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

Translational Oncology

Jens T. Siveke¹  Balazs Hegedüs²  Clemens Aigner³  Peter A. Horn⁴  Hans-Ulrich Schildhaus⁵  Alexander Schramm⁶  Martin Metzenmacher⁷  Smiths S. Lueong⁸  Jan Forster⁸  Martin Schuler⁸  Till Ploenes⁹  Dirk Theegarten^1,10  Nicola Bielefeld^1,11  Christoph A. Klein^1,12 

[1] Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany;Division of Thoracic Oncology, West German Cancer Center, University Medicine Essen-Ruhrlandklinik, University Duisburg-Essen, Tüschener Weg 40, Essen 45239, Germany;Fraunhofer-Institute for Toxicology and Experimental Medicine, Division of Personalized Tumor Therapy, Regensburg 93053, Germany;German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany;Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Hospital Essen, Essen 45122, Germany;Chair for Genome Informatics, Department of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany;Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, Essen 45122, Germany;Department of Thoracic Surgery, West German Cancer Center, University Medicine Essen Ruhrlandklinik, University Duisburg-Essen, Essen D-45239, Germany;Experimental Medicine and Therapy Research, University of Regensburg, Regensburg 93053, Germany;German Cancer Consortium (DKTK), Partner site University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany;Institute for Transfusion Medicine, University Hospital Essen, Essen 45122, Germany;Laboratory for Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen 45122, Germany;

关键词: Lung cancer;    ddPCR;    NGS;    cfDNA methylation;    Surveillance;   

DOI  :  

来源: DOAJ

【 摘 要 】

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

【 授权许可】

Unknown