精准医学时代下临床药学监护模式新进展
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摘要
精准医学已成为现代医学的发展新模式,个性化用药更是精准医学在临床应用的重要体现。生命科学技术的进步促进了精准医学的发展,同时也促进了临床药学监护模式从合理用药、个性化用药向精准用药模式的发展。精准用药的实现需借助于先进的生命科学技术,对患者个体差异、疾病病理差异和疾病进展相关标志物群进行精准分析和准确描述。文中阐述精准医学时代下药代/药效动力学技术、组学技术和液体活检技术等在给药方案制定、疗效及不良反应预测等方面的最新应用研究进展,并对面向精准医学的临床药学监护模式发展方向进行展望。
Precision medicine has become a new mode of modern medicine,and personalized medication is the important embodiment of clinical application of precision medicine. The advances of life science technologies greatly facilitated precision medicine,and also promoted the shift of the mode of clinical pharmacy care from rational drug use and individualized medication to precision medication. To achieve"one person,one mode"clinical dosage regimens,it is necessary to rely on the supports of advanced life science technologies and precisely analyzing and accurately characterizing the biomarker clusters related to individual differences among patients,pathological differences of disease,and disease progression. This article illustrated the recent advances in the application of pharmacokinetics/pharmacodynamics,omics technology and liquid biopsy to the design of dosage regimen,prediction of therapeutic effect and adverse drug reactions,etc. in the era of precision medicine. Furthermore,the development direction of the new model of clinical pharmaceutical care faced on the precision medicine is prospected.
Precision medicine has become a new mode of modern medicine,and personalized medication is the important embodiment of clinical application of precision medicine. The advances of life science technologies greatly facilitated precision medicine,and also promoted the shift of the mode of clinical pharmacy care from rational drug use and individualized medication to precision medication. To achieve"one person,one mode"clinical dosage regimens,it is necessary to rely on the supports of advanced life science technologies and precisely analyzing and accurately characterizing the biomarker clusters related to individual differences among patients,pathological differences of disease,and disease progression. This article illustrated the recent advances in the application of pharmacokinetics/pharmacodynamics,omics technology and liquid biopsy to the design of dosage regimen,prediction of therapeutic effect and adverse drug reactions,etc. in the era of precision medicine. Furthermore,the development direction of the new model of clinical pharmaceutical care faced on the precision medicine is prospected.
引文
[1]Ashley EA.The Precision Medicine Initiative:A New National Effort[J].Jama,2015,313(21):2119-2120.
[2]Collins FS,Varmus H.A New Initiative on Precision Medicine[J].N Engl J Med,2015,372(9):793-795.
[3]Ashley EA.Towards precision medicine[J].Nat Rev Genet,2016,17(9):507-522.
[4]Pirmohamed M,Burnside G,Eriksson N,et al.A randomized trial of genotype-guided dosing of warfarin[J].N Engl J Med,2013,369(24):2294-2303.
[5]Paez JG,Janne PA,Lee JC,et al.EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J].Science,2004,304(5676):1497-500.
[6]Jamal JA,Roberts DM,Udy AA,et al.Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration:A randomised controlled trial of continuous infusion versus intermittent bolus administration[J].Int J Antimicrob Ag,2015,45(1):41-45.
[7]替考拉宁临床应用剂量专家共识组,替考拉宁临床应用剂量专家共识[J].中华结核和呼吸杂志,2016,39(7):500.
[8]叶红波,李金恒,王弘,等.移植患者口服环孢素A常规监测的多中心数据群体药代动力学分析[J].中国临床药理学杂志,2010,26(6):454-459.
[9]Andrews LM,Hesselink DA,van Gelder T,et al.A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation[J].Clin Pharmacokinet,2017,57(9):1-15.
[10]Jutkowitz E,Dubreuil M,Lu N,et al.The cost-effectiveness of HLA-b*5801 screening to guide initial urate-lowering therapy for gout in the United States[J].Semin Arthritis Rheum,2016,46(5):S0049017216301147.
[11]Stamp LK,Barclay ML.Barclay,How to prevent allopurinol hypersensitivity reactions?[J]Rheumatology,2018,57(suppl_1):i35-i41.
[12]初亚男,张婕妤,封利颖,等,人类白细胞抗原基因HLA-B*58∶01基因型的快速低成本鉴别方法[J].分析化学,2016,44(5):693-697.
[13]Swen JJ,Nijenhuis M,de Boer A,et al.Pharmacogenetics:from bench to byte--an update of guidelines[J].Clin Pharmacol Ther,2011,89(5):662-673.
[14]Furuta T,Shirai N,Kodaira M,et al.Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H.pylori[J].Clin Pharmacol Ther,2007,81(4):521-528.
[15]Klein TE,Altman RB,Eriksson N,et al.Estimation of the warfarin dose with clinical and pharmacogenetic data[J].N Engl J Med,2009,360(8):753-764.
[16]Johnson J,Caudle K,Gong L,et al.Clinical pharmacogenetics implementation consortium(cpic)guideline for pharmacogenetics-guided warfarin dosing:2017 update[J].Clin Pharmacol Ther,2017,102(3):397.
[17]Wei M,Ye F,Xie D,et al.A new algorithm to predict warfarin dose from polymorphisms of CYP4F2,CYP2C9 and VKORC1 and clinical variables:Derivation in Han Chinese patients with non valvular atrial fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[18]Zhang L,Wei TT,Li Y,et al.Functional Metabolomics Characterizes a Key Role for N-Acetyl-Neuraminic Acid in Coronary Artery Diseases[J].Circulation,2017,137(13):CIRCULATIONAHA.117.031139.
[19]Zhou X,Cao L,Jiang C,et al.PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis[J].Nat Commun,2014,5:4573.
[20]Andrew Clayton T,Lindon JC,Cloarec O,et al.Pharmaco-metabonomic phenotyping and personalized drug treatment[J].Nature,2006,440(7087):1073-1077.
[21]Li H,Stokes W,Chater E,et al.Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer[J].Cell Discov,2016,2:16031.
[22]Clayton TA,Baker D,Lindon JC,et al.Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism[J].Proc Natl Acad Sci U S A,2009,106(34):14728-14733.
[23]Huang Q,Aa J,Jia H,et al.A Pharmacometabonomic Approach To Predicting Metabolic Phenotypes and Pharmacokinetic Parameters of Atorvastatin in Healthy Volunteers[J].J Proteome Res,2015,14(9):3970-3981.
[24]Macpherson AJ,de Agüero MG,Ganal-Vonarburg SC.Ganalvonarburg,How nutrition and the maternal microbiota shape the neonatal immune system[J].Nat Rev Immunol,2017,17(8):508.
[25]Yu T,Guo F,Yu Y,et al.Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy[J].Cell,2017,170(3):548.
[26]Roy S,Trinchieri G.Trinchieri,Microbiota:a key orchestrator of cancer therapy[J].Nat Rev Cancer,2017,17(5):271.
[27]Wallace BD,Roberts AB,Pollet RM,et al.Structure and Inhibition of Microbiomeβ-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity[J].Chem Biol,2015,22(9):1238-1249.
[28]Rooks MG,Garrett WS.Gut microbiota,metabolites and host immunity[J].Nat Rev Immunol,2016,16(6):341-352.
[29]Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J].Science,2017,359(6371):91.
[30]Maier L,Pruteanu M,Kuhn M,et al.Extensive impact of non-antibiotic drugs on human gut bacteria[J].Nature,2018.555(7698):623-628.
[31]Metzker ML.Sequencing technologies-the next generation[J].Nat Rev Genet,2010,11(1):31-46.
[32]Deamer D,Akeson M,Branton D.Three decades of nanopore sequencing[J].Nat Biotechnol,2016,34(5):518-524.
[33]Eisenstein M.Illumina swallows PacBio in long shot for market domination.Nat Biotechnol,2019,37(1):3-4.
[34]Szczerba BM,Castro-Giner F,Vetter M,et al.Neutrophils escort circulating tumour cells to enable cell cycle progression[J].Nature,2019,566(7745):553-557.
[35]Kozminsky M,Fouladdel S,Chung JS,et al.Detection of CTC Clusters and a Dedifferentiated RNA-Expression Survival Signature in Prostate Cancer[J].Adv Sci(Weinh),2019,6(2):1801254.
[36]Wang Z,Duan J,Cai S,et al.Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with nonsmall cell lung cancer with use of a next-generation sequencing cancer gene panel[J].JAMA Oncol,2019;doi:10.1001/jamaoncol,2018.7098.
[37]Liu C,Zhao J,Tian F,et al.lambda-DNA and Aptamer Mediated Sorting and Analysis of Extracellular Vesicles[J].J Am Chem Soc,2019,141(9):p.3817-3821.
[38]Di Cosimo S,Appierto V,Pizzamiglio S,et al.Plasma microRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer:Results from the NeoALTTO trial[J].Clin Cancer Res,2019.
[39]Urabe F,Matsuzaki J,Yamamoto Y,et al.Large-scale circulating microRNA profiling for the liquid biopsy of prostate cancer[J].Clin Cancer Res,2019.
[40]Moon DH,Lindsay DP,Hong S,et al.Clinical indications for,and the future of,circulating tumor cells[J].Adv Drug Deliv Rev,2018,125:143-150.
[41]Yu M,Bardia A,Aceto N,et al.Cancer therapy.Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility[J].Science,2014,345(6193):216-220.
[42]Carter L,Rothwell DG,Mesquita B,et al.Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer[J].Nat Med,2017,23(1):114-119.
[43]Kwan TT,Bardia A,Spring LM,et al.A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer[J].Cancer Discov,2018,8(10):1286-1299.
[44]Shaw JA,Guttery DS,Hills A,et al.Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts[J].Clin Cancer Res,2017,23(1):88-96.
[45]Lorente D,Olmos D,Mateo J,et al.Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer[J].Eur Urol,2016,70(6):985-992.
[46]Giacona M,Ruben G,Iczkowski K,et al.Cell-free DNA in human blood plasma:length measurements in patients with pancreatic cancer and healthy controls[J].Pancreas,1998,17(1):89-97.
[47]Sun K,Jiang P,Chan KCA,et al.Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal,cancer,and transplantation assessments[J].Proc Natl Acad Sci U S A,2015,112(40):E5503-E5512.
[48]Nygaard AD,Garm Spindler KL,Pallisgaard N,et al.The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer[J].Lung Cancer,2013,79(3):312-317.
[49]Santiago-Walker A,Gagnon R,Mazumdar J,et al.Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials[J].Clin Cancer Res,2016,22(3):567-574.
[50]Gray ES,Rizos H,Reid AL,et al.Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma[J].Oncotarget,2015,6(39):42008-42018.
[51]Jr Diaz LA,Bardelli A.Liquid biopsies:genotyping circulating tumor DNA[J].J Clin Oncol,2014,32(6):579-586.
[52]Douillard JY,Ostoros G,Cobo M,et al.First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients:a phase-IV,open-label,single-arm study[J].Br J Cancer,2014,110(1):55-62.
[53]Xiang Z,Wan R,Zou B,et al.Highly sensitive and specific real-time PCR by employing serial invasive reaction as a sequence identifier for quantifying EGFR mutation abundance in cfDNA[J].Anal Bioanal Chem,2018,410(26):6751-6759.
[54]Chi HC,Tsai CY,Tsai MM,et al.Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy-Resistant Cancer Stem Cells[J].Int J Mol Sci,2017,18(9):1903.
[55]Xu R,Greening DW,Zhu HJ,et al.Extracellular vesicle isolation and characterization:toward clinical application[J].J Clin Invest,2016,126(4):1152-1162.
[56]Kowal J,Tkach M,Théry C.Biogenesis and secretion of exosomes[J].Curr Opin Cell Biol,2014,29(1):116-125.
[57]Bai X,Ni J,Beretov J,Graham P,et al.Cancer stem cell in breast cancer therapeutic resistance[J].Cancer Treat Rev,2018,69:152-163.
[58]Srivastava A,Babu A,Filant J,et al.Exploitation of Exosomes as Nanocarriers for Gene-,Chemo-,and Immune-Therapy of Cancer[J].JBiomed Nanotechnol,2016,12(6):1159.
[59]Qu L,Ding J,Chen C,et al.Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA[J].Cancer Cell,2016,29(5):653-668.
[60]Zhou J,Kwak KJ,Wu Z,et al.PLAUR Confers Resistance to Gefitinib Through EGFR/P-AKT/Survivin Signaling Pathway[J].Cell Physiol Biochem,2018,47(5):1909.
[61]Kang M,Ren M,Li Y,et al.Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA[J].J Exp Clin Canc Res,2018,37(1):171.
[62]黄晓晖,刘雪姣,周国华.氯吡格雷个体化用药研究进展[J].医学研究生学报,2019,32(4):443-448.
[2]Collins FS,Varmus H.A New Initiative on Precision Medicine[J].N Engl J Med,2015,372(9):793-795.
[3]Ashley EA.Towards precision medicine[J].Nat Rev Genet,2016,17(9):507-522.
[4]Pirmohamed M,Burnside G,Eriksson N,et al.A randomized trial of genotype-guided dosing of warfarin[J].N Engl J Med,2013,369(24):2294-2303.
[5]Paez JG,Janne PA,Lee JC,et al.EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy[J].Science,2004,304(5676):1497-500.
[6]Jamal JA,Roberts DM,Udy AA,et al.Pharmacokinetics of piperacillin in critically ill patients receiving continuous venovenous haemofiltration:A randomised controlled trial of continuous infusion versus intermittent bolus administration[J].Int J Antimicrob Ag,2015,45(1):41-45.
[7]替考拉宁临床应用剂量专家共识组,替考拉宁临床应用剂量专家共识[J].中华结核和呼吸杂志,2016,39(7):500.
[8]叶红波,李金恒,王弘,等.移植患者口服环孢素A常规监测的多中心数据群体药代动力学分析[J].中国临床药理学杂志,2010,26(6):454-459.
[9]Andrews LM,Hesselink DA,van Gelder T,et al.A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation[J].Clin Pharmacokinet,2017,57(9):1-15.
[10]Jutkowitz E,Dubreuil M,Lu N,et al.The cost-effectiveness of HLA-b*5801 screening to guide initial urate-lowering therapy for gout in the United States[J].Semin Arthritis Rheum,2016,46(5):S0049017216301147.
[11]Stamp LK,Barclay ML.Barclay,How to prevent allopurinol hypersensitivity reactions?[J]Rheumatology,2018,57(suppl_1):i35-i41.
[12]初亚男,张婕妤,封利颖,等,人类白细胞抗原基因HLA-B*58∶01基因型的快速低成本鉴别方法[J].分析化学,2016,44(5):693-697.
[13]Swen JJ,Nijenhuis M,de Boer A,et al.Pharmacogenetics:from bench to byte--an update of guidelines[J].Clin Pharmacol Ther,2011,89(5):662-673.
[14]Furuta T,Shirai N,Kodaira M,et al.Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H.pylori[J].Clin Pharmacol Ther,2007,81(4):521-528.
[15]Klein TE,Altman RB,Eriksson N,et al.Estimation of the warfarin dose with clinical and pharmacogenetic data[J].N Engl J Med,2009,360(8):753-764.
[16]Johnson J,Caudle K,Gong L,et al.Clinical pharmacogenetics implementation consortium(cpic)guideline for pharmacogenetics-guided warfarin dosing:2017 update[J].Clin Pharmacol Ther,2017,102(3):397.
[17]Wei M,Ye F,Xie D,et al.A new algorithm to predict warfarin dose from polymorphisms of CYP4F2,CYP2C9 and VKORC1 and clinical variables:Derivation in Han Chinese patients with non valvular atrial fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[18]Zhang L,Wei TT,Li Y,et al.Functional Metabolomics Characterizes a Key Role for N-Acetyl-Neuraminic Acid in Coronary Artery Diseases[J].Circulation,2017,137(13):CIRCULATIONAHA.117.031139.
[19]Zhou X,Cao L,Jiang C,et al.PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis[J].Nat Commun,2014,5:4573.
[20]Andrew Clayton T,Lindon JC,Cloarec O,et al.Pharmaco-metabonomic phenotyping and personalized drug treatment[J].Nature,2006,440(7087):1073-1077.
[21]Li H,Stokes W,Chater E,et al.Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer[J].Cell Discov,2016,2:16031.
[22]Clayton TA,Baker D,Lindon JC,et al.Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism[J].Proc Natl Acad Sci U S A,2009,106(34):14728-14733.
[23]Huang Q,Aa J,Jia H,et al.A Pharmacometabonomic Approach To Predicting Metabolic Phenotypes and Pharmacokinetic Parameters of Atorvastatin in Healthy Volunteers[J].J Proteome Res,2015,14(9):3970-3981.
[24]Macpherson AJ,de Agüero MG,Ganal-Vonarburg SC.Ganalvonarburg,How nutrition and the maternal microbiota shape the neonatal immune system[J].Nat Rev Immunol,2017,17(8):508.
[25]Yu T,Guo F,Yu Y,et al.Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy[J].Cell,2017,170(3):548.
[26]Roy S,Trinchieri G.Trinchieri,Microbiota:a key orchestrator of cancer therapy[J].Nat Rev Cancer,2017,17(5):271.
[27]Wallace BD,Roberts AB,Pollet RM,et al.Structure and Inhibition of Microbiomeβ-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity[J].Chem Biol,2015,22(9):1238-1249.
[28]Rooks MG,Garrett WS.Gut microbiota,metabolites and host immunity[J].Nat Rev Immunol,2016,16(6):341-352.
[29]Routy B,Le Chatelier E,Derosa L,et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J].Science,2017,359(6371):91.
[30]Maier L,Pruteanu M,Kuhn M,et al.Extensive impact of non-antibiotic drugs on human gut bacteria[J].Nature,2018.555(7698):623-628.
[31]Metzker ML.Sequencing technologies-the next generation[J].Nat Rev Genet,2010,11(1):31-46.
[32]Deamer D,Akeson M,Branton D.Three decades of nanopore sequencing[J].Nat Biotechnol,2016,34(5):518-524.
[33]Eisenstein M.Illumina swallows PacBio in long shot for market domination.Nat Biotechnol,2019,37(1):3-4.
[34]Szczerba BM,Castro-Giner F,Vetter M,et al.Neutrophils escort circulating tumour cells to enable cell cycle progression[J].Nature,2019,566(7745):553-557.
[35]Kozminsky M,Fouladdel S,Chung JS,et al.Detection of CTC Clusters and a Dedifferentiated RNA-Expression Survival Signature in Prostate Cancer[J].Adv Sci(Weinh),2019,6(2):1801254.
[36]Wang Z,Duan J,Cai S,et al.Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with nonsmall cell lung cancer with use of a next-generation sequencing cancer gene panel[J].JAMA Oncol,2019;doi:10.1001/jamaoncol,2018.7098.
[37]Liu C,Zhao J,Tian F,et al.lambda-DNA and Aptamer Mediated Sorting and Analysis of Extracellular Vesicles[J].J Am Chem Soc,2019,141(9):p.3817-3821.
[38]Di Cosimo S,Appierto V,Pizzamiglio S,et al.Plasma microRNA levels for predicting therapeutic response to neoadjuvant treatment in HER2-positive breast cancer:Results from the NeoALTTO trial[J].Clin Cancer Res,2019.
[39]Urabe F,Matsuzaki J,Yamamoto Y,et al.Large-scale circulating microRNA profiling for the liquid biopsy of prostate cancer[J].Clin Cancer Res,2019.
[40]Moon DH,Lindsay DP,Hong S,et al.Clinical indications for,and the future of,circulating tumor cells[J].Adv Drug Deliv Rev,2018,125:143-150.
[41]Yu M,Bardia A,Aceto N,et al.Cancer therapy.Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility[J].Science,2014,345(6193):216-220.
[42]Carter L,Rothwell DG,Mesquita B,et al.Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer[J].Nat Med,2017,23(1):114-119.
[43]Kwan TT,Bardia A,Spring LM,et al.A Digital RNA Signature of Circulating Tumor Cells Predicting Early Therapeutic Response in Localized and Metastatic Breast Cancer[J].Cancer Discov,2018,8(10):1286-1299.
[44]Shaw JA,Guttery DS,Hills A,et al.Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts[J].Clin Cancer Res,2017,23(1):88-96.
[45]Lorente D,Olmos D,Mateo J,et al.Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer[J].Eur Urol,2016,70(6):985-992.
[46]Giacona M,Ruben G,Iczkowski K,et al.Cell-free DNA in human blood plasma:length measurements in patients with pancreatic cancer and healthy controls[J].Pancreas,1998,17(1):89-97.
[47]Sun K,Jiang P,Chan KCA,et al.Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal,cancer,and transplantation assessments[J].Proc Natl Acad Sci U S A,2015,112(40):E5503-E5512.
[48]Nygaard AD,Garm Spindler KL,Pallisgaard N,et al.The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer[J].Lung Cancer,2013,79(3):312-317.
[49]Santiago-Walker A,Gagnon R,Mazumdar J,et al.Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials[J].Clin Cancer Res,2016,22(3):567-574.
[50]Gray ES,Rizos H,Reid AL,et al.Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma[J].Oncotarget,2015,6(39):42008-42018.
[51]Jr Diaz LA,Bardelli A.Liquid biopsies:genotyping circulating tumor DNA[J].J Clin Oncol,2014,32(6):579-586.
[52]Douillard JY,Ostoros G,Cobo M,et al.First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients:a phase-IV,open-label,single-arm study[J].Br J Cancer,2014,110(1):55-62.
[53]Xiang Z,Wan R,Zou B,et al.Highly sensitive and specific real-time PCR by employing serial invasive reaction as a sequence identifier for quantifying EGFR mutation abundance in cfDNA[J].Anal Bioanal Chem,2018,410(26):6751-6759.
[54]Chi HC,Tsai CY,Tsai MM,et al.Roles of Long Noncoding RNAs in Recurrence and Metastasis of Radiotherapy-Resistant Cancer Stem Cells[J].Int J Mol Sci,2017,18(9):1903.
[55]Xu R,Greening DW,Zhu HJ,et al.Extracellular vesicle isolation and characterization:toward clinical application[J].J Clin Invest,2016,126(4):1152-1162.
[56]Kowal J,Tkach M,Théry C.Biogenesis and secretion of exosomes[J].Curr Opin Cell Biol,2014,29(1):116-125.
[57]Bai X,Ni J,Beretov J,Graham P,et al.Cancer stem cell in breast cancer therapeutic resistance[J].Cancer Treat Rev,2018,69:152-163.
[58]Srivastava A,Babu A,Filant J,et al.Exploitation of Exosomes as Nanocarriers for Gene-,Chemo-,and Immune-Therapy of Cancer[J].JBiomed Nanotechnol,2016,12(6):1159.
[59]Qu L,Ding J,Chen C,et al.Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA[J].Cancer Cell,2016,29(5):653-668.
[60]Zhou J,Kwak KJ,Wu Z,et al.PLAUR Confers Resistance to Gefitinib Through EGFR/P-AKT/Survivin Signaling Pathway[J].Cell Physiol Biochem,2018,47(5):1909.
[61]Kang M,Ren M,Li Y,et al.Exosome-mediated transfer of lncRNA PART1 induces gefitinib resistance in esophageal squamous cell carcinoma via functioning as a competing endogenous RNA[J].J Exp Clin Canc Res,2018,37(1):171.
[62]黄晓晖,刘雪姣,周国华.氯吡格雷个体化用药研究进展[J].医学研究生学报,2019,32(4):443-448.