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SHARE: Metastatic Breast Cancer: Cutting-Edge Research from National Cancer with Dr. Patricia Steeg

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Patricia Steeg, PhD, Chief of Women's Cancers Section at the Center for Cancer Research at NCI, will present her novel research relating to metastatic breast cancer, including the development of experimental models of brain metastasis. Join SHARE and Dr. Steeg for this nformative webinar.

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SHARE: Metastatic Breast Cancer: Cutting-Edge Research from National Cancer with Dr. Patricia Steeg

  1. 1. New Strategies to Prevent Breast Cancer Metastasis Patricia S. Steeg, Ph.D. Women’s Malignancies Branch NCI
  2. 2. Breast Cancer Survival by Subtype, After Initial Metastatic Diagnosis DFCI N= 188 The Netherlands N= 815 Br. Ca. Res. Trt. 141: 507, 2013 JNCCN 12: 71, 2014
  3. 3. Retrospective Evaluation of 199 MBC Patients (2004-2007) at DFCI Number of Lines of Chemotherapy by Disease Subtype
  4. 4. Metastasis can be prevented: Prevention of a first metastasis Prevention of additional metastases in limited metastatic setting We will need new clinical trial designs to validate this: Primary metastasis prevention Secondary metastasis prevention
  5. 5. Nature 485:S58, 2012
  6. 6. Nature 485:S58, 2012
  7. 7. Metastatic Dormancy What is it? Can we drug it? What trials are needed?
  8. 8. 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, 2003 Liu, Cancer Cell 15:539, 2009
  9. 9. 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
  10. 10. Histological Analysis of Liver and Lung Metastasis P < 0.0001 P < 0.0001 Average Liver Metastasis 35 Average Number of Metastasis 30 25 20 15 10 5 0 Control LPA1 Inhibitor Nm23-M1 Average Lung Metastasis 9 8 Slide 7 Per 6 Counts 5 4 Average 3 2 1 0 1 Control LPA1 Inhibitor Nm23-M1
  11. 11. LPA1 Inhibition Induced Aspects of Metastatic Dormancy P = NS P = 0.005 Dapi Ki67 Cell Cycle Quiescence Primary tumor, vehicle Primary tumor, Debio 0719 Liver Metastasis, vehicle Liver metastasis, Debio 0719 JNCI 104:1306, 2012
  12. 12. Metastatic Dormancy Asymptomatic clinical stage, well known in breast cancer, where metastatic progression is unapparent for years-decades. Thought to be caused by various factors including cell cycle quiescence, 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
  13. 13. Hypothetical mechanisms underlying metastasis dormancy. Zhang X H et al. Clin Cancer Res 2013;19:6389-6397 ©2013 by American Association for Cancer Research
  14. 14. 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
  15. 15. LPA1 Inhibitors are Under Clinical Development for Fibrosis Debio 0719 not orally bioavailable. SAR 100842 in phase II trial for systemic sclerosis. Other LPA1 inhibitors in trials for idiopathic pulmonary fibrosis Nature Med. 18: 1028, 2012
  16. 16. The Fibrosis: Metastasis Connection Cox T R et al. Cancer Res 2013;73:1721-1732
  17. 17. SAR100842, Experimental Designs SAR100842: LPA1, LPA3 antagonist in nm range Orally available In phase II trials for systemic scleroderma Will SAR100842 induce metastatic dormancy? 4T1 Model System: MDA-MB-231 Model System:
  18. 18. Primary Metastasis Prevention Scenarios – •Multiple positive lymph nodes •Chest wall recurrences •Post-neoadjuvant therapy Locally Advanced Breast Cancer Neoadjuvant therapy pCR No pCR FDA Guidance for Opportunity for Drug Approval Metastasis (Pertuzumab) Prevention ?
  19. 19. Post Neo-Adjuvant Randomized Phase II Trial to Prevent Metastasis “Primary” Metastasis Prevention Entry: Patients with locally advanced primary breast cancers Undergo neoadjuvant chemotherapy No Pathologic complete response Randomization: +/- Metastasis Preventive End Point: Metastasis Free Survival Toxicity, QOL Biopsies for molecular markers at progression
  20. 20. Brain Metastases Why doesn’t chemo work? Can it be prevented? What trials are needed?
  21. 21. Possible “soils” for brain metastatic colonization: Perivascular space Parenchyma, altered by neuroinflammation Leptomeninges Steeg, Camphausen and Smith Nat. Rev. Cancer 11: 1, 2011
  22. 22. Development of the 231-BR Brain Metastatic Model System MDA-MB-231 Parental cells (231P) Brain tumor isolation; growth in cell culture Intracardiac Inoculation Re-injection of 231-Brain cell line (six MDA 231- Brain Cell Line (231Br) 1. 2. 3. 4. 5. sequential rounds) Brain Metastasis 6. Yoneda et. al, (2001) J. Bone and Mineral Research
