This document provides an update on the management of triple negative breast cancer from Dr. Banu Arun at MD Anderson Cancer Center. It discusses that triple negative breast cancer is a heterogeneous disease comprised of several molecular subtypes with different characteristics and potential treatment targets. Clinical trials exploring chemotherapy regimens, platinum agents, PARP inhibitors, anti-angiogenic drugs, and immunotherapies are summarized. Ongoing research aims to better define the subtypes in order to personalize treatment for triple negative breast cancer patients.

1. Update on Management of Triple
Negative Breast Cancer
Banu Arun, M.D.
Professor, Breast Medical Oncology
Co-Director Clinical Cancer Genetics
The University of Texas
MD Anderson Cancer Center
August, 2015

2. 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
TNBC is Not One Disease
Lehmann et al. J Clin Invest 2011

3. Characteristics of TNBC
• At least 15% of breast cancers
• Higher incidence in AA and Hispanic women
• Germline BRCA mutation rate 11-37%
• Etiologic risk factors not known (except BRCA1 germline mutations carriers
and ? AA women who did not breastfed)
• Sensitive to standard chemotherapy (pCR 35-40%)- but ↓DFS/OS
• Early relapse (2-3 yrs); after relapse time to death shorter
• Significantly heterogeneous disease
• No targeted therapy currently available
Lehmann et al. J Clin Invest 2011, Kwon & Arun JCO 2010

4. Clinical Questions
• Specific type of chemotherapy?
– Metastatic
– Neoadjuvant, adjuvant
• BRCA-associated breast cancer, role of HRD assay in
sporadic TNBC (BRCAness)
• Role of antiangiogenic agents?
• What are the targets in subsets of TNBC?

5. How does TNBC respond to available
chemotherapeutic agents?
-Anthracyclines
-Taxanes
-Capecitabine
-Ixabepilone
-Eribulin

6. Anthracyclines for TNBC
Trial Phase/no.
TNBC pts
Setting Regimen Outcome in
TNBC
Di Leo (2008)
Meta-analysis
III (n=157) Adjuvant Anthracycline vs
CMF
23% reduction
in risk of relapse
Bidard (2008) II (n=120) Neoadjuvant CEF x 4-6 pCR: 17%
Gluz (2008) III (n=66) Neoadjuvant DD EC or CMF
vs HD EC-
ECThiotepa
5-yr EFS with
HD 71% vs 26%
with DD
Hudis C A , and Gianni L The Oncologist 2011;16:1-11

7. • Meta-analysis, stage IV, first-line trials
• Taxane-based vs anthracycline-based
• Results: Taxane better, ER-negative ~ ER-positive
– HER2 not evaluated
TNBC and Taxanes
Piccart-Gebhart et al, JCO 2008

8. 28-day cycle:
Paclitaxel 90 mg/m2 D1, 8, and
15.
Bevacizumab 10 mg/kg D1 and
15.
Paclitaxel +/- Bevacizumab as First-Line Therapy
for Locally Recurrent or Metastatic Breast
Cancer (E2100)
R
A
N
D
O
M
I
Z
E
Paclitaxel+
Bevacizumab
Paclitaxel
Miller et al. N Engl J Med 2007

9. 0
20
40
60
80
100
Months
Progression-freesurvivalestimate
0 10 20 30 40
6.7 13.3
HR=0.48; p<0.0001 13.3
6.7
99% increase
in median PFS
MedianPFS(months)
15
10
5
0
bevacizumab +
paclitaxel
Paclitaxel
Paclitaxel (n=354)
bevacizumab + paclitaxel (n=368)
HR = hazard ratio; bevacizumab Summary of Product Characteristics (SmPC)
Progression-free survival
Miller et al. N Engl J Med 2007

10. Paclitaxel +/- Bevacizumab as First-Line Therapy for Locally
Recurrent or Metastatic Breast Cancer (E2100)
Miller et al. N Engl J Med 2007

11. CALGB 40502/NCCTGN063H
Randomized phase III Trial, first-Line therapy for locally recurrent
or metastatic breast cancer
Rugo H et al, ASCO 2012
Paclitaxel vs nab-paclitaxel vs Ixabepilone
- -
Control
1
Exp 2
N = 799
Untreated
Stage IV
Strata:
Adj taxanes
ER/PR status
nab-paclitaxel 150 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks2
ixabepilone 16 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks3
Restage q 2
cycles until
disease
progression
paclitaxel 90 mg/m2 weekly +
bevacizumab 10 mg/kg q 2 wks1

