Debu Tripathy, MDProfessor of MedicineUniversity of Southern CaliforniaNorris Comprehensive Cancer Center

Challenges in Breast Cancer Management:

Navigating the Heterogeneity of Triple-Negative Breast

Cancerwithout getting lost in the details

Triple Negative is typically A-E“Basal” also may include F-H

High grade

ER- PR - HER-

p53Mut

HighKi-67 CK14 p63

Basal-like Breast Cancer

• Unique subtype seen in gene array analyses accounting for 10-15% of all breast cancer; 85% of BRCA-/- breast cancer

• ER-, PgR-, and HER2- • High grade• Scant DCIS component• Other characteristics

o Mutations in p53 tumor suppressor geneo EGFR + (approximately 50%)o C-kit +o CK 5/6, 14, 17 + (basal cytokeratins)o High Ki-67

• High degree of genomic instability

Basal subtype1. 10-15% of tumors2. ER/PR/HER2-negative3. very proliferative4. EGFR, c-kit, c-myc +5. includes BRCA1 mutations

HER2+ subtype1. 15-20% of tumors2. prognostic/predictive2. proliferation3. two types (ER -/+)

Luminal A and B (ER+)1. continuum 2. prognostic/predictive3. ER-GATA3-HNF3a-XBP14. proliferation (mutant p53)5. cyclin D1 and BCL2 +

Ki-67, STK6, Survivin, Cyclin B1 and MYBL2

Gene Expression Profiling Reveals Distinct Clusters

Sorlie T et al. PNAS 2003

BRCA1-Tumors Are Basal-like

Sorlie T, PNAS, 2003

p <0.0001

p <0.001

Sorlie T et al. PNAS 2003

What Should We Actually Be Doing for TNBC in 2014 ??

All Patients• Genetic counseling/testing for age <60 or positive family

history• Use standard evidence-based chemotherapyEarly Stage

• Increase estimation of recurrence risk and benefit from chemo

• No role (yet) for adding or extending therapy for higher risk or residual disease after NAC

Advanced Stage• Consider platinums earlier on (beware they may

exclude from clinical trials)• Clinical trials (PARP, PI3K, Stem cell inhibitors)

TNBC isHeterogeneous

Prat A, et al, Molec Oncol 2010

Prat A, et al, The Oncologist, 2013

Heterogeneity of Triple Negative Breast Cancer

Otto Metzger-Filho O et al., 2012

TN Cancers and Chromosomal Anomalies

Stephens PJ et al. Nature 2009

Cisplatin PaclitaxelDoxorubicin

BRCA1-Deficient Cells May Be Hypersensitive to Cisplatin

Tassone et al BJC 2003

TNBC Responses to Platinum Agents

Baselga J et al. ESMO 2010; O’Shaughnessy J et al. SABCS 2007; Carey L, et al ASCO 2008; Isakoff J, et al. ASCO 2011; Byrski T et al. JCO 2010; Gronwald, J, et al. ASCO 2009; Silver DP, et al. JCO 2010, Alba E, et al. BCRT 2012

Neo Adjuvant Population N pCR Rate RefCMF

BRCA 1 Mutation (retrospective)

14 7%

ByrskiAC 23 22%FAC 28 21%AT 25 8%Cisplatin 12 83%Cisplatin BRCA1 Mut 25 72% GronwaldCisplatin TNBC 28 21% SilverEC D

TNBC Basal46 35%

AlbaEC DP 48 30%

Stage IV Population ORR RefControl arm BALI-1 (CDDP) TNBC 10% BaselgaControl arm Phase III iniparib (Gem/carbo) TNBC 30% O’Shaughnessy

TBCRC 001 (Cetuximab/Carbo) TNBC 17% CareyTBCRC 009 (Carboplatin or Cisplatin) TNBC 30% Isakoff

Efficacy of Ixabepilone/Capecitabine in TN Metastatic Breast Cancer Resistant to

Anthracyclines and Taxanes

Rugo et al. SABCS 2007, Abstract 6069

Receptor Subgroup

All Patients ER/PR/HER2 Negative

Non-Triple-Negative HER2+ ER+

I + Cn=375

Cn=377

I + Cn=91

Cn=96

I + C n=284

Cn=281

I + Cn=59

Cn=53

I + Cn=173

Cn=178

ORR 35% 14% 27% 9% 37% 16% 31% 8% 40% 19%

Median PFS 5.8 mo 4.2 mo 4.1 mo 2.1 mo 7.1 mo 5.0 mo 5.3 mo 4.1 mo 7.6 mo 5.7 mo

HR 0.75 0.68 0.74 0.69 0.81

Eribulin vs. Capecitabine OS HR by Subsets

Kaufman P, et al. SABCS 2012, Abstr S6-6

E2100: Paclitaxel ± Bevacizumab as First-line Therapy in MBC (HER2-)

