New Strategies to Prevent Breast Cancer Metastasis

Patricia S. Steeg, Ph.D.Women’s Malignancies Branch

NCI

Breast Cancer Survival by Subtype, After Initial Metastatic Diagnosis

DFCIN= 188

The NetherlandsN= 815

Br. Ca. Res. Trt. 141: 507, 2013JNCCN 12: 71, 2014

Retrospective Evaluation of 199 MBC Patients (2004-2007) at DFCINumber of Lines of Chemotherapy by Disease Subtype

Metastasis can be prevented:Prevention of a first metastasisPrevention of additional metastases in limited metastatic setting

We will need new clinical trial designs to validate this:Primary metastasis preventionSecondary metastasis prevention

Nature 485:S58, 2012

Nature 485:S58, 2012

Metastatic DormancyWhat is it?Can we drug it?What trials are needed?

EDG2/LPA1/LPAR1

• High levels of Lysophosphatidic acid (LPA) in the blood stream – (approximately 0.1 to 0.5 uM)

• LPA is a potent motogen for tumor cells.

• LPA1 (or EDG2) is a G protein-coupled cell surface receptor for LPA.

• Several inhibitors of LPA1 have been described.

Mills, Nature Rev Cancer, :582-591, 2003Liu, Cancer Cell 15:539, 2009

Day: 0 2 10 70 Inject Randomize Remove Autopsy 4T1 Drug Primary PK Mfp vs. Vehicle Tumor Metastasis PD Markers

4T1

4T1 +Nm23-H1

Vehicle

Debio 0719

Vehicle

Experimental Outline

Histological Analysis of Liver and Lung Metastasis

P < 0.0001

P < 0.0001

Average Liver Metastasis

0

5

10

15

20

25

30

35

Av

era

ge

Nu

mb

er

of

Me

tas

tas

is

ControlLPA1 InhibitorNm23-M1

Average Lung Metastasis

0

1

2

3

4

5

6

7

8

9

1

Av

era

ge

Co

un

ts P

er

Slid

e

ControlLPA1 InhibitorNm23-M1

P = 0.005

P = NS

DapiKi67

Primary tumor, vehicle Primary tumor, Debio 0719

Liver Metastasis, vehicle Liver metastasis, Debio 0719

LPA1 Inhibition Induced Aspects of Metastatic DormancyCell Cycle Quiescence

JNCI 104:1306, 2012

Metastatic Dormancy

Asymptomatic clinical stage, well known in breast cancer, wheremetastatic progression is unapparent for years-decades.

Thought to be caused by various factors including cell cyclequiescence, lack of angiogenesis, immune responses, etc.

Factors inducing or breaking dormancy are poorly understood

Extending dormancy a clinical goal

Several metastasis suppressor genes promote metastatic dormancy

Hypothetical mechanisms underlying metastasis dormancy.

Zhang X H et al. Clin Cancer Res 2013;19:6389-6397

©2013 by American Association for Cancer Research

Doxorubicin inhibited growth of metastases but did not decrease the number of dormant cells as measured by signal void area.

Townson J L et al. Cancer Res 2009;69:8326-8331

©2009 by American Association for Cancer Research

LPA1 Inhibitors are Under Clinical Development for Fibrosis

Debio 0719 not orallybioavailable.

SAR 100842 in phase IItrial for systemicsclerosis.

Other LPA1 inhibitors intrials for idiopathicpulmonary fibrosis

Nature Med. 18: 1028, 2012

Cox T R et al. Cancer Res 2013;73:1721-1732

The Fibrosis: Metastasis Connection

SAR100842, Experimental Designs

SAR100842: LPA1, LPA3 antagonist in nm range Orally available In phase II trials for systemic scleroderma

Will SAR100842 induce metastaticdormancy?

4T1 Model System:

MDA-MB-231 Model System:

Primary Metastasis Prevention Scenarios –

•Multiple positive lymph nodes•Chest wall recurrences•Post-neoadjuvant therapy

Locally Advanced Breast CancerNeoadjuvant therapy

pCR No pCR

FDA Guidance for Opportunity forDrug Approval Metastasis(Pertuzumab) Prevention ?

Post Neo-Adjuvant Randomized Phase II Trial to Prevent Metastasis“Primary” Metastasis Prevention

Entry: Patients with locally advanced primary breast cancersUndergo neoadjuvant chemotherapyNo Pathologic complete response

Randomization: +/- Metastasis Preventive

End Point: Metastasis Free SurvivalToxicity, QOL

Biopsies for molecular markers at progression

Brain MetastasesWhy doesn’t chemo work?Can it be prevented?What trials are needed?

Possible “soils” for brain metastatic colonization:

Perivascular spaceParenchyma, altered by neuroinflammationLeptomeninges

Steeg, Camphausen and SmithNat. Rev. Cancer 11: 1, 2011

Development of the 231-BR Brain Metastatic Model System

MDA-MB-231 Parental cells (231P)

Brain tumor isolation; growth in cell culture

IntracardiacInoculation

MDA 231- Brain Cell Line(231Br)

1.2.

3.

4.

5.

Re-injection of 231-Brain cell line (six sequential rounds)

Brain Metastasis

6.

Yoneda et. al, (2001) J. Bone and Mineral Research

Additional Experimental Brain Metastasis Models Reflect the Heterogeneityof the Disease

Sum190 BR3 (Her-2+, IBC) 4T1 BR5 (triple neg)

Jimt1-BR3 (Her-2+) MCF7 Her-2 BR3(ER+, Her-2+)

What is the role of the Blood-Tumor Barrier ?

