1. Triple negative breast cancer 21st Annual NOCR Meeting
Las Vegas, NV, March 2015
Ruth M. O’Regan, MD
Visiting Professor and Division Chief Hematology and Medical Oncology,
Department of Medicine,
University of Wisconsin

2. TNBC: Topics to cover
Optimal pre-operative therapy for patients with TNBC
Management of metastatic TNBC
Sub-typing of TNBC
Goal of personalized therapy in TNBC
Residual disease following pre-operative therapy in TNBC

3. Importance of PCR in TNBC
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013
Importance of PCR in TNBC
Neoadjuvant Chemotherapy for TNBC
pCR (ypT0/is N0) rate: 34% (meta-analysis)
Given its prognostic importance, how can we increase
pCR rate in TNBC?
Cortazar et al SABCS 2012

5. CALGB 40603: pCR Breast/Axilla (ypT0/is N0)
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013
CALGB 40603: pCR Breast/Axilla (ypT0/is N0)
41% (35-48%)
54% (48-61%)
44% (38-51%)
52% (45-58%)
N=212
N=221
N=218
N=215
Odds ratio: p =
Odds ratio: p =
This presentation is the intellectual property of William Sikov, MD. Contact at for permission to reprint or distribute.

6. CALGB 40603: Select Grade >3 Toxicities
San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013
CALGB 40603: Select Grade >3 Toxicities
Chemo
Chemo Bev
Chemo Carbo
Chemo Carbo + Bev
Neutropenia
22%
27%
56%
67%
Thrombocytopenia 4% 3%
20%
26%
Febrile neutropenia 7% 9%
12%
24%
Hypertension 2% 0%
10%*
Nausea / Vomiting
4% / 2%
3% / 2%
8% / 4%
Fatigue
10%
Stopped treatment due to toxicity 6%
Difficult to give weekly paclitaxel without growth factors
This presentation is the intellectual property of William Sikov, MD. Contact at for permission to reprint or distribute.

7. Addition of carboplatin to standard chemotherapy increases PCR rate but..
Toxicity, particularly myelosuppression, is problematic resulting in decreased dose intensity of paclitaxel
Use of G-CSF is generally required
Could other schedules be effective?
Which sub-types of TNBC benefit from the addition of carboplatin?
Are there additional chemotherapeutic options?

8. Protocol Design CP-CEF R P-CEF Paclitaxel 80 mg/m2 qwk x 12 CEF
q3wks x 4
HER2 (-) BC
Stage II/IIIA
18-70 years
PS 0/1
Good Organ function
Written IC
Carboplatin
AUC5
q3wks x 4 R
S U R G E R Y
P-CEF
Paclitaxel
80 mg/m2 qwk x 12
CEF
500/100/500 mg/m2
q3wks x 4
Tamura Proc ASCO 2014

9. pCR rates by sub groups (%) TNBC Primary Endpoint P =0.04 P =0.02
Odds ratio
0.46
0.30
0.15
Tamura Proc ASCO 2014

10. Adverse Events Treatment arm CP-CEF P-CEF *12% in CALGB trial
All
CP phase
P phase
Adverse events
G3%
G4%
Anemia
18.2
1.1
14.8
Neutropenia
46.6
19.3
52.3
5.7
17.6
20.9
8.8
Thrombocytopenia
Febrile neutropenia
20.5
2.3*
15.4
Nausea
3.4
2.3
2.2
Vomiting
Fatigue
Infection
4.4
Sensory neuropathy
*12% in CALGB trial
Tamura Proc ASCO 2014

20. Pre-operative therapy of TNBC
Addition of carboplatin to paclitaxel – anthracycline backbone increases PCR rate in TNBC (BL and non-BL) but..
Toxic, resulting in decreased dose intensity of paclitaxel without growth factors
Other schedules should be investigated
? Assess response to anthracycline before adding carboplatin
Substitution with nab-paclitaxel may be an option

21. Management of metastatic TNBC
Highly aggressive course with propensity for visceral and brain mets
Progression-free survival approximately 6-months to first-line therapy with overall survival in the range of 12-months
Chemotherapy only approved therapy but TNBC is either inherently resistant or rapidly acquires resistance to available agents
Unclear if any one agent is better than another

22. Capecitabine 1250 mg/m2 BID orally Days 1-14, q21 days
Eribulin 301
Global, randomized, open-label phase III trial (Study 301)
Patients (N = 1102)
Locally advanced or MBC
≤ 3 prior chemotherapy regimens (≤ 2 for advanced disease)
Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced or MBC
Co-primary endpoint
OS and PFS
Secondary endpoints
Quality of life
ORR
Duration of response
1-, 2-, and 3-year survival
Tumor-related symptom assessments
Safety parameters
Population PK
Eribulin mesylate
1.4 mg/m2 2- to 5-min IV
Day 1 & 8 q21 days
Randomization 1:1
Capecitabine mg/m2 BID orally Days 1-14, q21 days
Kaufman PA, et al. SABCS December 7, Abstract S6-6.

23. Eribulin 301: Overall Survival By Receptor Status
Subgroup
HR (95% CI)
Eribulin
Capecitabine
Median (months)
Overall
0.879 (0.770, 1.003)
15.9
14.5
HER2 status
Positive
0.965 (0.688, 1.355)
14.3
17.1
Negative
0.838 (0.715, 0.983)
13.5
ER status
0.897 (0.737, 1.093)
18.2
16.8
0.779 (0.635, 0.955)
14.4
10.5
Triple negative
Yes
0.702 (0.545, 0.906)
9.4 No
0.927 (0.795, 1.081)
17.5
16.6
N = 755
N = 449
N = 284
0.2
0.5
1.0 2 5
Favors eribulin
ITT population
Favors capecitabine
Kaufman PA, et al. SABCS December 7, Abstract S6-6.
Kaufman et al, SABCS– December 7, 2012

24. TNT trial
90% TNBC

31. 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

32. Vanderbilt TNBC trials
AR-
positive
Bicalutamide +
GDC0941 (PI3K inhibitor)
Met
TNBC
AR-
negative
Cisplatin +/-
GDC0941 (PI3K inhibitor)*
*NCT

34. Pre-operative approach in TNBC
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

35. Deep sequencing of the residual disease in NAC-treated TNBC
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec , 2013
Deep sequencing of the residual disease in NAC-treated TNBC
182 oncogenes and tumor suppressors in a CLIA certified lab (Foundation Medicine, Cambridge MA)
Data were evaluable for 81 tumors, with a sufficient coverage to determine CNAs in 72/81 *
Balko et al, Cancer Discovery, in press.
This presentation is the intellectual property of the authors/presenters.  Contact them at permission to reprint and/or distribute

36. JAK2 copy number increases with treatment and metastatic progression
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – Dec , 2013
JAK2 copy number increases with treatment and metastatic progression
JAK2 gains and amplifications were more frequent in NAC-treated TNBC than in primary untreated BLBC (TCGA)
Ongoing randomized trial of JAK TKI in HER2-negative metastatic breast cancer

37. 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
Supported by Glenn Family
Pilot Grant

38. Conclusions TNBC
Use of pre-operative therapy is a consideration for most patients with TNBC
Addition of carboplatin to paclitaxel or substitution of paclitaxel with nab-paclitaxel increase PCR rate
Role of TNBC sub-typing is evolving as a means of personalized therapy