In this competitive renewal application, we will investigate specific aspects of the biology of locally advanced breast caners (LABCs) that were uncovered by our initial set of studies. Our previous specific aims were to (1) measure the response of LABC to neo-adjuvant chemotherapy using [Tc-99m]-sestamibi (MIBI) and [F-181]-fluorodeoxyglucose (FDG) PET and (2) to characterize the physiology of tumor response using MIBI, FDG, and [0-15]-water with the goal of identifying mechanisms of resistance. Our studies established serial MIBI imaging as an accurate toll for measuring response and indicated the accuracy of FDG PET for initial LABC staging and determining the extent of viable tumor post-therapy. In addition, we found a very striding set of findings regarding the physiology of responding tumors: (1) Tumors with a high rate of glycolysis (high FDG uptake) pre-therapy responded poorly to chemotherapy. (2) Patients who ultimately achieved a complete macroscopic response to therapy (CP) had a drop in tumor blood flow after two months of therapy, while all others had no change or an increase in blood flow; this pattern did not hold for the change in FDG uptake. Our studies also suggested that MIBI uptake is largely determined by blood flow and that neither pre-therapy MIBI uptake nor washout is a reliable predictor of chemotherapy resistance. Recent analysis has shown that the ratio of pre-therapy glycolysis to blood flow and the level of residual blood flow and MIBI uptake post-therapy predict disease-free survival. We now focus on mechanisms of tumor response and treatment resistance suggested by our first set of studies. By comparing PET measurements of tumor physiology to response and to in vitro assays of tumor biologic properties, we will investigate (1) the mechanisms underlying the apparent chemotherapy resistance of highly glycolytic LABC, in particular tumor hypoxia, (2) methods to measure response early in the course of therapy using PET cell proliferation tracers, and (3) the kinetic properties of MIBI using the positron-emitter [Tc-94m]-sestamibi to more precisely determine the effect of blood flow and efflux pump expression on MIBI uptake and washout. Our studies will increase the understanding of resistance and response to chemotherapy in advanced breast cancer and generate new approaches to individualizing patient treatment to optimize response. In this amended application, we focus on recent progress that has strengthened our preliminary data and further supports our proposed investigations of the biology of advanced breast cancer and its relationship to therapeutic response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Diagnostic Radiology Study Section (RNM)
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Menkens, Anne E
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University of Washington
Schools of Medicine
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Linden, Hannah M; Peterson, Lanell M; Fowler, Amy M (2018) Clinical Potential of Estrogen and Progesterone Receptor Imaging. PET Clin 13:415-422
Wangerin, Kristen A; Muzi, Mark; Peterson, Lanell M et al. (2017) A virtual clinical trial comparing static versus dynamic PET imaging in measuring response to breast cancer therapy. Phys Med Biol 62:3639-3655
Kurland, Brenda F; Muzi, Mark; Peterson, Lanell M et al. (2016) Multicenter Clinical Trials Using 18F-FDG PET to Measure Early Response to Oncologic Therapy: Effects of Injection-to-Acquisition Time Variability on Required Sample Size. J Nucl Med 57:226-30
Muzi, Mark; Peterson, Lanell M; O'Sullivan, Janet N et al. (2015) 18F-Fluoromisonidazole Quantification of Hypoxia in Human Cancer Patients Using Image-Derived Blood Surrogate Tissue Reference Regions. J Nucl Med 56:1223-8
Wangerin, Kristen A; Muzi, Mark; Peterson, Lanell M et al. (2015) Effect of (18)F-FDG uptake time on lesion detectability in PET imaging of early stage breast cancer. Tomography 1:53-60
Doot, Robert K; Kurland, Brenda F; Kinahan, Paul E et al. (2012) Design considerations for using PET as a response measure in single site and multicenter clinical trials. Acad Radiol 19:184-90
Kurland, Brenda F; Peterson, Lanell M; Lee, Jean H et al. (2011) Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by 18F-fluoroestradiol PET. J Nucl Med 52:1541-9
Dunnwald, Lisa K; Doot, Robert K; Specht, Jennifer M et al. (2011) PET tumor metabolism in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy: value of static versus kinetic measures of fluorodeoxyglucose uptake. Clin Cancer Res 17:2400-9
Linden, Hannah M; Kurland, Brenda F; Peterson, Lanell M et al. (2011) Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer. Clin Cancer Res 17:4799-805
Peterson, Lanell M; Kurland, Brenda F; Link, Jeanne M et al. (2011) Factors influencing the uptake of 18F-fluoroestradiol in patients with estrogen receptor positive breast cancer. Nucl Med Biol 38:969-78

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