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

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

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

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?

How does TNBC respond to available

chemotherapeutic agents?

-Anthracyclines

-Taxanes

-Capecitabine

-Ixabepilone

-Eribulin

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

• 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

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 OM I Z E

Paclitaxel+ Bevacizumab

Paclitaxel

Miller et al. N Engl J Med 2007

0

20

40

60

80

100

Months

Pro

gres

sio

n-f

ree

surv

ival

est

imat

e

0 10 20 30 40

6.7 13.3

HR=0.48; p<0.0001 13.3

6.7

99% increase

in median PFS

Med

ian

PFS

(m

onth

s)

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

Paclitaxel +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer (E2100)

Miller et al. N Engl J Med 2007

CALGB 40502/NCCTG N063H 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

CALGB 40502 Subset Analyses

Triple Negative Disease

Months From Study Entry

Pro

port

ion A

live

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

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

Pro

po

rtio

n P

rog

ressio

n F

ree

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

• 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

Arun et al JCO 2011

pCR: BRCA 1+: 46% Negative: 22.4%

Pathologic Complete Response

Arun et al JCO 2011

Further improvement with PARP inhibitors, Platinums?

Efficacy of Eribulin in Women with Metastatic Breast Cancer: A Pooled Analysis of two Phase 3 Studies

Twelves Breast Can Res Treat 2014

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

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?

TNT: Phase III Carboplatin versus Docetaxel in Metastatic TNBC or BRCA1/2 Breast Cancer

Institute of Cancer Research, UK

Tutt et al. SABCS 2014

Tutt et al. SABCS 2014

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

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

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

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

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

Antiangiogenic Drugs Added to Chemotherapy?

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

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)

• 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

PARP Inhibitors

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”

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

• 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

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

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

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

•

Novel agents in clinical trials

Other targets for triple-negative breast cancer

Hudis C A , and Gianni L The Oncologist 2011;16:1-11 ©2011 by AlphaMed Press

MDACC Moonshot Triaging

Platform

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

• 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

Thank you