Comprehensive molecular tumor profiling in radiation oncology: How it could be used for precision medicine

Bernier, 2004, Radiation oncology: a century of achievements, Nat. Rev. Cancer, 4, 737, 10.1038/nrc1451 Morris, 2014, Interaction of radiation therapy with molecular targeted agents, J. Clin. Oncol, 32, 2886, 10.1200/JCO.2014.55.1366 Lynch, 2004, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N. Engl. J. Med, 350, 2129, 10.1056/NEJMoa040938 Fraser, 2015, Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer, Urol. Oncol, 33, 85, 10.1016/j.urolonc.2013.10.020 Bristow, 2014, An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy, Br. J. Radiol, 87, 10.1259/bjr.20130753 Makinde, 2013, Radiation survivors: understanding and exploiting the phenotype following fractionated radiation therapy, Mol. Cancer Res, 11, 5, 10.1158/1541-7786.MCR-12-0492 John-Aryankalayil, 2010, Fractionated radiation therapy can induce a molecular profile for therapeutic targeting, Radiat. Res, 174, 446, 10.1667/RR2105.1 John-Aryankalayil, 2012, Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells, Radiat. Res, 178, 105, 10.1667/RR2703.1 Coleman, 2003, Linking radiation oncology and imaging through molecular biology (or now that therapy and diagnosis have separated, it's time to get together again!, Radiology, 228, 29, 10.1148/radiol.2281021567 Aryankalayil, 2014, Defining molecular signature of pro-immunogenic radiotherapy targets in human prostate cancer cells, Radiat. Res, 182, 139, 10.1667/RR13731.1 Palayoor, 2014, Differential expression of stress and immune response pathway transcripts and miRNAs in normal human endothelial cells subjected to fractionated or single-dose radiation, Mol. Cancer Res, 12, 1002, 10.1158/1541-7786.MCR-13-0623 Borghaei, 2015, Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer, N. Engl. J. Med, 373, 1627, 10.1056/NEJMoa1507643 Larkin, 2015, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma, N. Engl. J. Med, 373, 23, 10.1056/NEJMoa1504030 Crittenden, 2015, Current clinical trials testing combinations of immunotherapy and radiation, Semin. Radiat. Oncol, 25, 54, 10.1016/j.semradonc.2014.07.003 Mellor, 2002, Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses, J. Immunol, 168, 3771, 10.4049/jimmunol.168.8.3771 Löb, 2009, IDO1 and IDO2 are expressed in human tumors: levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism, Cancer Immunol. Immunother, 58, 153, 10.1007/s00262-008-0513-6 Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nat. Rev. Cancer, 12, 252, 10.1038/nrc3239 Kwon, 2014, Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial, Lancet Oncol, 15, 700, 10.1016/S1470-2045(14)70189-5 Howbrook, 2003, Developments in microarray technologies, Drug Discov. Today, 8, 642, 10.1016/S1359-6446(03)02773-9 Lockhart, 2000, Genomics, gene expression and DNA arrays, Nature, 405, 827, 10.1038/35015701 Grada, 2013, Next-generation sequencing: methodology and application, J. Invest. Dermatol, 133, e11, 10.1038/jid.2013.248 Metzker, 2010, Sequencing technologies – the next generation, Nat. Rev. Genet, 11, 31, 10.1038/nrg2626 England, 2013, Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme, Tumour Biol, 34, 2063, 10.1007/s13277-013-0871-3 Balça-Silva, 2012, Effect of miR-34b overexpression on the radiosensitivity of non-small cell lung cancer cell lines, Anticancer Res, 32, 1603 Lalonde, 2014, Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study, Lancet Oncol, 15, 1521, 10.1016/S1470-2045(14)71021-6 de Jong, 2015, Pretreatment microRNA expression impacting on epithelial-to-mesenchymal transition predicts intrinsic radiosensitivity in head and neck cancer cell lines and patients, Clin. Cancer