Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer

Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and...

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Autores principales:	Martin Metzenmacher, Balazs Hegedüs, Jan Forster, Alexander Schramm, Peter A. Horn, Christoph A. Klein, Nicola Bielefeld, Till Ploenes, Clemens Aigner, Dirk Theegarten, Hans-Ulrich Schildhaus, Jens T. Siveke, Martin Schuler, Smiths S. Lueong
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Lung cancer ddPCR NGS cfDNA methylation Surveillance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d3b1076963f443d6a11522f1b04db4d4
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spelling	oai:doaj.org-article:d3b1076963f443d6a11522f1b04db4d42021-11-20T05:05:19ZCombined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer1936-523310.1016/j.tranon.2021.101279https://doaj.org/article/d3b1076963f443d6a11522f1b04db4d42022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1936523321002709https://doaj.org/toc/1936-5233Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility. Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays. Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (methcfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in methcfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status. Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoringMartin MetzenmacherBalazs HegedüsJan ForsterAlexander SchrammPeter A. HornChristoph A. KleinNicola BielefeldTill PloenesClemens AignerDirk TheegartenHans-Ulrich SchildhausJens T. SivekeMartin SchulerSmiths S. LueongElsevierarticleLung cancerddPCRNGScfDNA methylationSurveillanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENTranslational Oncology, Vol 15, Iss 1, Pp 101279- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Lung cancer ddPCR NGS cfDNA methylation Surveillance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Lung cancer ddPCR NGS cfDNA methylation Surveillance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Martin Metzenmacher Balazs Hegedüs Jan Forster Alexander Schramm Peter A. Horn Christoph A. Klein Nicola Bielefeld Till Ploenes Clemens Aigner Dirk Theegarten Hans-Ulrich Schildhaus Jens T. Siveke Martin Schuler Smiths S. Lueong Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
description	Background: Radiology is the current standard for monitoring treatment responses in lung cancer. Limited sensitivity, exposure to ionizing radiations and related sequelae constitute some of its major limitation. Non-invasive and highly sensitive methods for early detection of treatment failures and resistance-associated disease progression would have additional clinical utility. Methods: We analyzed serially collected plasma and paired tumor samples from lung cancer patients (61 with stage IV, 48 with stages I-III disease) and 61 healthy samples by means of next-generation sequencing, radiological imaging and droplet digital polymerase chain reaction (ddPCR) mutation and methylation assays. Results: A 62% variant concordance between tumor-reported and circulating-free DNA (cfDNA) sequencing was observed between baseline liquid and tissue biopsies in stage IV patients. Interestingly, ctDNA sequencing allowed for the identification of resistance-mediating p.T790M mutations in baseline plasma samples for which no such mutation was observed in the corresponding tissue. Serial circulating tumor DNA (ctDNA) mutation analysis by means of ddPCR revealed a general decrease in ctDNA loads between baseline and first reassessment. Additionally, serial ctDNA analyses only recapitulated computed tomography (CT) -monitored tumor dynamics of some, but not all lesions within the same patient. To complement ctDNA variant analysis we devised a ctDNA methylation assay (methcfDNA) based on methylation-sensitive restriction enzymes. cfDNA methylation showed and area under the curve (AUC) of > 0.90 in early and late stage cases. A decrease in methcfDNA between baseline and first reassessment was reflected by a decrease in CT-derive tumor surface area, irrespective of tumor mutational status. Conclusion: Taken together, our data support the use of cfDNA sequencing for unbiased characterization of the molecular tumor architecture, highlights the impact of tumor architectural heterogeneity on ctDNA-based tumor surveillance and the added value of complementary approaches such as cfDNA methylation for early detection and monitoring
format	article
author	Martin Metzenmacher Balazs Hegedüs Jan Forster Alexander Schramm Peter A. Horn Christoph A. Klein Nicola Bielefeld Till Ploenes Clemens Aigner Dirk Theegarten Hans-Ulrich Schildhaus Jens T. Siveke Martin Schuler Smiths S. Lueong
author_facet	Martin Metzenmacher Balazs Hegedüs Jan Forster Alexander Schramm Peter A. Horn Christoph A. Klein Nicola Bielefeld Till Ploenes Clemens Aigner Dirk Theegarten Hans-Ulrich Schildhaus Jens T. Siveke Martin Schuler Smiths S. Lueong
author_sort	Martin Metzenmacher
title	Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
title_short	Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
title_full	Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
title_fullStr	Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
title_full_unstemmed	Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer
title_sort	combined multimodal ctdna analysis and radiological imaging for tumor surveillance in non-small cell lung cancer
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/d3b1076963f443d6a11522f1b04db4d4
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Combined multimodal ctDNA analysis and radiological imaging for tumor surveillance in Non-small cell lung cancer

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