None-Gadolinium gets into brain metastases for imagingMice harboring experimental brain metastases, when injected with Evans Blue, get blue lesions.

Uh-uh, the blood-tumor barrier is still at least partially functional-Chemotherapy does not work in the brain

Inject with brain-tropic breast cancer cells, allow mets to formInject dyes or radiolabelled drugs into the circulationPerfuse dyes and drugs from the circulationAt necropsy, make a single section of the brain

Image Image Image drug uptakeMetastases Marker uptake using phospho-imagerUsing GFP on Red flourescent

channel

ReducedEfflux

Transport

EffluxTransport

BRAINSYSTEMIC

TUMOR

Heterogeneous Uptake of C-Paclitaxel in Brain Metastases14

Metastasis 3kDa TR Dextran C- Paclitaxel14

Clin. Cancer Res. 16: 5664, 2010

15% = normal brain47% increased < 10-fold; 27% increased 10-50-fold; 10% > 50-fold

Pearson r2 = 0.034

Concentrations of Capecitabine and its Metabolites in Craniotomy Specimens

Patient, Drug

Morikawa et al, Neuro-Oncology, In press

Detectable Metastasis : Single Metastatic Cell or aMicrometastasis:

Millions of tumor cells A few tumor cells

Tortuous blood supply Fairly normal blood supply

Needs to induce tumor cell Cytostatic moleculardeath inhibitors could keep it dormant

Drug delivery difficult Drug delivery ok

NONE of the Drugs Tested Had “Treatment” Activity in the 231-BR Model

Clinical Trial Designs for Brain Metastasis Patients

Progression after WBRT. Most trials. Easy to recruit. Endpoint- lesion shrinkageIs this different biologically from less advanced disease?

Concurrent with WBRT. The elusive radiation sensitizersEndpoint – lesion shrinkage

Brain metastasis prevention. Metastatic settingEndpoint: Time until brain metastasisTime, $$$, recruitment criteria?

Clinical Trial Designs for Brain Metastasis Patients

Progression after WBRT. Most trials. Easy to recruit. Endpoint- lesion shrinkageIs this different biologically from less advanced disease?

Concurrent with WBRT. The elusive radiation sensitizersEndpoint – lesion shrinkage

Secondary Prevention. Prevention of additional metastases in patients withlimited brain metastases.Endpoint: Time until a new brain metastasisExamples: Lapatinib, Temozolomide, Pazopanib

Brain metastasis prevention. Metastatic settingEndpoint: Time until brain metastasisTime, $$$, recruitment criteria?

Nature 485:S58, 2012

VehicleTMZ

TMZ

Days: 0 20 40 60 80 100 120 140

TMZ is Ineffective in a Brain Metastasis Treatment Scenario

Also:TMZ prevention of brain metastasis was MGMT dependent

Randomized Secondary Brain Metastasis Prevention Trial Christina Tsien, PI University of Michigan for SWOG

Enrollment: HER2+ Patients with 1-3 brain metastases, treated with SRS or surgery, No WBRT.At very high risk for development of additional metastatses.

Randomize: T-DM1 as backbone systemic therapyTMZ, metronomic dose and schedule- or none

Endpoint: Time to development of a new metastasis outside of the SRS bed, at 3 mo. NOT shrinkage of the existing lesionToxicity, QOLTime to WBR

Status: Phase I run in under development, in collaboration with Genentech

Single arm phase 2 trialHER2+ MBC with brain mets no WBRT, Lapatinib, CapecitabinePrimary endpt- 50% volumetric response in absence of increased steroid no progressive neurological symptoms no progressive CNS disease

Trials of Interest: LANDSCAPE

Lancet Oncol. 14: 64, 2013

“Window of Opportunity” study

Phase II trial of Laptinib/Capecitabine in patients withBrain metastases, locally treated

Minesh MehtaUniversity of Maryland

Trial under development

Pazopanib Preclinical Data231-BR-HER2:

MCF7-HER2-BR3:By MRI

B-Raf inhibitor

No change invessel density

Clin. Cancer Res. 17:142, 2010

Experimental Metastases

Human Craniotomy Specimen

Pazopanib Inhibits the Astrocytic Neuro-inflammatory Response

Am. J. Pathol. 182:2368, 2013

A Subpopulation of Astrocytes are Phospho-PDGFR-+

How To Enroll Primary Brain Metastasis Prevention Trials?

BrainMetsBC.orgBrainMetsBC.org

Understanding brain metastases, available treatments, and emerging research. A Website for Patients and Families . . .

Musa MayerHelen SchiffLilla Romeo (deceased)

GEORGE SLEDGE, STANFORDANDY SEIDMAN, MSKCCDAVID PEEREBOOM, CCFRENATA DUCHNOWSKA,JACEK JASSEM, POLANDQUENTIN SMITH, TEXAS TECHPAUL LOCKMAN, W VA UNIVERSITY

SWOG:CHRISTINA TSIENMARK GILBERTGABRIEL HORTOBAGYI

FUNDING:DOD CENTER OF EXCELLENCENCIBREAST CANCER STAMP FUND

NCI:DIANE PALMIERIBRUNILDE GRILSTEPHAN WODITSCHKATIFFANY LYLEEMILY HUAYONG QIAN

JEAN CLAUDE MARSHALLJOSHUA COLLINS

ADVOCATES:MUSA MAYERLILA ROMEO (DECEASED)HELEN SCHIFF