Molecular Imaging to Guide Targeted Therapy

PL-31 Molecularly targeted therapy holds great promise for improving cancer treatment; however, it creates new demands for tools to guide treatment selection. While treatment selection has traditionally depended on tissue-based biomarkers, functional and molecular imaging can play an important and complementary role in directing targeted cancer therapy and monitoring early response. Imaging has several capabilities distinct from tissue sampling and assay, including the ability to measure the heterogeneity of target expression and to characterize in vivo pharmacodynamics.The use of molecular imaging to direct cancer therapy departs from the traditional role of cancer imaging to detect and localize cancer sites. This implies an expansion of the scope of cancer imaging from detection methods that rely on features such as aberrant glycolysis in tumors but not in normal tissues, to a broader approach using imaging to quantify in vivo phenotype. In the latter case, the absence of a particular tumor feature, such as a target receptor, may be as important as its presence. The need to simultaneously localize and characterize tumor sites places an emphasis on multi-modality imaging such as PET/CT or multiple PET images using combinations of different imaging probes.For molecular imaging used to guide cancer therapy, new approaches to validating the imaging test are needed. For traditional cancer imaging tasks, studies compare imaging against biopsy results or clinical follow-up to measure the sensitivity and specificity for cancer detection. For imaging used as a biomarker to direct therapy, studies must test the ability of the imaging procedure to serve as a reliable prognostic or predictive factor, to measure therapeutic response and to predict patient outcomes such as time-to-progression and survival. This requires a new approach to imaging validation studies, which may need to occur in the setting of a cancer clinical trial.In this talk, we review potential applications of molecular imaging to targeted therapy clinical trials and clinical practice, using the example of endocrine therapy for breast cancer, perhaps one of the earliest forms of targeted cancer therapy. We demonstrate how PET imaging using a variety of probes, including 18F-fluoroestradiol (FES) PET can be used to (1) quantify the expression of the therapeutic target, (2) measure in vivo pharmacodynamics, and (3) measure early response to targeted therapy. We show how the use of FES PET in the setting of metastatic breast cancer can improve the selection of patients for endocrine therapy and how serial FES PET can measure the early effects of hormonal agents such as tamoxifen or fulvestrant and be useful for modifying dosing and/or drug delivery. Finally, we examine a variety of methods to evaluate early response to targeted therapy, also citing some recent examples of other targeted therapies in addition to breast cancer endocrine therapy. The theme of the presentation will be that quantitative in vivo measures of tumor phenotype using imaging are complementary to in vitro assay in directing targeted, individualized cancer therapy.Supported by NIH Grants CA42045, CA72064, and S10 RR17229ReferencesKelloff GJ, Krohn KA, Larson SM, Weissleder R, Mankoff DA, Hoffman JM, et al. The progress and promise of molecular imaging probes in oncologic drug development. Clin Cancer Res 2005;11(22):7967-85.Kiesewetter DO, Kilbourn MR, Landvatter SW, Heiman DF, Katzenellenbogen JA, Welch MJ. Preparation of four fluorine-18-labeled estrogens and their selective uptakes in target tissue of immature rats. J Nucl Med 1984;25:1212-1221.Linden HM, Stekhova S, Link JM, Gralow JR, Livingston RB, Ellis GK, et al. Quantitative fluoroestradiol (FES) PET predicts response to endocrine treatment. J Clin Oncol 24:2793-2799 2006.Mankoff DA and Krohn KA. PET imaging of response and resistance to cancer therapy, in Teicher B, Drug Resistance In Cancer, pp 1-5-122. Totowa, NJ: Humana Press, 2006.Mintun MA, Welch MJ, Siegel BA, Mathias CJ, Brodack JW, McGuire AH, Katzenellenbogen JA. Breast cancer: PET imaging of estrogen receptors. Radiology 1988;169:45-48.Mortimer JE, Dehdashti F, Siegel BA, Trinkaus K, Katzenellenbogen JA, Welch MJ. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol 2001;19(11):2797-803.Price P. Monitoring response to treatment in the development of anticancer drugs using PET. Nucl Med Biol 2000;27(7):691.Weber WA. Use of PET for monitoring cancer therapy and for predicting outcome. J Nucl Med 2005;46(6):983-95.