1. 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

2. Natural history of “triple negative” breast cancers
Basal/TN
Sorlie et al PNAS 2003
Copyright ©2003 by the National Academy of Sciences

3. 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

4. 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

5. BiPar Sciences
Iniparib does not improve outcome in unselected metastatic triple negative breast cancer
PFS GC
(N=258)
GCI
(N=261)
Median PFS, mos (95% CI)
4.1
(3.1, 4.6)
5.1
(4.2, 5.8)
HR (95% CI)
0.79 (0.65, 0.98)
p-value
0.027 OS GC
(N=258)
GCI
(N=261)
Median OS, mos (95% CI)
11.1
(9.2, 12.1)
11.8
(10.6, 12.9)
HR (95% CI)
0.88 (0.69, 1.12)
p-value
0.28
1.0
1.0
0.9
Pre-specified alpha = 0.01
0.9
Pre-specified alpha = 0.04
0.8
0.8
0.7
0.7
0.6
0.6
Probability of Progression Free Survival
0.5
Probability of Survival
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Months Since Study Entry
Months
No. at risk GC
258
171
116 63 38 18 6 1
GCI
261
187
138 83 53 11 2
No. at risk GC
258
239
214
181
151 99 38 11
GCI
261
248
230
204
169
111 52 15
O’Shaughnessy PASCO 2011

6. 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

7. Click on image to magnify. Basal-like 1: cell cycle, DNA repair and
       
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)
LAR: Androgen receptor
and downstream genes,
luminal features
Lehmann et al JCI 2011

8. Sub-types demonstrate differential response to therapies in vivo
Click on image to magnify. 
       
Sub-types demonstrate differential response to therapies in vivo
Vehicle
Cisplatin
Anti-androgen
P13K/mTOR
inhibitor
Lehmann et al JCI 2011

9. Importance of Pathologic CR
Overall Survival
Liedtke et al. JCO 2008; 26(8):

10. 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 10

11. 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 3
pCR 16 27 36
Carey et al; Clin Cancer Res 2007; 13(8) 11

12. 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
6 (22%)**
(n = 51)
Cisplatin 75 mg/m2 q3w X4 + bevacizumab 15 mg/kg q3w X3
8 (16%)
(n = 78)
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 Garber et al. Breast Cancer Res Treat 2006
Ryan et al. J Clin Oncol Leone et al. J Clin Oncol 2009

13. GEICAM Phase II Study ARM A pCR =35% ARM B pCR =30%
Epirubicin 90mg/m2 + Cyclophosphamide 600mg/m2 (q 21 days x 4 courses) followed by
Docetaxel 100mg/m2
(q 21 days x 4 courses)
ARM A
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 T
pCR =35%
Epirubicin 90mg/m2 + Cyclophosphamide 600mg/m2 (q 21 days x 4 courses) followed by
Docetaxel 75mg/m2 + Carboplatin AUC 6 mg/ml/min
(q 21 days x 4 courses)
ARM B
pCR =30%
Alba E, et al. Abstract 74933, ASCO 2011 13

16. Capecitabine ± Ixabepilone in Triple Negative MBC
Efficacy
Ixa + Cape (n = 191)
Cape (n = 208)
ORR
31%
15% CR 3% 1% PR
28%
14%
Median PFS
4.2 mos
1.7 mos HR
0.63
P value
< .0001
Median OS
10.3 mos
(n = 213)
9.0 mos
(n = 230)
0.87
.18
Pooled triple negative subgroup (n = 443)
Rugo et al. SABCS 2008, Abstract 3057 16 16