12. CALGB 40502 Subset Analyses
Triple Negative Disease
Months From Study Entry
ProportionAlive
0 5 10 15 20 25 30
0.00.20.40.60.81
Pac
Nab
Ixa
Triple Negative Disease
Comparison HR P-value 95% CI
nab vs. pac 0.93 0.7354 0.62 – 1.40
ixa vs. pac 1.46 0.0647 0.98 – 2.18
ProportionProgressionFree
paclitaxel
nab-paclitaxel
ixabepilone
• 40502 overall findings:
- Weekly paclitaxel > ixabepilone
- Weekly paclitaxel less toxic
than either (in general)
• TNBC Subset:
- No real difference from
parent trial
- 98% received bevacizumab

13. • Women who underwent BRCA genetic
testing and were treated with NST for breast
cancer between 1997 and 2009
• 25% were positive for BRCA mutations
• Treatment with T+A or A, or T only
Arun et al JCO 2011

14. Arun et al JCO 2011
pCR:
BRCA 1+: 46%
Negative: 22.4%

15. Pathologic Complete Response
Arun et al JCO 2011
Further improvement
with PARP inhibitors,
Platinums?

16. Efficacy of Eribulin in Women with Metastatic Breast
Cancer: A Pooled Analysis of two Phase 3 Studies
Twelves Breast Can Res Treat 2014

17. TNBC: BRCA Germline associated
vs BRCAness
• Sporadic TNBC (without germline BRCA mutations), shares
clinical and molecular features with BRCA-associated cancers
including defective DNA repair:
– methylation-induced silencing of BRCA
– mutations in other genes that encode proteins involved in DNA repair
• Opportunity for DNA damaging agents: Platinums
• DNA repair inhibitors: PARPi
Foulkes NEJM 2010; Lips BrJ Ca 2013; Maxwell KN JCO a1510, 2014;
Turner N Nat Rev Can 2004; Lehmann BD JCO 2011

18. TNBC and Platinums in Stage IV
Stage IV Trials Population Results
Control arm BALI-1 (CDDP) Sporadic TNBC 10% RR
Control arm Phase III iniparib (Gem/carbo) Sporadic TNBC 30% RR
TBCRC 001 (Cetuximab/Carbo) Sporadic TNBC 17% RR
TBCRC 009 (Carboplatin or Cisplatin) Sporadic TNBC 30% RR
Baselga, ESMO’10; O’Shaughnessy, ASCO’11; Carey et al, JCO’12; Isakoff, ASCO’11
Platinums:
 Reasonable in sporadic TNBC – but what line?

19. TNT: Phase III Carboplatin versus Docetaxel in
Metastatic TNBC or BRCA1/2 Breast Cancer
Institute of Cancer Research, UK
Tutt et al. SABCS 2014

20. Tutt et al. SABCS 2014

26. Trial Type n Drugs Population pCR
DFCI1 Single arm Ph 2 21 CDDP x 4 TNBC 21%
DFCI2 Single arm Ph 2 51 CDDP+bev TNBC 15%
Polish Retrospective 13 CDDP x 4 BRCA+ 83%
GEICAM Randomized Ph 2 94 EC-D
EC-D+carbo
Basal-like (IHC) 30%
35%
GeparSixto Randomized Ph 3 315 wP/LDox/bev
+/- Carbo
TNBC (subset) 43%
57%
PreCOG0105 Single arm Ph 2 80 G/Carbo/iniparib TNBC 36%
CALGB 40603 Randomized Ph 2 455 T-AC(bev)
T/carbo-AC(bev)
TNBC 41%
54%
Neodjuvant Platinum in TNBC
Silver et al, JCO’12; Ryan et al, ASCO’09; Byrski et al, JCO’10; Alba et al, BCRT’12;
von Minckwitz et al, Lancet Oncol ‘14; Telli et al, ASCO a 1003’13; Sikov et al, SABCS’13

27. Schema of randomized phase II CALGB 40603 Trial
Sikov W M et al. JCO 2015;33:13-21
©2015 by American Society of Clinical Oncology

28. Pathologic complete response in breast
and breast/axilla
©2015 by American Society of Clinical Oncology
Sikov W M et al. JCO 2015;33:13-21

29. Sikov W M et al. JCO 2015;33:13-21

30. Do we add carboplatin to every TNBC?
• Addition of either carboplatin or bevacizumab to
NACT increased pCR rates; ↑DFS/OS??
• Given results from recently reported adjuvant trials,
further investigation of bevacizumab in this setting is
unlikely
• Role of carboplatin could be evaluated in definitive
studies in biologically defined patient subsets most
likely to benefit from this agent (BRCA?)
• Decreased rate of completing all taxol and all AC
cycles