Res, 10.1158/1078-0432.CCR-15-0454 Baschnagel, 2009, Vorinostat enhances the radiosensitivity of a breast cancer brain metastatic cell line grown in vitro and as intracranial xenografts, Mol. Cancer Ther, 8, 1589, 10.1158/1535-7163.MCT-09-0038 Krauze, 2015, A phase II study of concurrent radiation therapy, temozolomide and the histone deacetylase inhibitor valproic acid for newly diagnosed patients with glioblastoma, Int. J. Radiat. Oncol. Biol. Phys, 92, 986, 10.1016/j.ijrobp.2015.04.038 Bauer, 2010, Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation, Clin. Cancer Res, 16, 681, 10.1158/1078-0432.CCR-09-1091 Eke, 2013, EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells, Cancer Res, 73, 297, 10.1158/0008-5472.CAN-12-2021 Eke, 2015, Simultaneous β1 integrin-EGFR targeting and radiosensitization of human head and neck cancer, J. Natl Cancer Inst, 107, dju419, 10.1093/jnci/dju419 Wibom, 2010, Metabolomic patterns in glioblastoma and changes during radiotherapy: a clinical microdialysis study, J. Proteome Res, 9, 2909, 10.1021/pr901088r Shin, 2014, An atlas of genetic influences on human blood metabolites, Nat. Genet, 46, 543, 10.1038/ng.2982 Yun, 2008, The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP, Proc. Natl. Acad. Sci. U.S.A., 105, 2070, 10.1073/pnas.0709662105 Chapman, 2011, Improved survival with vemurafenib in melanoma with BRAF V600E mutation, N. Engl. J. Med, 364, 2507, 10.1056/NEJMoa1103782 Poulikakos, 2011, RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E), Nature, 480, 387, 10.1038/nature10662 Lièvre, 2006, KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer, Cancer Res, 66, 3992, 10.1158/0008-5472.CAN-06-0191 Zhou, 2011, Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study, Lancet Oncol, 12, 735, 10.1016/S1470-2045(11)70184-X Bonner, 2010, Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival, Lancet Oncol, 11, 21, 10.1016/S1470-2045(09)70311-0 Bonner, 2006, Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck, N. Engl. J. Med, 354, 567, 10.1056/NEJMoa053422 Kripp, 2015, Does the addition of cetuximab to radiochemotherapy improve outcome of patients with locally advanced rectal cancer? Long-term results from phase ii trials, Gastroenterol. Res. Pract, 2015, 10.1155/2015/273489 Alberts, 2012, Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial, JAMA, 307, 1383, 10.1001/jama.2012.385 Lynch, 2010, Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099, J. Clin. Oncol, 28, 911, 10.1200/JCO.2009.21.9618 Di Nicolantonio, 2008, Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer, J. Clin. Oncol, 26, 5705, 10.1200/JCO.2008.18.0786 Khambata-Ford, 2007, Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab, J. Clin. Oncol, 25, 3230, 10.1200/JCO.2006.10.5437 Garrett, 2014, Predicting cetuximab efficacy in patients with advanced colorectal cancer, Curr. Biomark. Find, 4, 61, 10.2147/CBF.S54310 Bronte, 2015, New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?, Oncotarget, 6, 24780, 10.18632/oncotarget.4959 Dewdney, 2012, Multicenter randomized phase Ii clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C), J. Clin. Oncol, 30, 1620, 10.1200/JCO.2011.39.6036 Maughan, 2011, Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial, Lancet, 377, 2103, 10.1016/S0140-6736(11)60613-2 Kim, 2013, KRAS mutation status and clinical outcome of preoperative chemoradiation with cetuximab in locally advanced rectal cancer: a pooled analysis of 2 phase II trials, Int. J. Radiat. Oncol. Biol. Phys, 85, 201, 10.1016/j.ijrobp.2012.03.048 Giaccone, 2004, Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 1, J. Clin. Oncol, 22, 777, 10.1200/JCO.2004.08.001 Paez, 