Therapy Monitoring of EGFR-Positive Non–Small-Cell Lung Cancer Patients Using ddPCR Multiplex Assays

Abstract

The detection of EGFR-sensitizing and EGFR-resistance mutations in advanced non–small-cell lung cancer patients is important for the selection and monitoring of EGFR tyrosine-kinase inhibitor therapy. Droplet digital PCR (ddPCR) multiplex assays allow for sensitive and simultaneous detection of multiple mutations in cell-free DNA (cfDNA) with a minimum of extract needed and at lower cost. Patients were screened for the EGFR tyrosine-kinase inhibitor–sensitizing mutations Ex19Del, L858R, L861Q, G719S, and S768I using a novel ddPCR pentaplex assay. Patients who tested positive subsequently were monitored during treatment for the EGFR-sensitizing mutation and two EGFR-resistance mutations, T790M and C797S, using a ddPCR monitor triplex assay. The ddPCR multiplex assays enabled reliable detection of each mutation with a fractional abundance of at least 0.1%. For six patients, longitudinal data were analyzed and the ddPCR results provided a good reflection of the course of the disease and radiologic response. This study confirms that ddPCR on cfDNA supports the diagnosis and therapy selection, and shows that ddPCR multiplex assays on cfDNA could be a valuable additional diagnostic tool for therapy monitoring of non–small-cell lung cancer patients. The detection of EGFR-sensitizing and EGFR-resistance mutations in advanced non–small-cell lung cancer patients is important for the selection and monitoring of EGFR tyrosine-kinase inhibitor therapy. Droplet digital PCR (ddPCR) multiplex assays allow for sensitive and simultaneous detection of multiple mutations in cell-free DNA (cfDNA) with a minimum of extract needed and at lower cost. Patients were screened for the EGFR tyrosine-kinase inhibitor–sensitizing mutations Ex19Del, L858R, L861Q, G719S, and S768I using a novel ddPCR pentaplex assay. Patients who tested positive subsequently were monitored during treatment for the EGFR-sensitizing mutation and two EGFR-resistance mutations, T790M and C797S, using a ddPCR monitor triplex assay. The ddPCR multiplex assays enabled reliable detection of each mutation with a fractional abundance of at least 0.1%. For six patients, longitudinal data were analyzed and the ddPCR results provided a good reflection of the course of the disease and radiologic response. This study confirms that ddPCR on cfDNA supports the diagnosis and therapy selection, and shows that ddPCR multiplex assays on cfDNA could be a valuable additional diagnostic tool for therapy monitoring of non–small-cell lung cancer patients. Targeted therapy aimed at EGFR tyrosine-kinase inhibitor (TKI)-sensitizing mutations has improved the outcome of eligible non–small-cell lung cancer (NSCLC) patients compared with chemotherapy.1Nan X. Xie C. Yu X. Liu J. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer.Oncotarget. 2017; 8: 75712-75726Crossref PubMed Scopus (68) Google Scholar However, most TKI-treated patients eventually develop resistance mechanisms, 50% of which is caused by the T790M mutation.2Oxnard G.R. Thress K.S. Alden R.S. Lawrance R. Paweletz C.P. Cantarini M. Yang J.C.-H. Barrett J.C. Jänne P.A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer.J Clin Oncol. 2016; 34: 3375-3382Crossref PubMed Scopus (585) Google Scholar,3Thress K.S. Paweletz C.P. Felip E. Cho B.C. Stetson D. Dougherty B. Lai Z. Markovets A. Vivancos A. Kuang Y. Ercan D. Matthews S.E. Cantarini M. Barrett J.C. Jänne P.A. Oxnard G.R. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.Nat Med. 2015; 21: 560-562Crossref PubMed Scopus (992) Google Scholar These patients can be treated with second-line TKIs (eg, osimertinib). Nevertheless, in 22% to 40% of reported cases, patients become resistant again to second-line therapy as a result of the C797S mutation.3Thress K.S. Paweletz C.P. Felip E. Cho B.C. Stetson D. Dougherty B. Lai Z. Markovets A. Vivancos A. Kuang Y. Ercan D. Matthews S.E. Cantarini M. Barrett J.C. Jänne P.A. Oxnard G.R. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.Nat Med. 2015; 21: 560-562Crossref PubMed Scopus (992) Google Scholar,4Oxnard G.R. Hu Y. Mileham K.F. Husain H. Costa D.B. Tracy P. Feeney N. Sholl L.M. Dahlberg S.E. Redig A.J. Kwiatkowski D.J. Rabin M.S. Paweletz C.P. Thress K.S. Jänne P.A. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib.JAMA Oncol. 