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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EPrecision medicine uses traditional and emerging concepts of the genetic and environmental basis of disease to individualize prevention, diagnosis and treatment [National Cancer Institute, 2011]. It integrates the tumor genetics of individual patients into medical practice. The potential value of the targeted and precise approach is great. This article discusses advances in precision medicine from the perspective of prospective clinical trials. A specific example of melanoma as a model for personalized cancer medicine is also presented.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EApostolia M. Tsimberidou, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, discussed advances in precision medicine from the perspective of prospective clinical trials. Precision medicine uses traditional and emerging concepts of the genetic and environmental basis of disease to individualize prevention, diagnosis and treatment [National Cancer Institute, 2011]. It integrates the tumor genetics of individual patients into medical practice. The potential value of the targeted and precise approach is great. For instance, in a multicenter study in patients with metastatic lung adenocarcinoma, the median survival was longer in patients with an oncogenic driver and genotype-directed therapy compared with those with any oncogenic driver who did not receive genotype-directed therapy [Kris MG et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ECurrent challenges to precision medicine include incomplete validation of the plethora of tests that are constantly evolving, because the patients with specific targetable alterations treated with targeted agents are too few to analyze, and limited access to targeted agents. Prospective randomized trials with innovative designs that explore different types of genetic profiling and modeling hold the potential of permitting the assessment of the effectiveness of molecular profiling, which will enable the selection and use of the optimal targeted therapy.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EONGOING CLINICAL TRIALS WITH TARGETED THERAPY BASED ON TUMOR TYPE\u003C\/h2\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EThe Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination study [BATTLE 2; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01248247\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT01248247\u003C\/a\u003E] is a randomized Phase 2 trial with patients with advanced, refractory non\u2013small cell lung cancer (NSCLC). The primary objective is 8-week disease control rate; 400 patients are to be randomly assigned based on the results of patient tumor profiling. To date, results from 167 patients have demonstrated an improved disease control rate with the combined use of AKT and MEK inhibitors [Papadimitrakopoulou VA et al. \u003Cem\u003EASCO\u003C\/em\u003E 2014].\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe Intergroup Trial UNICANCER UC 0105\u20131305\/IFCT 1301: Efficacy of Targeted Drugs Guided by Genomic Profiles in Metastatic NSCLC Patients, an Intergroup study assessing the efficacy of targeted drugs guided by genomic profiles in patients with metastatic NSCLC [SAFIR 02 \u2013 Lung trial; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT02117167\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT02117167\u003C\/a\u003E] is a multicenter, randomized Phase 2 trial that uses high-throughput genome analysis to guide treatment based on identified tumor aberrations.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe Lung-MAP: S1400 Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IIIB-IV Non\u2013Small Cell Lung Cancer study [Lung-MAP (SWOG 1400); \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT02154490\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT02154490\u003C\/a\u003E] is a Phase 2\/3 screening\/clinical registration \u201cmaster protocol\u201d that will molecularly profile patients with advanced NSCLC. Patients with genetic alterations will be randomly assigned to investigational targeted therapy versus standard therapy (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Schema of the Lung-MAP: S1400 Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IIIB-IV Non\u0026#x2013;Small Cell Lung Cancer Trial\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1106791270\u0022 data-figure-caption=\u0022Schema of the Lung-MAP: S1400 Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IIIB-IV Non\u0026#x2013;Small Cell Lung Cancer Trial\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14584\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003ESchema of the Lung-MAP: S1400 Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IIIB-IV Non\u2013Small Cell Lung Cancer Trial\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003ECT=chemotherapy (docetaxel or gemcitabine); E=erlotinib; TT=targeted therapy.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from A. M. Tsimberidou, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EThe Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 trial [I-SPY TRIAL 2; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01042379\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT01042379\u003C\/a\u003E] is a multicenter, Phase 2, neoadjuvant trial for women with high-risk stage II or III breast cancer. This study uses adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. The primary endpoint is pathologic complete response. In 2013, the investigators announced the graduation of 2 regimens for 2 different biomarker signatures: for patients with triple-negative breast cancer when added to standard, presurgery chemotherapy, veliparib combined with carboplatin improved the response rate. Neratinib also demonstrated a high probability for success in a Phase 3 study in patients with \u003Cem\u003EHER2\u003C\/em\u003E-positive, hormone receptor\u2013negative disease.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EONGOING CLINICAL TRIALS WITH TARGETED THERAPY ACROSS TUMOR TYPES\u003C\/h2\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EIn an international study to select rational therapeutics on the basis of the analysis of matched tumor and normal biopsies in subjects with advanced malignancies (A Study to Select Rational Therapeutics Based on the Analysis of Matched Tumor and Normal Biopsies in Subjects With Advanced Malignancies [WINTHER; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01856296\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT01856296\u003C\/a\u003E]), tumor tissue will be used for molecular profiling and tumor and normal tissue for functional genomic microarrays and gene expression profiling. Patients with targetable molecular alterations will be treated with targeted therapy, and the remaining patients will be treated using a predetermined predictive algorithm of efficacy of drugs based on functional genomic analysis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe Randomized Phase 2 Trial Comparing Therapy Based on Tumor Molecular Profiling Versus Conventional Therapy in Patients With Refractory Cancer trial [SHIVA; NCT0177458] has almost completed patient accrual.