2004, EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Science, 304, 1497, 10.1126/science.1099314 Yang, 2015, Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials, Lancet Oncol, 16, 141, 10.1016/S1470-2045(14)71173-8 Komaki, 2015, Adding erlotinib to chemoradiation improves overall survival but not progression-free survival in stage iii non-small cell lung cancer, Int. J. Radiat. Oncol. Biol. Phys, 92, 317, 10.1016/j.ijrobp.2015.02.005 Iyengar, 2014, Phase II trial of stereotactic body radiation therapy combined with erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer, J. Clin. Oncol, 32, 3824, 10.1200/JCO.2014.56.7412 Lilenbaum, 2015, A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: results of CALGB 30605 (Alliance)/RTOG 0972 (NRG), J. Thorac. Oncol, 10, 143, 10.1097/JTO.0000000000000347 Cantwell-Dorris, 2011, BRAFV600E: implications for carcinogenesis and molecular therapy, Mol. Cancer Ther, 10, 385, 10.1158/1535-7163.MCT-10-0799 Wagle, 2011, Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling, J. Clin. Oncol, 29, 3085, 10.1200/JCO.2010.33.2312 Satzger, 2013, Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy, J. Clin. Oncol, 31, e220, 10.1200/JCO.2012.44.4265 Joseph, 2010, The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner, Proc. Natl. Acad. Sci. U.S.A., 107, 14903, 10.1073/pnas.1008990107 Anforth, 2013, Cutaneous toxicities of RAF inhibitors, Lancet Oncol, 14, e11, 10.1016/S1470-2045(12)70413-8 Farmer, 2005, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature, 434, 917, 10.1038/nature03445 Tutt, 2010, Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial, Lancet, 376, 235, 10.1016/S0140-6736(10)60892-6 Miki, 1994, A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1, Science, 266, 66, 10.1126/science.7545954 Jones, 2007, The epigenomics of cancer, Cell, 128, 683, 10.1016/j.cell.2007.01.029 Smits, 2014, Epigenetics in radiotherapy: where are we heading?, Radiother. Oncol, 111, 168, 10.1016/j.radonc.2014.05.001 Storch, 2010, Three-dimensional cell growth confers radioresistance by chromatin density modification, Cancer Res, 70, 3925, 10.1158/0008-5472.CAN-09-3848 Camphausen, 2007, Inhibition of histone deacetylation: a strategy for tumor radiosensitization, J. Clin. Oncol, 25, 4051, 10.1200/JCO.2007.11.6202 Rivera, 2010, MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma, Neuro Oncol, 12, 116, 10.1093/neuonc/nop020 Stupp, 2009, Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial, Lancet Oncol, 10, 459, 10.1016/S1470-2045(09)70025-7 Hamilton, 2006, Promoter methylation and response to chemotherapy and radiation in esophageal cancer, Clin. Gastroenterol. Hepatol, 4, 701, 10.1016/j.cgh.2006.03.007 Takahashi, 2015, ZNF695 methylation predicts a response of esophageal squamous cell carcinoma to definitive chemoradiotherapy, J. Cancer Res. Clin. Oncol, 141, 453, 10.1007/s00432-014-1841-x Siegel, 2014, Epigenomic characterization of locally advanced anal cancer: a radiation therapy oncology group 98-11 specimen study, Dis. Colon Rectum, 57, 941, 10.1097/DCR.0000000000000160 Halvorsen, 2014, Differential DNA methylation analysis of breast cancer reveals the impact of immune signaling in radiation therapy, Int. J. Cancer, 135, 2085, 10.1002/ijc.28862 Manuyakorn, 2010, Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704, J. Clin. Oncol, 28, 1358, 10.1200/JCO.2009.24.5639 Barlési, 2007, Global histone modifications predict prognosis of resected non small-cell lung cancer, J. Clin. Oncol, 25, 4358, 10.1200/JCO.2007.11.2599 Seligson, 2005, Global histone modification patterns predict risk of prostate cancer recurrence, Nature, 435, 1262, 10.1038/nature03672 Mercer, 