Plasma-based longitudinal mutation monitoring as a potential predictor of disease progression in subjects with adenocarc
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RESEARCH ARTICLE
Open Access
Plasma-based longitudinal mutation monitoring as a potential predictor of disease progression in subjects with adenocarcinoma in advanced non-small cell lung cancer John Jiang1, Hans-Peter Adams2, Maria Lange2, Sandra Siemann2, Mirjam Feldkamp2, Sylvie McNamara2, Sebastian Froehler2, Stephanie J. Yaung1, Lijing Yao1, Aarthi Balasubramanyam3, Nalin Tikoo3, Christine Ju3, H. Jost Achenbach4, Rainer Krügel5 and John F. Palma1*
Abstract Background: Identifying and tracking somatic mutations in cell-free DNA (cfDNA) by next-generation sequencing (NGS) has the potential to transform the clinical management of subjects with advanced non-small cell lung cancer (NSCLC). Methods: Baseline tumor tissue (n = 47) and longitudinal plasma (n = 445) were collected from 71 NSCLC subjects treated with chemotherapy. cfDNA was enriched using a targeted-capture NGS kit containing 197 genes. Clinical responses to treatment were determined using RECIST v1.1 and correlations between changes in plasma somatic variant allele frequencies and disease progression were assessed. Results: Somatic variants were detected in 89.4% (42/47) of tissue and 91.5% (407/445) of plasma samples. The most commonly mutated genes in tissue were TP53 (42.6%), KRAS (25.5%), and KEAP1 (19.1%). In some subjects, the allele frequencies of mutations detected in plasma increased 3–5 months prior to disease progression. In other cases, the allele frequencies of detected mutations declined or decreased to undetectable levels, indicating clinical response. Subjects with circulating tumor DNA (ctDNA) levels above background had significantly shorter progression-free survival (median: 5.6 vs 8.9 months, respectively; log-rank p = 0.0183). Conclusion: Longitudinal monitoring of mutational changes in plasma has the potential to predict disease progression early. The presence of ctDNA mutations during first-line treatment is a risk factor for earlier disease progression in advanced NSCLC. Keywords: Next-generation sequencing (NGS), Cell-free DNA (cfDNA), Circulating tumor DNA (ctDNA), Liquid biopsy, Non-small cell lung cancer (NSCLC)
* Correspondence: [email protected] 1 Roche Sequencing Solutions, 4300 Hacienda Dr, Pleasanton & Potsdam, California 94588, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you w
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