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe NCI Molecular Profiling-Based Assignment of Cancer Therapy Study for Patients With Advanced Solid Tumors [MPACT; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01827384\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT01827384\u003C\/a\u003E] is designed to assess the utility of genome sequencing to determine therapy and improve patient outcomes in early-phase trials independent of tumor histology.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EThe Randomized Study Evaluating Molecular Profiling and Targeted Agents in Metastatic Cancer 2 trial [IMPACT; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT02152254\u0026amp;atom=%2Fspmdc%2F14%2F14%2F6.atom\u0022\u003ENCT02152254\u003C\/a\u003E] is a large-scale, randomized Phase 2 study evaluating molecular profiling and targeted therapy in metastatic cancer. The objective of the study is to determine whether patients treated with a targeted therapy selected based on tumor molecular analysis have longer PFS from the time of randomization than do those whose treatment is not selected based on molecular analysis (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Schema of the IMPACT 2 Trial\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1106791270\u0022 data-figure-caption=\u0022Schema of the IMPACT 2 Trial\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14586\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003ESchema of the IMPACT 2 Trial\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EReproduced with permission from A. M. Tsimberidou, MD, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EThese and future prospective trials should speed the identification of drugs that are specifically effective for the target tumors.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EAlexander M. Eggermont, MD, PhD, Gustave Roussy Comprehensive Cancer Center, Paris, France, discussed melanoma as a model for personalized cancer medicine. The presentation focused on 2 main aspects of personalized cancer medicine: mutation-driven drug development and the use of innovative immunomodulation strategies.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EThe genesis of mutation-driven drug development was a study almost a decade old that chronicled the different oncogenic mutations profiles in primary melanomas, which identified the potential selective advantage of the tyrosine kinase inhibitor imatinib in this setting [Curtin JA. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2006]. The influence of patient age on the changing pattern of prevalent mutations has since been documented [Rubenstein JC et al. \u003Cem\u003EJ Transl Med\u003C\/em\u003E 2010], as has the nature of the mutation and the treatment offered (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E) [Jakob JA et al. \u003Cem\u003ECancer\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Overall Survival of Wild-Type Versus BRAF With and Without Treatment With Inhibitor and NRAS                \u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1106791270\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Overall Survival of Wild-Type Versus \u0026amp;lt;em\u0026amp;gt;BRAF\u0026amp;lt;\/em\u0026amp;gt; With and Without Treatment With Inhibitor and \u0026amp;lt;em\u0026amp;gt;NRAS\u0026amp;lt;\/em\u0026amp;gt;                \u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/14\/6\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14588\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n               \u003Cp id=\u0022p-17\u0022 class=\u0022first-child\u0022\u003EOverall Survival of Wild-Type Versus \u003Cem\u003EBRAF\u003C\/em\u003E With and Without Treatment With Inhibitor and \u003Cem\u003ENRAS\u003C\/em\u003E\n               \u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EOS=overall survival; WT=wild-type.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EReproduced with permission from John Wiley \u0026amp; Sons from Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. \u003Cem\u003ECancer\u003C\/em\u003E 2012;118(16):4014\u20134023.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EStill, the improvements documented in PFS in therapies to \u003Cem\u003EBRAF\u003C\/em\u003E mutations may be more transient than long lasting [McArthur GA et al. \u003Cem\u003ELancet Oncol\u003C\/em\u003E 2014]. Whether this is the case with other mutation-targeted therapies requires study. Furthermore, contrary to expectations, targeted therapy is not free from adverse effects. Toxicity is always major consideration in the adjuvant setting, which includes even precisely targeted therapies. Dr. Eggermont cautioned that one needs to remember that tumors are not a static target; they can change with time, acquiring resistance to the treatment agent through mutations that can change tumor physiology, which in turn influences treatment efficacy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EInnovative immunomodulation is being increasingly used in targeted therapy. The central tenet of immunomodulation is breaking tolerance using immune checkpoint blockers. In this approach, targeting an inhibitor of the checkpoint blockers is more important and fundamentally useful than stimulation of activators. For example, blocking antibodies to T cell surface receptors, including CTLA-4, PD-1, TIM-3, and LAG-3, can blunt cell stimulation. This receptor blockade can occur naturally when T cells interact with tumor cells. In essence, the tumor cells stifle T cell action. But blockade of the T cell receptors prior to tumor cell interaction can help preserve the antitumor activity. The anti-CTLA-4 monoclonal antibody ipilimumab was the first therapy to improve overall survival (OS) in unresectable or metastatic melanoma [Hodi FS et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010]. The benefit was not instantaneous but rather required about 3 months to manifest. Thereafter, OS was significantly better than treatment with glycoprotein 100 peptide vaccine. Furthermore, blockade of PD-1 can also obviate interaction of the T cell surface protein with tumor cells receptor, which otherwise blunts T cell function. By blocking the inhibitor, the immune response against tumors can be bolstered.\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003ETargeted therapy is best envisioned in concert with radiation therapy and chemotherapy as a multipronged treatment strategy. This approach is in its infancy.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/14\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp4s6\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp4s6\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}