HR = 0.60 (0.51-0.70)Log Rank Test p<0.001

Pac.+ Bev. 11.8 monthsPaclitaxel 5.9 months

Miller K et al. N Engl J Med. 2007

Prog

ress

ion-

free

Sur

viva

l (%

)

Month

80

6

20

12

40

100

60

00 18 24 30 36 42 48 54

Paclitaxel

Paclitaxel plus bevacizumab

Subgroups: PFS HR

ER-/PR-ER+/PR-ER+/PR+Overall

Randomized Trials of Bevacizumab in TNBCStage IV Trial Regimen DFS HR (95% CI)ECOG 2100 Weekly paclitaxel + bevacizumab 0.53 (0.41-0.70)AVADO Docetaxel + bevacizumab 0.68 (NR~1.00)RIBBON-1 Chemotherapy + bevacizumab 0.72 (0.49-1.06

OS HR (95% CI)Meta-analysis 3 first-line studies chemo + bevacizumab

0.96 (0.79-1.16)

TNBC subsetRIBBON II

chemo + bevacizumab

HR (95% CI)PFS 0.494(0.33–0.74)OS 0.624(0.39–1.007)

O’Shaughnessy J et al, ASCO 2011;Brufsky A, et al. BCRT 2012

EGFR is Expressed in 30-50% of TNBCRandomized Trials Testing Cetuximab in TNBC

Carey L, et al JCO 2012; O’Shaughnessy J et al. SABCS 2007; Baselga J et al. JCO 2013

TBCRC 001N=102

USONN=138

BALI-1N=173

Endpoint Cetux Cetux + Carbo

Irino +Carbo

Irino/ Carbo + Cetux

Cisplatin Cisplatin + Cetux

ORR (%) 6 17 30 49 11 20

CBR (%) 9 31 NR NR

PFS (mo) 1.4 2.1 5.1 4.7 1.5 3.7

OS (mo) 12.3 15.5

Replication Lesions• Base excision repair

PARP1

Mechanisms of DNA Repair

Single Strand Breaks• Nucleotide excision

repair• Base excision repair

PARP1

Double Strand Breaks• Non-homologous end-joining• Homologous recombination

BRCA1/BRCA2• Fanconi anemia pathway• Endonuclease-mediated repair

DNA DAMAGE

Cell Death

Environmental factors(UV, radiation, chemicals)

Normal physiology(DNA replication, ROS)

MAJOR DNA REPAIRPATHWAYS

Chemotherapy(alkylating agents, antimetabolites)

Radiotherapy

Helleday et al. Nature Reviews. 2008

x

DNA Adducts/Base Damage • Alkyltransferases• Nucleotide excision repair• Base excision repair

PARP1x

• Mostly low grade toxicities• Grade III/IV toxicities (400 mg

cohort)– Fatigue 15%– Nausea 19%– Vomiting 11%

• 30% dose interruptions or reductions

Tutt A et al. Lancet 2010

400 mg bidN=27

100 mg bidN=27

ORR 11 (41%) 6 (22%)

CR 1 (4%) 0 (0)

PR 10 (37%) 6 (22%)

PFS (mo)

5.7 (4.6 – 7.4)

3.8 (1.9-5.5)

A Phase II trial of the Oral PARPInhibitor Olaparib in BRCA Deficient

Advanced Breast Cancer

BRCA 1BRCA 2

Phase II Veliparib (ABT-888) + Temozolamide in TNBC

-80-70-60-50-40-30-20-100

102030405060708090100

* * * * *

* = BRCA carriers

% c

hang

e

p-value = 0.0042

Noncarriers: PFS = 1.8 Mo

BRCA carriers: Median PFS = 5.5 Mo

Isakoff S, et al, ASCO 2011

Response rate = 7% - ONLY in BRCA1/2+ (RR 38%)

• Phase I dose escalation. Mixed tumor types.