2009, Long non-coding RNAs: insights into functions, Nat. Rev. Genet, 10, 155, 10.1038/nrg2521 He, 2004, MicroRNAs: small RNAs with a big role in gene regulation, Nat. Rev. Genet, 5, 522, 10.1038/nrg1379 Josson, 2008, Radiation modulation of microRNA in prostate cancer cell lines, Prostate, 68, 1599, 10.1002/pros.20827 Czochor, 2014, microRNAs in cancer cell response to ionizing radiation, Antioxid. Redox Signal, 21, 293, 10.1089/ars.2013.5718 Bader, 2011, Developing therapeutic microRNAs for cancer, Gene Ther, 18, 1121, 10.1038/gt.2011.79 Pan, 2015, MiR-200b regulates autophagy associated with chemoresistance in human lung adenocarcinoma, Oncotarget, 6, 32805, 10.18632/oncotarget.5352 Maachani, 2015, Modulation of miR-21 signaling by MPS1 in human glioblastoma, Oncotarget Wong, 2003, Expression genomics of cervical cancer: molecular classification and prediction of radiotherapy response by DNA microarray, Clin. Cancer Res, 9, 5486 Hwang, 2010, Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer, PLoS ONE, 5, e10630, 10.1371/journal.pone.0010630 Snipstad, 2010, New specific molecular targets for radio-chemotherapy of rectal cancer, Mol. Oncol, 4, 52, 10.1016/j.molonc.2009.11.002 Zempolich, 2008, Changes in gene expression induced by chemoradiation in advanced cervical carcinoma: a microarray study of RTOG C-0128, Gynecol. Oncol, 109, 275, 10.1016/j.ygyno.2008.01.027 Debucquoy, 2009, Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer, J. Clin. Oncol, 27, 2751, 10.1200/JCO.2008.18.5033 Prensner, 2014, RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1, Lancet Oncol, 15, 1469, 10.1016/S1470-2045(14)71113-1 Sun, 2014, EZH2-mediated epigenetic suppression of long noncoding RNA SPRY4-IT1 promotes NSCLC cell proliferation and metastasis by affecting the epithelial-mesenchymal transition, Cell Death Dis, 5, e1298, 10.1038/cddis.2014.256 Wulfkuhle, 2006, Technology insight: pharmacoproteomics for cancer – promises of patient-tailored medicine using protein microarrays, Nat. Clin. Pract. Oncol, 3, 256, 10.1038/ncponc0485 Frederick, 2011, Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples, Am. J. Pathol, 178, 548, 10.1016/j.ajpath.2010.10.044 Rikova, 2007, Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer, Cell, 131, 1190, 10.1016/j.cell.2007.11.025 Mammano, 2012, Multiplexed protein signal pathway mapping identifies patients with rectal cancer that responds to neoadjuvant treatment, Clin. Colorectal Cancer, 11, 268, 10.1016/j.clcc.2012.05.003 Zakharchenko, 2013, A role of TGFß1 dependent 14-3-3σ phosphorylation at Ser69 and Ser74 in the regulation of gene transcription, stemness and radioresistance, PLoS ONE, 8, e65163, 10.1371/journal.pone.0065163 Lee, 2014, Phosphoproteomic profiling identifies focal adhesion kinase as a mediator of docetaxel resistance in castrate-resistant prostate cancer, Mol. Cancer Ther, 13, 190, 10.1158/1535-7163.MCT-13-0225-T Yoshida, 2014, Tyrosine phosphoproteomics identifies both codrivers and cotargeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer, Clin. Cancer Res, 20, 4059, 10.1158/1078-0432.CCR-13-1559 Myllynen, 2015, Quantitative proteomics unveiled: regulation of DNA double strand break repair by EGFR involves PARP1, Radiother. Oncol, 10.1016/j.radonc.2015.09.018 Eke, 2013, Cetuximab attenuates its cytotoxic and radiosensitizing potential by inducing fibronectin biosynthesis, Cancer Res, 73, 5869, 10.1158/0008-5472.CAN-13-0344 Eke, 2012, β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy, J. Clin. Invest, 122, 1529, 10.1172/JCI61350 Lee, 2012, Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response, EMBO J., 31, 2403, 10.1038/emboj.2012.86 Boyer, 