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
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