We propose to develop integrated high field (3T) magnetic resonance imaging (MRI) and positron emission tomography (PET) methods for assessing the effects of molecularly targeted anti-angiogenesis and cytoxic treatments in breast cancer clinical trials. Our goal is to provide the breast cancer community with practical data acquisition and analysis protocols that facilitate the translation of advanced imaging technologies into patient management and clinical trials. Dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted MRI (DW-MRI) can report on vascular status, tissue volume fractions, and cellularity, while fluorodeoxythymidine PET (FLT-PET) can report on cell proliferation. We propose to combine these MRI and PET data to provide anatomical, physiological, and molecular assessments of the response of breast tumors to novel anti-angiogenic and cytoxic treatments in clinical trials. To accomplish these goals we will pursue the following specific aims: 1. We will develop high field breast MRI protocols that measure tissue cellularity and vascularity. We will then develop methods for the rigorous registration of these MRI measures with quantitative PET characterization of cell proliferation. We will develop the algorithms and software architecture necessary for synthesizing the imaging data with (traditional) clinical data to assisting in clinical decision making. 2. In an ongoing Phase II study we will employ DCE-MRI, DW-MRI, and FLT-PET to assess the degree of tumor response after one and two cycles of Carboplatin and nab-Paclitaxel with or without Vorinostat in HER2-negative primary operable breast cancer. 3. In our planned Phase II study we will employ DCE-MRI, DW-MRI, and FLT-PET to assess the degree of tumor response after one and two cycles of neoadjuvant cisplatin, paclitaxel and the TOI inhibitor everolimus in patients with triple negative breast tumors. As the anti-cancer agents employed in these clinical trials are implicated in apoptosis and/or inhibition of cellular proliferation and/or inhibition of angiogenesis, we hypothesize that changes in metrics of cellular proliferation and vascularity, when merged with traditional clinical biomarkers, will provide significantly more accurate predictions on patient response than traditional methods of tumor response including RECIST.

Public Health Relevance

We propose to develop integrated magnetic resonance imaging (MRI) and positron emission tomography (PET) methods for assessing the effects of molecularly targeted treatments in breast cancer clinical trials. We hypothesize that the synthesis of imaging metrics reporting on vascularity, cellularity, and cell proliferation will provide predictive measurements of tumor response to treatment in appropriately selected clinical trials. Our goal is to provide the breast cancer community with practical data acquisition and analysis protocols that facilitate the translation of advanced imaging technologies into patient management and clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA142565-01
Application #
7767472
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Nordstrom, Robert J
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$416,680
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Weis, Jared A; Miga, Michael I; Yankeelov, Thomas E (2017) Three-dimensional Image-based Mechanical Modeling for Predicting the Response of Breast Cancer to Neoadjuvant Therapy. Comput Methods Appl Mech Eng 314:494-512
Sorace, Anna G; Syed, Anum K; Barnes, Stephanie L et al. (2017) Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer. Mol Imaging Biol 19:130-137
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Malyarenko, Dariya I; Newitt, David; J Wilmes, Lisa et al. (2016) Demonstration of nonlinearity bias in the measurement of the apparent diffusion coefficient in multicenter trials. Magn Reson Med 75:1312-23
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Whisenant, Jennifer G; Dortch, Richard D; Grissom, William et al. (2016) Bloch-Siegert B1-Mapping Improves Accuracy and Precision of Longitudinal Relaxation Measurements in the Breast at 3 T. Tomography 2:250-259
Chan, Emily; Arlinghaus, Lori R; Cardin, Dana B et al. (2016) Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol 119:312-8
Pineda, Federico D; Medved, Milica; Wang, Shiyang et al. (2016) Ultrafast Bilateral DCE-MRI of the Breast with Conventional Fourier Sampling: Preliminary Evaluation of Semi-quantitative Analysis. Acad Radiol 23:1137-44
Malyarenko, Dariya I; Wilmes, Lisa J; Arlinghaus, Lori R et al. (2016) QIN DAWG Validation of Gradient Nonlinearity Bias Correction Workflow for Quantitative Diffusion-Weighted Imaging in Multicenter Trials. Tomography 2:396-405

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