• 7/35 partial responses– 6/13 BRCA1/2+

Phase I Veliparib + oral Cyclophosphamide

*

Veliparib (ABT-888) + Chemotherapy Combinations

Kummar, et al, Clin Cancer Res 2012

HRD Score Distribution – A New Measure of “BRCAness”

Neoadjuvant gemcitabine, carboplatin and iniparib

HRD score

Non-responders

BRCA1/2 intact responders

BRCA1/2 mutant responders

HRD score ≥ 10 in 16/19 BRCA1/2 mutants

No difference in mean HRD scores in BRCA1/2 mutant vs. intact responders

Telli ML, et al. SABCS 2012

The PI3K/Akt/mTOR pathway and Breast Cancer

Ras

4EBP1

Raf

Erk

Rsk

PI3K

TORC1

S6K

Rheb

S6

PIP3

Tuberin

PTEN

TORC2MEKAkt PDK1

HER2/HER3Agent Target

BYL719 PI3Kα

INK-1117 PI3Kα

GDC-0032 PI3Kα,δ,ϒ

XL-147 Pan-PI3K

BKM120 Pan-PI3K

GDC-0941 Pan-PI3K

PKI-587 Pan-PI3K

XL-765 PI3K / mTOR

BEZ-235 PI3K / mTOR

PF-4691502 PI3K / mTOR

Everolimus mTOR (mTORC1)

AZD8055 mTOR (mTORC1/2)

INK 128 mTOR (mTORC1/2)

MK-2206 AKT1,2,3

GDC-0068 AKT

Phase I Trial of mTOR Inhibitor BKM120

Bendell JC, et al. JCO 2012

TNBC

TBCRC 011: Bicalutamide in AR+ TNBC

Consented for AR testing

(n=452)

Screened for AR expression

(n=424)

AR(+)(n=51)

On study (n=28)

Eligible on study (n=26)

Ineligible for testing(n=28)

AR(-)(n=373)

Ineligible for therapy(n=8)

Eligible for therapy; trial closed to accrual

(n=15)Ineligible post therapy

(n=2)

Bicalutamide 50 mg daily• No Responses• Clinical Benefit

Rate = 5/26 evaluable (19%) (95% CI 7-39%)

Gucalp A, et al. Clin Cancer Res 2013

12%

Also in testing: enzalutamide, abiraterone

Tigatuzumab (Anti-DR5) for TNBCDeath Receptor DR5on 2LMP TNBC Cells

In Phase II trial with nab-paclitaxelfor advanced TNBC

Buchsbaum DJ , et al. Clin Cancer Res 2003

Triple-Negative Breast Cancers: Potential Therapeutic Targets

Cell Cycle

Transcriptional Control

MAP Kinase Pathway Akt Pathway

IGF-1R EGFR

Tyrosine Kinase

C-KIT tyrosine kinase

Cell DeathModified from:

Cleator S et al. Lancet Oncol 2006

DNA Repair pathways

Anti-Angiogenesis

Cetuximab

Dasatinib Sunitinib

PARP inhibitors; Trabectedin

Bevacizumab

Wnt, NOTCH inhibitors

Src inhibitors

PI3K, Akt, MEK inhibitors

HDAC, DNMT inhibitors

Multiple potential targets?• Basal-like 1 and 2 – DNA damage response genes, growth factor

paths (EGFR)• Immunomodulatory - ? Immune approaches• Mesenchymal and mesenchymal / stem cell – PI3K/mTOR pathway• LAR – androgen receptor signaling

Targeting Heterogeneity of TNBC

Lehmann BD, et al, JCI 2011

Prat et al, Molec Oncol 2010

Triple Negative Breast Cancer is Heterogeneous and Includes a “HER2-like” Subset

Reverse Phase Protein Array Reveals HER2 signaling in TNBC (I-SPY1)

Wulfkuhleet JD al, Clin Cancer Res 2012

HER2 Somatic Mutations in 25 Patients

• 8 publications, total of 1499 patients (estimated incidence of 1.7%)• 20% of mutations at AA 309 or 310• 80% of mutations from 755-781

Bose R, et al. Nature Discovery, 2013

Bose R, et al. Nature Discovery, 2013

Bose R, et al. Nature Discovery, 2013

HER2 Mutations Differentially Activate HER2 Signaling

Bose R, et al. Nature Discovery, 2013

Colony formation of HER2 Mutants inhibited by HER1/2 Kinase Inhibitor Neratinib

Bose R, et al.

CancerDiscovery

2013

Multi-center Phase IITrial withNeratinib Initiated

TNBC: Where are We Going?

• Risk-based stratification for additional chemotherapy or radiotherapy

• Testing of post (neo) adjuvant of platinum agents and PARP inhibitors

• Sequencing and target-drive therapy (eg. PI3K inhibitors, JAK2 inhibitors)

• Use of gene profiling to identify and treat variantso Androgen blockade for AR expressorso HER2 TKIs for HER2 mutationso Stem cell pathways inhibitor for Notch/Wnt

upregulation