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Sci Rep. 2016 Sep 19;6:33505. doi: 10.1038/srep33505.

Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients.

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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.
Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
Department of Oncology, Thoraxklinik at University Hospital Heidelberg, Amalienstraße 5, 69126 Heidelberg, Germany.
German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.


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.

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