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Imaging in the Era of Targeted Therapy Imaging as a Biomarker 2007 ASCO

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    1. Imaging in the Era of Targeted Therapy Imaging as a Biomarker 2007 ASCO/AACR Methods in Clinical Research David A. Mankoff, MD, PhD University of Washington and Seattle Cancer Care Alliance Seattle, WA USA

    2. Imaging and Cancer Therapy: Outline What is functional/molecular imaging? Imaging as a cancer biomarker Goals and imaging targets Prognosis Prediction Response

    3. Audience Response Slides 1-3

    4. Cautions Focus on cancer and nuclear medicine imaging Many of the imaging methods presented are considered investigational Discussion of results and possible applications is not a claim of clinical efficacy

    5. What is Functional/Molecular Imaging?

    6. Anatomic versus Functional Imaging Anatomic Imaging Relies on tumor size, shape, density e.g., mammography, CT Measures response by changes in size Functional imaging Relies on in vivo tumor biology: perfusion, metabolism, molecular features e.g., MRI, PET Measures response by changes in functional/molecular processes

    7. Functional Imaging Modalities Magnetic Resonance (MR) Magnetic Resonance Imaging (MRI) Magnetic Resonance Spectroscopy (MRS) Radionuclide imaging Positron Emission Tomography (PET) Single-Photon Emission Computed Tomography (SPECT) Ultrasound (U/S) Optical imaging

    8. Imaging Modalities: MRI Creates 3D image related to proton environment Contrast can be made using atoms like Gd and Fe Novel measures possible - e.g., diffusion imaging Capability influenced by field strength - current clinical maximum 3T Advantages High spatial resolution No radiation dose Disadvantages Confined environment, high magnetic field Contrast possibilities limited by concentration needs and need for elements like Gd or Fe

    9. Imaging Modalities: MRS Collects spatially localized MR spectra Calculates regional concentrations - e.g., choline With higher field strength, 3D voxel sets (i.e., images) possible Advantages No contrast needed Wide range of native molecules same time Disadvantages Limited spatial resolution Challenging data analysis

    10. Imaging Modalities: PET and SPECT Detects emission of administered radionuclides SPECT: 99mTc, 123I PET: 11C, 18F 3D image of radionuclide concentration Dynamic imaging possible Advantages Sensitive - tracer conditions Quantification - esp. PET Wide range of tracers - esp. PET Disadvantages Limited spatial resolution/anatomy (PET/CT helps) Some radiation dose (< diagnostic CT)

    11. Beyond FDG: PET Tracers for Imaging Cancer Biology

    12. Imaging Modalities: Ultrasound Creates 3D image using reflected or transmitted ultrasound - especially at interfaces Currently used mostly for anatomic imaging Blood flow, tissue characterization and contrast possible and increasingly sophisticated Advantages No radiation dose Widely available, portable, inexpensive Disadvantages Contrast design challenging Can be operator dependent

    13. Imaging Modalities: Optical Imaging based upon visible light Can use transmitted or reflected light Can use light emitted by contrast agent or embedded molecule - bioluminescence, near-infrared spectroscopy Advantages Highly portable Inexpensive Minimally invasive Molecular contrast agents Disadvantages Limited penetration

    14. Imaging as a Cancer Biomarker

    15. Existing Paradigm for Cancer Imaging: Find the Cancer Established role: Detect cancer Find how far cancer has spread

    16. Existing Cancer Imaging Paradigm: Targets for Detecting Tumor Cells Higher in Tumor than Normal Tissue

    17. FDG PET: Axillary Nodal Metastases

    18. A New Paradigm for Cancer Imaging: Help Direct Cancer Treatment New role for imaging: Guide cancer treatment selection Evaluate early treatment response

    19. Imaging and Cancer Therapy Help Match Therapy to Tumor Biology Goals in targeted cancer treatment Characterize tumor biology pre-Rx Individualized, specific therapy Static response may be acceptable The implied needs for cancer imaging Characterize in vivo tumor biology Identify targets, predict response Measure tumor response (early!) Identify progression/recurrence

    20. Emerging Cancer Imaging Paradigm: Measure Factors Affecting Response Variable Levels in Tumor - Quantification!

    21. Imaging Requirement for Biomarker Imaging: Simultaneously Localize and Characterize Disease Sites

    22. Imaging Requirement for Biomarker Imaging: Quantitative Analysis Dynamic protocols Allows kinetic modeling Full range of analysis options But not for everyone

    23. Guiding Cancer Therapy: Imaging Goals

    25. FDG Uptake and Retention

    27. FDG Predicts Survival in Recurrent Thyroid Cancer - Robbins, JCEM, 2006

    29. Tumor Hypoxia Quantified by PET Predicts Survival

    30. Guiding Cancer Therapy: Imaging Goals

    31. Predictive Assays Examples of in vitro assay ER - Endocrine therapy for breast cancer TS - 5-FU for colon cancer HER2 - Trastuzumab for breast cancer

    32. [F-18]-Fluoroestradiol (FES): PET Estrogen Receptor (ER) Imaging

    33. FES Uptake Predicts Breast Cancer Response to Hormonal Therapy

    35. Guiding Cancer Therapy: Imaging Goals

    36. Measuring Response (Image Quantification is Key)

    37. Biologic Events in Response to Successful Cancer Therapy Rationale for Measuring Early Response by Functional/molecular Imaging

    38. Small Cell Lung Cancer: PET Imaging Pre-and Post One Cycle of Rx

    40. Bone-Dominant Breast Cancer: Response then Progression

    41. Imaging Response - Better Predictor than Size: Neo-Adjuvant Therapy of Locally Advanced Breast Cancer (LABC)

    42. Change in MIBI Uptake Predicts Response

    43. Functional Imaging Predicts Outcome 99mTc-MIBI Serial Imaging

    44. Residual MIBI Uptake Versus DFS Comparison to Established Markers (Dunnwald, Cancer, 103:680, 2005)

    45. Imaging as a Cancer Biomarker: Summary New paradigm for cancer imaging - beyond cancer detection Requires novel approaches to image acquisition and analysis Matches imaging to clinical questions and cancer biology Imaging outcomes match approach to therapy How aggressive? Prognosis What target? Prediction Is it working? Response Is the tumor back? Surveillance new study designs for cancer imaging research Image quantification key Complementary to tissue/serum biomarkers