
Biopsy
PET
Biopsy
Early Stage
Triple Negative
BreastCancer
Sorafenib
400 mg po
bid x 4 weeks
Biopsy
Cisplatin
mg/m2
75
q3wk
x 4 cycles
PET
Paclitaxel
175 mg/m2 q2wk
x 4 cycles
Sorafenib 400 mg po bid
Surgery
Is EGFR a viable target for triple negative
breast cancer?
EGFR/HER1
K-Ras
GRO1
TCF4
Frizzled 7
Laminin gamma 2
c-KIT
Keratin 5
Keratin 17
P-Cadherin
Randomized Phase II:
Cetuximab +/- Carboplatin for Triple-Negative MBC
R
A
N
D
O
M
I
Z
E
Cetuximab + Carboplatin at
Progression
N=22
Cetuximab
N=31
Cetuximab + Carboplatin
N=49
Arm 1
Cetuximab  Cetuximab +
carboplatin
N
Arm 2
Cetuximab +
carboplatin
Arm 1b + 2
31
24
71
95
ORR
CR
PR
2 (6%)
0
2 (6%)
4 (17%)
0
4 (17%)
12 (17%)
1 (1%)
11 (15%)
16 (17%)
1 (1%)
15 (16%)
SD
5 (16%)
6 (25%)
16 (23%)
22 (23%)
Carey et al. J Clin Oncol 2012
EGFR inhibitors in TNBC
PD01-01
Met TNBC
≤ 1 chemo
for mets
Cisplatin + Cetuximab (n=114)
R
Cisplatin (n=57)
Cis + EGFR
Cis
p
Response (%)
20
10
0.5
PFS (mo)
3.7
1.5
0.032
Baselga et al SABCS 2010
Phase 2 trial of bicalutamide
in AR+ ER- PR- MBC
• Screening 452 patients with TNBC: 51
(12%) were AR+
• 26 patients were treated with
bicalutamide 150mg daily
• No responses, stable disease > 6-months
in 5 patients
• Median PFS 12-months
Gucalp et al Proc ASCO 2012 Abstract 1006
Use of pre-operative approach
for prognosis and novel trials
PCR
Early stage
triple negative
breast cancer
Good prognosis
25 to 30%
Pre-operative
chemotherapy SX
70%
BX
Residual
chemoresistant
disease
Trials with
novel agents/
approaches
Pre-operative trial in triple negative
breast cancer
PET
Biopsy
PET
Biopsy
Early
Stage
TNBC
(not
LABC)
Biopsy
PET
PCR
SORAFENIB
CISPLATIN
Cell surface receptors
Stem cell isolation
Genomic Analysis
Wnt pathway inhibitor
(BL2, Mes, Mes-stem subtypes)
PACLITAXEL
Surgery
SORAFENIB
Residual cancer
Targeting growth factors in
chemo-resistant TNBC
Mouse
“clinical trial”
Residual
Chemo-resistant
TNBC
Pre-operative
Chemotherapy
(Phase 2 clinical trials)
Gene expression
(Vanderbilt subtypes)
TNBC
Human TNBC
Xenografts
Theranostic
Nanoparticles
(EGFR/IGF1R)
Summary
• TNBC remains a major therapeutic
challenge
• TNBC is an umbrella term for a
heterogeneous group of breast cancer
• Major issues include chemo-resistance
and lack of therapeutic targets
• Use of pre-operative approach appears
optimal