1. Future therapeutic approaches for metastatic triple negative breast cancer 18th Annual Perspective in Breast Cancer New York, August 18th, 2012
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. Triple negative breast cancers have a high recurrence rate following initial diagnosis with a poor survival
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 associated with
Chemo-resistance (only about one-third respond to chemotherapy)
Lack of molecular targets towards which novel agents can be developed

4. Triple Negative Tumors Triple Negative Tumors (%) By Age (%) By Age
56.6
42.2
55.4
28.6
17.3
41.2
19.6
44.2
19.5 10 20 30 40 50 60
20-34
35-39
40-44
45-49
50-54
Black
White %
Lund Breast Cancer Res Treat 2008

5. Topics to be covered
Triple negative breast cancers represent a heterogeneous group of cancers which likely require different therapeutic approaches
Potential therapeutic targets
Chemo-resistance – how can we manage patients with early stage breast cancer who have resistant cancers

6. 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

7. 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

8. 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

9. Cell lines correspond to the 6 triple negative subtypes
Click on image to magnify. 
       
Cell lines correspond to the 6 triple negative subtypes
Lehmann et al JCI 2011

10. 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

11. 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

12. 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

13. 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

14. mTOR inhibition sensitizes triple negative breast cancer
cells to EGFR inhibition 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
110%
120%
130%
Rapa .78
Lapa
.156 uM
1.56 nM
.3125 uM
3.125 nM
.625 uM
6.25 nM
1.25 uM
12.50 nM
2.50 uM
25.0 nM
5.00 uM
50.0 nM
10.0 uM
100 nM
20.0 uM
Concentration
Cell Survival Rate
Rapamycin
Lapatnib
Rapamycin+ Lapatnib  +
MDA-MB-468
Rapamycin
Erlotinib
Lapatinib
p-EGFR
pMAPK
p-S6
-actin
p-Akt
P=0.0001 50
100
150
200
250
300
Day 14
Day 17
Day 21
Day 24
Day 28
Tumor volume (mm3)
Control
Rapamycin
Lapatinib
Rapa+Lapa
p<0.0001
p=.01
Liu et al Mol Cancer Ther 2011

15. Phase 2 trial of Lapatinib and Everolimus in metastatic TN breast cancer
prior taxanes
and anthracyclines
Second/third-line
n = 40
TN in metastatic
setting
Lapatinib 1250mg daily
RAD001 5mg daily BX CT CT
Primary endpoint: response rate

16. Expression of IGF1R in triple negative breast cancer cell lines
Triple Negative Breast Cancer Cells ER
HER2/neu
MDA-MB-468 (BL1)
HCC1806 (BL2)
HCC70 (BL2)
MDA-MB-231 (MSL)
Hs578t (MSL)
BT549 (M)
BT474
MCF7
β-actin
IGF1R
IRS-1
Parent EV IGF1R-/-
Parent EV IGF1R-/-
MDA-MB-468
MDA-MB-231
IGF1R
β-actin
Taliaferro-Smith et al SABCS 2011

17. Knock-down of IGF1R changes morphology of triple negative breast cancers cells
EV IGF1R-/-
EV IGF1R-/-
MDA-MB-468
MDA-MB-231
E-cad
Vimentin
GAPDH
Empty Vector
IGF1R-/-
MDA-MB-468
MDA-MB-231
E-cad
Vimentin
GAPDH
EV IGF1R-/-
MDA-MB-468
MDA-MB-231
EV IGF1R-/-
Taliaferro-Smith et al SABCS 2011

18. Knock-down of IGF1R induces mesenchymal to
epithelial transition in MDA-231 triple negative cells
MDA-MB-468
E-cadherin
DAPI
Merge
Empty Vector
IGF1R(-/-)
Vimentin
MDA-MB-231
Taliaferro-Smith et al SABCS 2011

19. IGF1R knock-down affects invasive properties
of triple negative breast cancers
dependent on underlying morphology
MDA-MB-231
MDA-MB-468 EV
IGF1R-/-
***
Matrigel Invasion
MDA-231 cells with IGF1R knock-down compared to WT cells also exhibit decreased colony formation
Taliaferro-Smith et al SABCS 2011

20. Pharmacologic inhibition of IGF1R alters morphology
of triple negative breast cancer cells
MDA-MB-468
MDA-MB-231
UNT
0.175 µM PPP
Taliaferro-Smith et al SABCS 2011

21. 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) 21

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

23. 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 23

24. Chemo-resistance is a significant issue with TNBC
PCR is clearly a very robust prognostic factor for outcome in TNBC
How can we increase PCR rate?
How should we manage patients with residual cancer following pre-operative chemotherapy?

25. No adjuvant chemo planned
Neoadjuvant Chemo plus Carboplatin +/- Bevacizumab in Stage II-III TNBC (Phase II CALBG 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).

26. 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

27. Triple negative cancers
Behave very aggressively
Develop (chemo)-resistance rapidly
In clinical trials, many patients experience disease progression before their first staging scan1
Maybe micro-metastatic disease is a better way of evaluating novel agents in triple negative disease
1. Carey et al Proc ASCO 2008

28. Pre-operative approach
PCR
Good prognosis
Early stage
triple negative
breast cancer
25 to 30%
Pre-operative
chemotherapy
70% BX
Trials with
novel agents/
approaches
Residual
disease SX

29. Pre-operative trial in triple negative breast cancer (PI: Zelnak)
PET
Biopsy
PET
Biopsy
Biopsy
PET
PCR
Early Stage
TNBC
(not LABC)
SORAFENIB
CISPLATIN
PACLITAXEL
Surgery
SORAFENIB
Residual cancer
Gene expression
Focused on EGFR,
IGF1R,
Wnt, Vimentin
Clinical trial
based on genes
expressed

30. Conclusions
Triple negative breast cancers have an aggressive natural history with a poor outcome due to intrinsic or rapid onset of resistance
There is an urgent need for new therapies
Triple negative breast cancers do not represent a single entity and individual subtypes will require different treatment approaches
Pre-operative or post-operative residual disease settings may be optimal for evaluation of novel agents