title: Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients.
abstract: Long-lasting success in lung cancer therapy using tyrosine kinase inhibitors (TKIs) is rare since the tumors develop resistance due to the occurrence of molecularly altered subclones. The aim of this study was to monitor tumors over time based on the quantity of mutant plasma DNA and to identify early indications for therapy response and tumor progression. Serial plasma samples from lung adenocarcinoma patients treated with TKIs were used to quantify EGFR and KRAS mutations in circulating DNA by digital PCR. Mutant DNA levels were compared with the courses of responses to treatment with TKIs, conventional chemotherapy, radiotherapy, or combinations thereof. Variations in plasma DNA mutation levels over time were found in 15 patients. We categorize three major courses: First, signs of therapy response are associated with a fast clearing of plasma DNA mutations within a few days. Second, periods of stable disease are accompanied by either absence of mutations or fluctuation at low levels. Finally, dramatic increase of mutational load is followed by rapid tumor progression and poor patient survival. In summary, the serial assessment of EGFR mutations in the plasma of NSCLC patients allows conclusions about controlled disease and tumor progression earlier than currently available methods.
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.|Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.
authors.forename: Anja Lisa
authors.initials: AL
authors.lastname: Riediger
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.|Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Dietz
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.|Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schirmer
authors.affiliation: Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.|Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Heinzmann-Groth
authors.affiliation: Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.|Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.|Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.|Department of Oncology, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Cancer Genome Research Group, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.|Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research (DZL), Im Neuenheimer Feld 156, Heidelberg, Germany.|German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
mesh_terms: D000230:Adenocarcinoma / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000483:Alleles; D000074141:Circulating Tumor DNA / Q000097:blood* / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000074141:Circulating Tumor DNA; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)