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Chapter 15  Precision Medicine in Oncology

institutions in less than 2 years. Over 90% of the successful biop- sies underwent NGS analysis with a validated assay performed by a centralized laboratory network with a median turnaround time of 15 days; 1,004 patients were assigned to treatment based on a rules-based algorithm, and 689 patients have been treated as of January 2018 on one of 30 different treatment arms. Therapeutic activity has been demonstrated on multiple trial arms. Although the primary focus of the NCI-MATCH trial is hypothesis gener- ation, it does demonstrate the possibility of studying the utility of molecularly targeted therapy for low-prevalence mutations when the trial population and the range of drug choices are both large. It has also clearly shown that the entire oncology community can be enlisted to examine the feasibility of scaling the precision med- icine paradigm if it provides novel treatment options for patients across a broad geographic distribution. IMAGING AND PRECISION ONCOLOGY Current functional molecular imaging techniques (such as positron emission tomography [PET], single-photon emission computed to- mography [SPECT], and dynamic contrast-enhanced magnetic res- onance imaging [DCE-MRI]) can provide a noninvasive approach

to quantitating the presence in tumors of specific molecular targets, the spatial heterogeneity of target expression, intratumoral drug pharmacokinetics, and target modulation following treatment with a therapeutic agent. 89,90 Examples of molecular targets and receptor occupancy that can be imaged include epidermal growth factor re- ceptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF). 89,91,92 Substantial progress has also been made in the use of [ 18 F]-fluoro-17-  -estradiol (FES) for PET scanning to demonstrate the presence of the estrogen receptor (ER) in breast cancers and modulation of ER occupancy by tamoxifen (Fig. 15.5). Recent studies suggest that uptake of FES in ER-positive breast cancers is correlated with objective response to antiestrogen therapy and that heterogeneous ER expression, when detected, may indicate the development of resistance to hormonal therapy. 93 Thus, molecular imaging techniques provide an import- ant means of defining patient populations that may benefit from specific molecularly targeted treatments as well as delineating sites of clinical tumoral heterogeneity noninvasively. Recently, improved analytical processing capabilities for both anatomic and molecular imaging data have allowed the quantita- tion of a range of phenotypic features from these images (e.g., tumor shape, texture, edge, and intensity) and the subsequent development of image signatures (radiomics) as well as a better understanding of

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Figure 15.5  Functional imaging of the estrogen receptor in a patient with metastatic breast cancer and receptor blockade by the tamoxifen metabolite endoxifen. A,C: [ 18 F]-Fluoro-17-  -estradiol (FES) scan of a patient with metastatic breast cancer in the pelvis; the metastatic site is shown ( circled ) in C . B,D: When the patient underwent repeat positron emission tomography–computed tomography (PET-CT) imaging on day 6 after 5 days of treatment with the active metabolite of tamoxifen, endoxifen, uptake of FES at that site was substantially decreased. SUV, standardized uptake value. (Reproduced from Doroshow JH, Kummar S. Translational research in oncology—10 years of progress and future prospects. Nature Rev Clin Oncol 2014;11:649–662, with permission.)