  23. 23. Additional Experimental Brain Metastasis Models Reflect the Heterogeneity of the Disease Sum190 BR3 (Her-2+, IBC) 4T1 BR5 (triple neg) Jimt1-BR3 (Her-2+) MCF7 Her-2 BR3(ER+, Her-2+)
  24. 24. What is the role of the Blood-Tumor Barrier ? None- Gadolinium gets into brain metastases for imaging Mice 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
  25. 25. BRAIN SYSTEMIC Reduced Efflux Transport Inject with brain-tropic breast cancer cells, allow mets to form Inject dyes or radiolabelled drugs into the circulation Perfuse dyes and drugs from the circulation At necropsy, make a single section of the brain Image Image Image drug uptake Metastases Marker uptake using phospho-imager Using GFP on Red flourescent channel Efflux Transport TUMOR
  26. 26. 14 Heterogeneous Uptake of C-Paclitaxel in Brain Metastases Metastasis 3kDa TR Dextran C- 14 Paclitaxel Clin. Cancer Res. 16: 5664, 2010 15% = normal brain 47% increased < 10-fold; 27% increased 10-50-fold; 10% > 50-fold Pearson r2 = 0.034
  27. 27. Concentrations of Capecitabine and its Metabolites in Craniotomy Specimens Patient, Drug Morikawa et al, Neuro-Oncology, In press
  28. 28. NONE of the Drugs Tested Had “Treatment” Activity in the 231-BR Model Detectable Metastasis : Single Metastatic Cell or Micrometastasis: Millions of tumor cells A few tumor cells Tortuous blood supply Fairly normal blood supply Needs to induce tumor cell Cytostatic molecular death inhibitors could keep it dormant Drug delivery difficult Drug delivery ok
  29. 29. Clinical Trial Designs for Brain Metastasis Patients Progression after WBRT. Most trials. Easy to recruit. Endpoint- lesion shrinkage Is this different biologically from less advanced disease? Concurrent with WBRT. The elusive radiation sensitizers Endpoint – lesion shrinkage Brain metastasis prevention. Metastatic setting Endpoint: Time until brain metastasis Time, $$$, recruitment criteria?
  30. 30. Clinical Trial Designs for Brain Metastasis Patients Progression after WBRT. Most trials. Easy to recruit. Endpoint- lesion shrinkage Is this different biologically from less advanced disease? Concurrent with WBRT. The elusive radiation sensitizers Endpoint – lesion shrinkage Secondary Prevention. Prevention of additional metastases in patients with limited brain metastases. Endpoint: Time until a new brain metastasis Examples: Lapatinib, Temozolomide, Pazopanib Nature 485:S58, 2012 Brain metastasis prevention. Metastatic setting Endpoint: Time until brain metastasis Time, $$$, recruitment criteria?
  31. 31. Vehicle TMZ TMZ Days: 0 20 40 60 80 100 120 140
  32. 32. TMZ is Ineffective in a Brain Metastasis Treatment Scenario Also: TMZ prevention of brain metastasis was MGMT dependent
  33. 33. 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 therapy TMZ, 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 lesion Toxicity, QOL Time to WBR Status: Phase I run in under development, in collaboration with Genentech
  34. 34. Trials of Interest: LANDSCAPE Single arm phase 2 trial HER2+ MBC with brain mets no WBRT, Lapatinib, Capecitabine Primary endpt- 50% volumetric response in absence of increased steroid no progressive neurological symptoms no progressive CNS disease Lancet Oncol. 14: 64, 2013
  35. 35. “Window of Opportunity” study Phase II trial of Laptinib/Capecitabine in patients with Brain metastases, locally treated Minesh Mehta University of Maryland Trial under development
  36. 36. Pazopanib Preclinical Data 231-BR-HER2: B-Raf inhibitor No change in vessel density MCF7-HER2-BR3: By MRI Clin. Cancer Res. 17:142, 2010
  37. 37. Pazopanib Inhibits the Astrocytic Neuro-inflammatory Response A Subpopulation of Astrocytes are Phospho-PDGFR-b+ Experimental Metastases Human Craniotomy Specimen Am. J. Pathol. 182:2368, 2013
  38. 38. How To Enroll Primary Brain Metastasis Prevention Trials?
  39. 39. BBrraaiinnMMeettssBBCC..oorrgg Understanding brain metastases, available treatments, and emerging research. A Website for Patients and Families . . . Musa Mayer Helen Schiff Lilla Romeo (deceased)
  40. 40. GEORGE SLEDGE, STANFORD ANDY SEIDMAN, MSKCC DAVID PEEREBOOM, CCF RENATA DUCHNOWSKA, JACEK JASSEM, POLAND QUENTIN SMITH, TEXAS TECH PAUL LOCKMAN, W VA UNIVERSITY SWOG: CHRISTINA TSIEN MARK GILBERT GABRIEL HORTOBAGYI FUNDING: DOD CENTER OF EXCELLENCE NCI BREAST CANCER STAMP FUND NCI: DIANE PALMIERI BRUNILDE GRIL STEPHAN WODITSCHKA TIFFANY LYLE EMILY HUA YONG QIAN JEAN CLAUDE MARSHALL JOSHUA COLLINS ADVOCATES: MUSA MAYER LILA ROMEO (DECEASED) HELEN SCHIFF

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