2013, Quantitative proteomics with siRNA screening identifies novel mechanisms of trastuzumab resistance in HER2 amplified breast cancers, Mol. Cell. Proteomics, 12, 180, 10.1074/mcp.M112.020115 Cairns, 2013, Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities, Cancer Discov, 3, 730, 10.1158/2159-8290.CD-13-0083 Mardis, 2009, Recurring mutations found by sequencing an acute myeloid leukemia genome, N. Engl. J. Med, 361, 1058, 10.1056/NEJMoa0903840 Parsons, 2008, An integrated genomic analysis of human glioblastoma multiforme, Science, 321, 1807, 10.1126/science.1164382 Turcan, 2012, IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype, Nature, 483, 479, 10.1038/nature10866 Chowdhury, 2011, The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases, EMBO Rep, 12, 463, 10.1038/embor.2011.43 Zeng, 2015, IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma, Oncotarget, 6, 30232, 10.18632/oncotarget.4920 Choi, 2012, 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas, Nat. Med, 18, 624, 10.1038/nm.2682 DiNardo, 2013, Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia, Blood, 121, 4917, 10.1182/blood-2013-03-493197 Spratlin, 2009, Clinical applications of metabolomics in oncology: a review, Clin. Cancer Res, 15, 431, 10.1158/1078-0432.CCR-08-1059 Kim, 2015, Identification of hypoxanthine and phosphoenolpyruvic acid as serum markers of chemoradiotherapy response in locally advanced rectal cancer, Cancer Res. Treat, 47, 78, 10.4143/crt.2013.127 Mörén, 2015, Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information, Metabolites, 5, 502, 10.3390/metabo5030502 Qiu, 2014, A distinct metabolic signature of human colorectal cancer with prognostic potential, Clin. Cancer Res, 20, 2136, 10.1158/1078-0432.CCR-13-1939 Giskeødegård, 2010, Multivariate modeling and prediction of breast cancer prognostic factors using MR metabolomics, J. Proteome Res, 9, 972, 10.1021/pr9008783 Budczies, 2013, Comparative metabolomics of estrogen receptor positive and estrogen receptor negative breast cancer: alterations in glutamine and beta-alanine metabolism, J. Proteomics, 94, 279, 10.1016/j.jprot.2013.10.002 Xu, 2013, Global and targeted metabolomics of esophageal squamous cell carcinoma discovers potential diagnostic and therapeutic biomarkers, Mol. Cell. Proteomics, 12, 1306, 10.1074/mcp.M112.022830 Yi, 2013, A metabolic discrimination model for nasopharyngeal carcinoma and its potential role in the therapeutic evaluation of radiotherapy, Metabolomics, 10, 697, 10.1007/s11306-013-0606-x Pantel, 2013, Real-time liquid biopsy in cancer patients: fact or fiction?, Cancer Res, 73, 6384, 10.1158/0008-5472.CAN-13-2030 Diaz, 2014, Liquid biopsies: genotyping circulating tumor DNA, J. Clin. Oncol, 32, 579, 10.1200/JCO.2012.45.2011 Quach, 2004, In vitro mutation artifacts after formalin fixation and error prone translesion synthesis during PCR, BMC Clin. Pathol, 4, 1, 10.1186/1472-6890-4-1 Taniguchi, 2011, Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas, Clin. Cancer Res, 17, 7808, 10.1158/1078-0432.CCR-11-1712 Murtaza, 2013, Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA, Nature, 497, 108, 10.1038/nature12065 Carpinetti, 2015, The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation, Oncotarget, 6, 38360, 10.18632/oncotarget.5256 Mohiuddin, 1996, c-Ki-ras mutations in peripheral blood of pancreatic cancer patients: a marker for early tumor metastasis, Int. J. Radiat. Oncol. Biol. Phys, 34, 161, 10.1016/0360-3016(95)02004-7 Mak, 2015, Selective paired ion contrast analysis: a novel algorithm for analyzing postprocessed LC-MS metabolomics data possessing high experimental noise, Anal. Chem, 87, 3177, 10.1021/ac504012a