2018; 4: 1527-1534Crossref PubMed Scopus (314) Google Scholar Until now, mutations have been analyzed mostly on tumor tissue. In recent years, liquid biopsies have shown to be a promising minimally invasive method for the detection of driver and therapy resistance mutations.5Madic J. Jovelet C. Lopez J. André B. Fatien J. Miran I. Honoré A. Mezquita L. Besse B. Lacroix L. Droniou M. EGFR C797S, EGFR T790M and EGFR sensitizing mutations in non-small cell lung cancer revealed by six-color crystal digital PCR.Oncotarget. 2018; 9: 37393-37406Crossref PubMed Google Scholar, 6Lee J.Y. Qing X. Xiumin W. Yali B. Chi S. Bak S.H. Lee H.Y. Sun J.-M. Lee S.-H. Ahn J.S. Cho E.K. Kim D.-W. Kim H.R. Min Y.J. Jung S.-H. Park K. Mao M. Ahn M.-J. Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02).Oncotarget. 2016; 7: 6984-6993Crossref PubMed Scopus (107) Google Scholar, 7Wood-Bouwens C.M. Haslem D. Moulton B. Almeda A.F. Lee H. Heestand G.M. Nadauld L.D. Ji H.P. Therapeutic monitoring of circulating DNA mutations in metastatic cancer with personalized digital PCR.J Mol Diagn. 2020; 22: 247-261Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 8Sacher A.G. Paweletz C. Dahlberg S.E. Alden R.S. O’Connell A. Feeney N. Mach S.L. Jänne P.A. Oxnard G.R. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer.JAMA Oncol. 2016; 2: 1014-1022Crossref PubMed Scopus (400) Google Scholar, 9Jovelet C. Madic J. Remon J. Honoré A. Girard R. Rouleau E. André B. Besse B. Droniou M. Lacroix L. Crystal digital droplet PCR for detection and quantification of circulating EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer.PLoS One. 2017; 12: e0183319Crossref PubMed Scopus (21) Google Scholar, 10Oxnard G.R. Paweletz C.P. Kuang Y. Mach S.L. O’Connell A. Messineo M.M. Luke J.J. Butaney M. Kirschmeier P. Jackman D.M. Jänne P.A. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA.Clin Cancer Res. 2014; 20: 1698-1705Crossref PubMed Scopus (573) Google Scholar, 11Mok T. Wu Y.-L. Lee J.S. Yu C.-J. Sriuranpong V. Sandoval-Tan J. Ladrera G. Thongprasert S. Srimuninnimit V. Liao M. Zhu Y. Zhou C. Fuerte F. Margono B. Wen W. Tsai J. Truman M. Klughammer B. Shames D.S. Wu L. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy.Clin Cancer Res. 2015; 21: 3196-3203Crossref PubMed Scopus (354) Google Scholar, 12Taus Á. Camacho L. Rocha P. Hardy-Werbin M. Pijuan L. Piquer G. López E. Dalmases A. Longarón R. Clavé S. Salido M. Albanell J. Bellosillo B. Arriola E. Dynamics of EGFR mutation load in plasma for prediction of treatment response and disease progression in patients with EGFR-mutant lung adenocarcinoma.Clin Lung Cancer. 2018; 19: 387-394.e2Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Goldberg S.B. Narayan A. Kole A.J. Decker R.H. Teysir J. Carriero N.J. Lee A. Nemati R. Nath S.K. Mane S.M. Deng Y. Sukumar N. Zelterman D. Boffa D.J. Politi K. Gettinger S.N. Wilson L.D. Herbst R.S. Patel A.A. Early assessment of lung cancer immunotherapy response via circulating tumor DNA.Clin Cancer Res. 2018; 24: 1872-1880Crossref PubMed Scopus (149) Google Scholar Droplet digital PCR (ddPCR) is a sensitive and robust method and allows for absolute quantification of circulating tumor DNA (ctDNA). In addition, ddPCR can be used for multiplexing, enabling the detection of various targets in parallel with a minimum of ctDNA extract required and with relatively low exploitation costs.14de Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar In our cohort of patients with suspected lung carcinoma, various EGFR mutations were found, of which the L858R (44%), exon 19 deletion (Ex19Del, 20%), S768I (12%), G719S (4%), and L861Q (4%) were the most frequent and clinically relevant. Therefore, based on the previously described ddPCR EGFR screening triplex assay,14de Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar a sensitive and robust ddPCR pentaplex assay was developed that allows for simultaneous detection of the EGFR TKI-sensitizing mutations Ex19Del, L858R, L861Q, G719S, and S768I. In addition, for each EGFR TKI-sensitizing mutation, a monitor ddPCR triplex assay was set up, including the detection of EGFR TKI-resistance mutations T790M and C797S. In this study, the EGFR mutation status of six NSCLC patients was monitored by ddPCR multiplex assays on liquid biopsies. These results then were compared with the clinical classification of tumor response based on imaging results, to investigate the added value in therapy response and on therapy management. The patients described are part of an ongoing multicenter study (Netherlands Trial Register, https://www.trialregister.nl, trial NL9146), which was approved by the Medical Research Ethics Committees United (Nieuwegein, the Netherlands). The cohort consists of patients with suspected lung carcinoma (n = 644). After signed written informed consent was was during a a driver mutation was by ddPCR on cell-free DNA (cfDNA) next-generation on tumor additional were with on the treatment In this study, six lung cancer patients who tested positive for the L858R, Ex19Del, L861Q EGFR TKI-sensitizing mutation were monitored during The was at the of diagnosis the of for the S768I for this the therapy at the of The between the and the of therapy was and the between the of therapy and the was ctDNA was as two with response to were during clinical to ctDNA to in The were as response as response the of the of at least as disease the of the of at least and as disease the for the for were and the ctDNA as described Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The of detection of the EGFR multiplex assays was by and cfDNA of the EGFR cfDNA The of the EGFR multiplex assays was tested using cfDNA of patients harboring EGFR mutation, as by on tumor tissue. The of was by the multiplex assays on The screening pentaplex is based on the previously described EGFR triplex Ex19Del, L858R, and Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar For G719S, G719S and were For and were ddPCR was monitoring assay consists of T790M G.R. Paweletz C.P. Kuang Y. Mach S.L. O’Connell A. Messineo M.M. Luke J.J. Butaney M. Kirschmeier P. Jackman D.M. Jänne P.A. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA.Clin Cancer Res. 2014; 20: 1698-1705Crossref PubMed Scopus (573) Google Scholar C797S and of C797S and on the EGFR monitoring the set of and of the EGFR TKI-sensitizing For Ex19Del, the and as described previously for the EGFR triplex Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar was For L858R, G. X. Z. Sun Y. Liu Y. R. Y. Liu X. sensitive droplet digital PCR method for detection of mutations in plasma cell-free DNA from patients with advanced non-small cell lung cancer.J Mol Diagn. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar and the as described Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar were For L861Q, and were For G719S, and were For and were The monitoring assay consists of T790M G.R. Paweletz C.P. Kuang Y. Mach S.L. O’Connell A. Messineo M.M. Luke J.J. Butaney M. Kirschmeier P. Jackman D.M. Jänne P.A. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA.Clin Cancer Res. 2014; 20: 1698-1705Crossref PubMed Scopus (573) Google Scholar C797S of and For monitor ddPCR for was was on the ddPCR using the for of for for by for and to were analyzed using and were to the positive Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar at least including were a was Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The fractional abundance was for the of targets in the multiplex assay (eg, the was by two two were in the on the EGFR screening triplex described Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar an EGFR screening pentaplex was developed for the simultaneous detection of the Ex19Del, L858R, L861Q, G719S, and S768I mutations using the EGFR cfDNA In to the which is used in the EGFR Kock R. Deiman B. Kraaijvanger R. Scharnhorst V. Optimized (pre) analytical conditions and workflow for droplet digital PCR analysis of cell-free DNA from patients with suspected lung carcinoma.J Mol Diagn. 2019; 21: 895-902Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar a was added to the the G719S mutation to a from of the G719S to For each mutation a was and by on with a EGFR mutation The pentaplex was by of the EGFR cfDNA and was that the of the was and in the of as the In addition, droplet was in the and droplet was in the the and of the of the EGFR fractional are on the of and targets assay. The are based on the EGFR cell-free DNA with The are patients harboring EGFR mutation, as based on next-generation on tumor exon 19 fractional are on the of and targets assay. The are based on the EGFR cell-free DNA with The are patients harboring EGFR mutation, as based on next-generation on tumor tissue. in a Ex19Del, exon 19 The of detection of the screening pentaplex was on cfDNA using cfDNA (n = was that to a of the of each mutation was and However, was that patients with to lung carcinoma have a cfDNA of C. S. P. D. M. J. C. M. S. DNA is an in lung J. 2015; PubMed Scopus Google Scholar Therefore, to a clinical in which patients with to NSCLC are the of detection was using cfDNA (n = this the of each mutation was to a of on a DNA with a of are shown with Ex19Del, exon 19 in a are shown with Ex19Del, exon 19 In addition, the screening pentaplex was tested on with a EGFR mutation and compared with the was that the of Ex19Del, L858R, L861Q, and S768I with the pentaplex the were in the of that the pentaplex is as sensitive as the was for the G719S mutation at diagnosis this was treatment at the of of the EGFR with the are shown with Ex19Del, exon 19 in a are shown with Ex19Del, exon 19 monitor multiplex assays were developed to monitor the course of the EGFR TKI-sensitizing mutation for the of therapy and to the EGFR TKI-resistance mutations, T790M and C797S, during In the EGFR monitor triplex for each mutation a was and by on with a EGFR mutation The monitoring assays were shown to be and robust The of detection of was on cfDNA with a of to using cfDNA (n = was using this assays could each to a of at least and be with a clinical in which cfDNA were in patients with to C. S. P. D. M. J. C. M. S. DNA is an in lung J. 2015; PubMed Scopus Google Scholar was that monitor triplex assays could each to a of at least using cfDNA (n = The monitor triplex assays were tested on with a EGFR mutation and was that the using the monitor screening were and that was using the monitor for the G719S mutation was positive to the of the the been For monitor triplex an EGFR TKI-sensitizing mutation is the of the this mutation and the could with the in the Therefore, an EGFR monitor for the detection of T790M and C797S was set which is used to the of a resistance mutation are In to the pentaplex and monitor the assay was shown to be and robust could be to using cfDNA each could be to using cfDNA In addition, for a T790M-positive a and were using the assay the T790M assay and This study a harboring the C797S longitudinal data were from six NSCLC patients harboring the EGFR mutations L861Q, L858R, Ex19Del, S768I as by ddPCR on plasma and by on tumor tissue. with a NSCLC the L861Q mutation at the of diagnosis The was treated with a of erlotinib and and eventually with erlotinib the of the L861Q and were a therapy which was by a on a the of the L861Q and were again in with based on However, the of the L861Q and disease This was by as was In addition, on the T790M mutation was in resistance to the EGFR TKI therapy. with a the L858R mutation at the of diagnosis and was treated with erlotinib After the of the L858R and a therapy which was by the of the L858R and disease the results of the were as and The T790M mutation was resistance to the EGFR TKI therapy. After was by and the treatment was to this the T790M the L858R and disease This was on the harboring the L858R mutation, was with a NSCLC and was treated with a of erlotinib and by erlotinib treatment After the of the L858R and to an a therapy which was by imaging The L858R and the of a therapy which again was with the of the L858R mutation and the T790M mutation was disease which was as on was and treatment was to the of osimertinib the of the L858R and T790M was and the of L858R and T790M a response to the therapy The L858R mutation was in the plasma of who was with a NSCLC The was treated with and After the ctDNA to an The ctDNA during a therapy response. This is in with the two which were as the treatment and was was that the ctDNA and in disease This was by the on which was as this was with a on tumor was was the of the L858R mutation was by on tumor and TKI treatment with was treatment with the L858R to an a therapy which was by was with a cell carcinoma and to the on tumor was The was treated with However, was on cfDNA and was based on the the analysis was and was that the an that the of was by on tumor tissue. The was to erlotinib on and was that the and to an a therapy which was in with was with a NSCLC and the S768I and L858R mutations were by on tumor tissue. the of the was treated with The S768I and L858R mutations in liquid biopsies for a therapy response. This was in with the two which were as response and However, on was reported based on and a the liquid analysis was on the of the L858R, and T790M the was to osimertinib and was that the L858R, and T790M and a response to the therapy. This was by the results of the during osimertinib of the of during osimertinib the therapy to be which in S768I and L858R and on EGFR multiplex assays were in this an EGFR screening pentaplex for the parallel detection of the EGFR TKI-sensitizing mutations Ex19Del, L858R, L861Q, G719S, and and EGFR monitoring the EGFR TKI-sensitizing mutation with two EGFR TKI-resistance mutations, T790M and C797S. In clinical the EGFR screening pentaplex could be used for patients with suspected lung carcinoma to the is eligible for EGFR TKI therapy. an EGFR mutation is the EGFR monitor triplex could be used to the and fractional abundance of the EGFR TKI-sensitizing mutation and resistance mutations in longitudinal plasma that therapy can be the of the T790M C797S mutation could be by using the monitor assay that the and of the sensitizing mutation, from the T790M C797S mutation This allows for reliable detection of EGFR and TKI-resistance mutations to a of at least 0.1%. of this study was that cfDNA extract was from a harboring the In to the G719S mutation, the and mutations the ddPCR a to could be Nevertheless, the ddPCR multiplex assays described in this study enabled detection of the most EGFR TKI-sensitizing mutations in our cohort in a Therefore, the of ddPCR multiplex assays allows for and sensitive of multiple targets with a minimum of cfDNA extract needed and at low In patients the detection of the sensitizing mutation and the T790M mutation was in with the of based on which in a therapy from erlotinib to a response to osimertinib was by the monitored ctDNA and fractional In a the detection of in plasma the of disease as by in a therapy from immunotherapy to the therapy the to an which was in with the imaging response to as These the added clinical value of the EGFR mutation status in plasma during the diagnostic and of patients with which has been described J. Jovelet C. Lopez J. André B. Fatien J. Miran I. Honoré A. Mezquita L. Besse B. Lacroix L. Droniou M. EGFR C797S, EGFR T790M and EGFR sensitizing mutations in non-small cell lung cancer revealed by six-color crystal digital PCR.Oncotarget. 2018; 9: 37393-37406Crossref PubMed Google J.Y. Qing X. Xiumin W. Yali B. Chi S. Bak S.H. Lee H.Y. Sun J.-M. Lee S.-H. Ahn J.S. Cho E.K. Kim D.-W. Kim H.R. Min Y.J. Jung S.-H. Park K. Mao M. Ahn M.-J. Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02).Oncotarget. 2016; 7: 6984-6993Crossref PubMed Scopus (107) Google A.G. Paweletz C. Dahlberg S.E. Alden R.S. O’Connell A. Feeney N. Mach S.L. Jänne P.A. Oxnard G.R. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer.JAMA Oncol. 2016; 2: 1014-1022Crossref PubMed Scopus (400) Google Á. Camacho L. Rocha P. Hardy-Werbin M. Pijuan L. Piquer G. López E. Dalmases A. Longarón R. Clavé S. Salido M. Albanell J. Bellosillo B. Arriola E. Dynamics of EGFR mutation load in plasma for prediction of treatment response and disease progression in patients with EGFR-mutant lung adenocarcinoma.Clin Lung Cancer. 2018; 19: 387-394.e2Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar In the the the is based on the between the and this was caused by a of the compared with the The clinical for the in is this could have been caused by the the This shows that the the therapy and by the in to the a of therapy response is ddPCR is used in the clinical for the analysis of is that the be reported during the which is in with a R. M. F. C. N. E. from the cfDNA on the for clinical ctDNA 2019; PubMed Scopus Google Scholar L858R mutation was by ddPCR on liquid of a on tumor was was and and were the disease progression was reported which was in with a in the L858R and in the L858R mutation was by on tumor which in the of treatment and subsequently to an L858R an to TKI treatment could have the of the L858R and the of mutation analysis on is for to lung carcinoma patients to the of of Medical this shows that mutation analysis on liquid could the diagnosis in the of the disease enabling the selection of the therapy. the described ddPCR multiplex assays longitudinal monitoring of EGFR mutation status in liquid biopsies. In the course of the ctDNA and the therapy response and is in with the course of the be a diagnostic tool in personalized therapy of NSCLC patients. the of patients in this cohort is the be in a In addition, investigate additional C.M. Haslem D. Moulton B. Almeda A.F. Lee H. Heestand G.M. Nadauld L.D. Ji H.P. Therapeutic monitoring of circulating DNA mutations in metastatic cancer with personalized digital PCR.J Mol Diagn. 2020; 22: 247-261Abstract Full Text Full Text PDF PubMed Scopus (6) Google R. H. Wu J. A. S. B. C. H. Z. J. of and for diagnosis and monitoring of lung cancer.Oncotarget. 2017; 8: PubMed Scopus Google T. Y. V. B. A. A. C. M. F. for the 19 and to during monitoring of of the Cancer. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar could therapy monitoring of NSCLC patients. with with with with with with with

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