31. Antiangiogenic Drugs Added to
Chemotherapy?

32. Bevacizumab and Response in Metastatic
HER2-Negative Breast Cancer
Trial Regimen RR Bev arm RR placebo
Initial Ph 3 Capecitabine + B 20%* 9%
E2100 Paclitaxel + B 37%* 21%
AVADO Docetaxel + B 64%* 46%
RIBBON-1 Chemotherapy + B 35%* 24%
RIBBON-2
(TNBC subset)
Chemotherapy + B 41%* 18%
Miller et al, JCO‘05; Miller et al, NEJM‘07; Miles et al, JCO’10; Robert et al, JCO’11 Brufsky et al, BCRT’12
*statistically significant

33. Bevasuzumab: Neoadjuvant and Adjuvant
in TNBC
Trial Setting Outcome P value
Gepar-Quinto Neoadjuvant pCR:33% → 43% 0.007
NSABP-B40 Neoadjuvant pCR:47% → 52% NS
BEATRICE Adjuvant No DFS benefit
E5103 Adjuvant No DFS benefit
Von Minckwithz NEJM 2012; Bear NEJM 2014, Cameron Lancet Oncol 2013; Miller JCO 2014)

34. • Metastatic setting: increases RR when added to
chemotherapy, but has no impact on OS- therefore,
when response is the endpoint, adding Bev is an
option
• Neoadjuvant setting: Increase pCR; but DFS/OS
impact is unknown
• Adjuvant setting: No impact on DFS and OS
Bevacizumab: Practical Conclusions

35. PARP Inhibitors

36. Principles of Cancer Biology: DNA Repair
Adapted from Carey L. Oncologist 2010 (In Press)
Chemo, XRT and Other Insults
DNA DAMAGE
Normal cell BRCA loss PARP deficient BRCA loss +
PARP deficient
VIABLE VIABLE VIABLE DEAD
HR BER HR BER HR BER HR BER
HR: Homologous Recombination
BER: Base Excision Repair
X X X X
“Synthetic
Lethality”

37. 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
Fong et al. N Engl J Med 2009 Tutt et al. Lancet 2010 Isakoff et al. ASCO 2010

38. • Non-BRCA ovarian cancer responds to
olaparib…Evidence of BRCAness.
Breast Cancer, Ovarian Cancer and PARPi
• Not seen with non-BRCA breast cancer.
– Triple negative
Gelmon K et al, Lancet Oncol 2011

39. Identifying BRCA Deficiency
• Major consequence is
homologous recombination
(HR) DNA repair defect
• Functional assays in
development
Birkbak NJ et al. Cancer Discovery 2012
HRD score
Non-responders
BRCA1/2 intact responders
BRCA1/2 mutant responders
Telli M et al, SABCS 2012

40. What is next for TNBC?
Targets Within Triple Negative Subsets?

41. Immunomodulatory TNBC
Lehmann et al. J Clin Invest 2011
IM: immune cell
processes (medullary
breast cancer)
• - 10-15% of TNBCs
• - enriched in immune
cell processes
• -medullary breast
cancers
• - ?BRCA1 carriers?
• - p53 mutant
•

42. Novel agents in clinical trials

43. Other targets for triple-negative breast cancer
Hudis C A , and Gianni L The Oncologist 2011;16:1-11
©2011 by AlphaMed Press

44. MDACC Moonshot Triaging
Platform

45. Chemo-insensitive (prediction & interim imaging)
Vimentin +
(mesenchymal)
AR+ Other
(Enriched for Basal-like)
mTORi +
chemo
Improved rate
of pCR/RCB-I?
ARi +
chemo
PDL-1i +
chemo
*comparison to control ‘predictor unknown’ group
BRCA1/2 +
PARPi+
chemo
• Single arm phase II trials
• pCR improvement: 5%20%
• N=37
• Two stage design; close if
pCR/RCB-I not seen in >1 of 14
patients
EGFRi +
chemo

46. • TNBC is heterogeneous
• Stage 4: Chemotherapy is mainstay and (at the moment) is the
same as for other subtypes.
– First-line taxanes or platinum appropriate
– Second+ lines: Eribulin to other options
• Neoadjuvant: Platinums ? Toxicity- clinical benefit ratio? No ↑EFS,
BCS rate- additional markers needed: HRD score, TILs….more
studies ongoing
• Residual disease ?: EA1131 phase III ECOG-ACRIN: Evaluate
platinum after Tax based NAST. Endpoint: EFS
• BRCA1-associated TNBC may be different:
Platinums, PARP inhibition
• Subtype specific studies and novel study designs are ongoing
Conclusion

47. Thank you