17. BiPar Sciences
Iniparib does not improve outcome in unselected metastatic triple negative breast cancer
PFS GC
(N=258)
GCI
(N=261)
Median PFS, mos (95% CI)
4.1
(3.1, 4.6)
5.1
(4.2, 5.8)
HR (95% CI)
0.79 (0.65, 0.98)
p-value
0.027 OS GC
(N=258)
GCI
(N=261)
Median OS, mos (95% CI)
11.1
(9.2, 12.1)
11.8
(10.6, 12.9)
HR (95% CI)
0.88 (0.69, 1.12)
p-value
0.28
1.0
1.0
0.9
Pre-specified alpha = 0.01
0.9
Pre-specified alpha = 0.04
0.8
0.8
0.7
0.7
0.6
0.6
Probability of Progression Free Survival
0.5
Probability of Survival
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Months Since Study Entry
Months
No. at risk GC
258
171
116 63 38 18 6 1
GCI
261
187
138 83 53 11 2
No. at risk GC
258
239
214
181
151 99 38 11
GCI
261
248
230
204
169
111 52 15
O’Shaughnessy PASCO 2011

18. No response in normal BRCA status
PARP Inhibitor Trials – Activity Seen Only in BRCA1/2 Mutation Carriers
Agent
Author
BRCA1/BRCA2
TNBC
Response Rate
Olaparib
(phase I; mixture tumor types)
Fong
60 patients
37% -BRCA1/2 mutations
N/A
63% clinical benefit rate
(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 Vol. 376 No pp ; 3. Isakoff et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 1019) ;

19. 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

23. No adjuvant chemo planned
Neoadjuvant Chemo plus Carboplatin +/- Bevacizumab in Stage II-III TNBC (Phase II CALGB 40603)
Paclitaxel 80mg/m2 wkly x4
ddAC x4
Surgery
4-8 wks after last ddAC
XRT
No adjuvant chemo planned
Paclitaxel 80mg/m2 wkly x4
ddAC x4
Bevacizumab 10mg/kg q2w x 9
Paclitaxel 80mg/m2 wkly x4
ddAC x4
Carboplatin AUC 6 q3w x 4
Paclitaxel 80mg/m2 wkly x4
ddAC x4
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).

24. 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
Biopsy
PET
Early Stage
Triple Negative
BreastCancer
Sorafenib
400 mg po bid x 4 weeks
Cisplatin
75 mg/m2 q3wk x 4 cycles
Paclitaxel
175 mg/m2 q2wk x 4 cycles
Surgery
Sorafenib 400 mg po bid

25. 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

26. Randomized Phase II: Cetuximab +/- Carboplatin for Triple-Negative MBC
Cetuximab + Carboplatin at Progression
N=22
Cetuximab + Carboplatin
N=49
Arm 1
Cetuximab  Cetuximab + carboplatin
Arm 2
Cetuximab + carboplatin
Arm 1b + 2 N 31 24 71 95
ORR CR PR
2 (6%)
4 (17%)
12 (17%)
1 (1%)
11 (15%)
16 (17%)
15 (16%) SD
5 (16%)
6 (25%)
16 (23%)
22 (23%)
Carey et al. J Clin Oncol 2012

27. 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

28. 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

29. Use of pre-operative approach for prognosis and novel trials
PCR
Good prognosis
Early stage
triple negative
breast cancer
25 to 30%
Pre-operative
chemotherapy SX
70% BX
Residual
chemo-
resistant
disease
Trials with
novel agents/
approaches

32. Pre-operative trial in triple negative breast cancer
PET
Biopsy
PET
Biopsy
Biopsy
PET
PCR
Early Stage
TNBC
(not LABC)
SORAFENIB
CISPLATIN
PACLITAXEL
Surgery
SORAFENIB
Residual cancer
Cell surface receptors
Stem cell isolation
Genomic Analysis
Wnt pathway inhibitor
(BL2, Mes, Mes-stem subtypes)

33. Targeting growth factors in chemo-resistant TNBC
Mouse
“clinical trial”
Residual
Chemo-resistant
TNBC
Gene expression
(Vanderbilt subtypes)
Pre-operative
Chemotherapy
(Phase 2 clinical trials)
TNBC
Theranostic
Nanoparticles
(EGFR/IGF1R)
Human TNBC
Xenografts

34. 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