Concordance between Comprehensive Cancer Genome Profiling in Plasma and Tumor Specimens Judith N. Müller, PhD, Markus Falk, PhD, Jatin Talwar, MSc, Nicole.

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Concordance between Comprehensive Cancer Genome Profiling in Plasma and Tumor Specimens Judith N. Müller, PhD, Markus Falk, PhD, Jatin Talwar, MSc, Nicole Neemann, Erika Mariotti, PhD, Miriam Bertrand, MSci, Tobias Zacherle, PhD, Sotirios Lakis, MD, Roopika Menon, PhD, Christian Gloeckner, PhD, Markus Tiemann, MD, PhD, Lukas C. Heukamp, PhD, Roman K. Thomas, MD, Frank Griesinger, MD, Johannes M. Heuckmann, PhD Journal of Thoracic Oncology Volume 12, Issue 10, Pages 1503-1511 (October 2017) DOI: 10.1016/j.jtho.2017.07.014 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 NEOplus and routine testing of tumor specimens show maximal concordance of driver mutations. (A) Patient cohort evaluated in this study. (B–D) ROS1 fusion in a patient with lung adenocarcinoma identified by routine testing and NEOplus. Adenocarcinoma of the lung of T1N2M0 stage IIIA was initially diagnosed in the male patient. After induction therapy with carboplatin and docetaxel, definitive chemoradiotherapy with cisplatin and vinorelbine was performed. Relapse in the right upper lobe with mediastinal lymph nodes was diagnosed, and a repeat biopsy was performed to permit routine testing and NEOplus molecular profiling. Fluorescence in situ hybridization staining identified a rearrangement in ROS1 with positive break-apart signals, as indicated by the arrow (B). The exact breakpoints in ezrin gene (EZR) and ROS1 were identified by NEOplus, as indicated by the Intregrative Genomics Viewer screenshot (C). Crizotinib treatment was started in July 2015, and the patient is currently in continuous partial remission (D). Arrows indicate tumor mass at time of treatment initiation. (E) Comparison of 75 tissue samples analyzed by routine testing and hybrid capture–based NEOplus, revealed a concordance, sensitivity, and specificity of 100%. NOS, not otherwise specified; CI, confidence interval. Journal of Thoracic Oncology 2017 12, 1503-1511DOI: (10.1016/j.jtho.2017.07.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 NEOliquid reveals a high concordance to routine tissue testing. (A) NEOliquid identifies a broad range of genomic alterations in tumor-associated genes. (B) The concordance of 82 liquid biopsies with the respective fresh frozen paraffin-embedded (FFPE) sample was 98%, with a sensitivity of 71% and a specificity of 100%. (C) The distribution of allele frequencies for point mutations and insertion/deletions (InDels) as identified in FFPE samples (left panel) and liquid biopsies (right panel) is shown. (D) Liquid biopsies are stratified by metastatic disease (at time of blood withdrawal) and plotted for the amount of cell-free DNA (cfDNA) (18 mL of whole blood, assay sensitivity, and specificity). For statistical evaluation a two-sided t test was applied. ***p Value lower than 0.01. ID, identifier; TP53, tumor protein 53 gene; MET, MNNG HOS Transforming gene; ALK, ALK receptor tyrosine kinase gene; RET, ret proto-oncogene; ERBB2, erb-b2 receptor tyrosine kinase 2 gene; IDH1, isocitrate dehydrogenase (NADP(+)), 1 systolic gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; CTNNB1, catenin beta 1; STK11, serine/threonine kinase 11 gene; KEAP1, kelch like ECH associated protein 1 gene; MAP2K1, mitogen-activated protein kinase kinase 1 gene; RB1, retinoblastoma 1 gene; CI, confidence interval; MAF, minor allele frequency. Journal of Thoracic Oncology 2017 12, 1503-1511DOI: (10.1016/j.jtho.2017.07.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 NEOliquid identifies actionable alterations that are not covered by routine testing. (A) Breakpoints of the kinesin family member 5B gene (KIF5B)–ret proto-oncogene (RET) translocation are visualized in the Intregrative Genomics Viewer. (B) Clinical response of a tumor harboring a KIF5B-RET translocation before and after treatment with cabozantinib. Arrows indicate tumor mass at time of treatment initiation. Journal of Thoracic Oncology 2017 12, 1503-1511DOI: (10.1016/j.jtho.2017.07.014) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions