Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non–Small Cell Lung Cancer Alexa B. Schrock, PhD, Allison.

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Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non–Small Cell Lung Cancer Alexa B. Schrock, PhD, Allison Welsh, PhD, Jon H. Chung, PhD, Dean Pavlick, BS, Eric H. Bernicker, MD, Benjamin C. Creelan, MD, Brady Forcier, BS, Jeffrey S. Ross, MD, Philip J. Stephens, PhD, Siraj M. Ali, MD, PhD, Ibiayi Dagogo-Jack, MD, Alice T. Shaw, MD, PhD, Tianhong Li, MD, PhD, Sai-Hong Ignatius Ou, MD, PhD, Vincent A. Miller, MD Journal of Thoracic Oncology Volume 14, Issue 2, Pages 255-264 (February 2019) DOI: 10.1016/j.jtho.2018.10.008 Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Genomic alterations identified in circulating tumor DNA (ctDNA) from patients with NSCLC. Samples with evidence of ctDNA in the blood (maximum somatic allele frequency >0) are included. (A) Longtail of genes altered in more than 1% of cases. X-axis indicates percent of altered cases. (B) Frequency of National Comprehensive Cancer Network (NCCN) NSCLC gene alterations and KRAS mutations detected in NSCLC ctDNA samples. Mut, mutation; RE, rearrangement; amp, amplification; TP53, TP53, tumor protein p53 gene; NF1, neurofibromin 1 gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; CDKN2A, cyclin dependent kinase inhibitor 2A gene; MET, MNNG HOS Transforming gene; PTEN, phosphatase and tensin homolog gene; ALK, ALK receptor tyrosine kinase gene; TERT, telomerase reverse transcriptase gene; JAK2, Janus kinase 2 gene; ERBB2, erb-b2 receptor tyrosine kinase 2 gene; BRCA2, BRCA2, DNA repair associated gene; CTNNB1, catenin beta 1 gene; RET, ret proto-oncogene gene; FGFR1, fibroblast growth factor receptor 1 gene; BRCA1, BRCA1, DNA repair associated gene; MDM2, MDM2 proto-oncogene gene. Journal of Thoracic Oncology 2019 14, 255-264DOI: (10.1016/j.jtho.2018.10.008) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC versus in tissue. Comparison of the most frequently mutated (A), amplified (B), or rearranged (C) genes observed in ctDNA in this study with tissue-based genomic profiling of a similar distribution of NSCLC cases (FoundationCORE database) or with a published tissue-based genomic profiling study of primarily early-stage lung adenocarcinoma (adeno) (The Tumor Cancer Genome Atlas [TCGA], 2014). Data from the TCGA study were extracted from the cBioPortal. TP53, tumor protein p53 gene; NF1, neurofibromin 1 gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; CDKN2A, cyclin dependent kinase inhibitor 2A gene; PTEN, phosphatase and tensin homolog gene; JAK2, Janus kinase 2 gene; TERT, telomerase reverse transcriptase gene; BRCA2, BRCA2, DNA repair associated gene; MET, MNNG HOS Transforming gene; CTNNB1, catenin beta 1 gene; ERBB2, erb-b2 receptor tyrosine kinase 2 gene; BRCA1, BRCA1, DNA repair associated gene; MYD88, MYD88 innate immune signal transduction adaptor gene; CDH1, cadherin 1 gene; FGFR1, fibroblast growth factor receptor 1 gene; MDM2, MDM2 proto-oncogene gene; MYC, v-myc avian myelocytomatosis viral oncogene homolog gene; CDK6, cyclin-dependent kinase 6 gene; CDK4, cyclin-dependent kinase 4 gene; CCND1, cyclin D1 gene; ALK, ALK receptor tyrosine kinase gene; RET, ret proto-oncogene gene; FGFR3, fibroblast growth factor receptor 3 gene; PDGFRA, platelet derived growth factor receptor alpha gene. Journal of Thoracic Oncology 2019 14, 255-264DOI: (10.1016/j.jtho.2018.10.008) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Concordance between genomic alterations (GAs) found in circulating tumor DNA (ctDNA) and matched tissue from 33 patients with NSCLC. (A) Days between ctDNA and tissue collection (<30 for all cases) and maximum somatic allele frequency (MSAF) (>0 for all cases) are shown. Concordant/shared GAs are in blue, GAs found only in tissue are in red, and GAs found only in ctDNA are in pink. All alterations covered by both the tissue and ctDNA assay are shown. For samples with multiple unique mutations in a given gene, the number of mutations is indicated. (B) Box-and-whisker plot showing mutant allele frequency of short variant alteration detected in match ctDNA samples: box spans first and third quartiles, the median is denoted by the horizontal line in the box, whiskers indicate maximum and minimum values within 1.5 times the inner quartile range. ERBB2, erb-b2 receptor tyrosine kinase 2 gene; FGFR2, fibroblast growth factor receptor 2 gene; ARAF, A-Raf proto-oncogene, serine threonine kinase gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PTEN, phosphatase and tensin homolog gene; NF1, neurofibromin 1 gene; GNAS, GNAS complex locus gene; TP53, TP53, tumor protein p53 gene; BRCA2, BRCA2, DNA repair associated gene; CTNNB1, catenin beta 1 gene; CDH1, cadherin 1 gene; CDKN2A, cyclin dependent kinase inhibitor 2A gene; JAK2, Janus kinase 2 gene; KIT, KIT proto-oncogene receptor tyrosine kinase gene; CDK4, cyclin-dependent kinase 4 gene; CDK6, cyclin-dependent kinase 6 gene; CCND1, cyclin D1 gene; MDM2, MDM2 proto-oncogene gene; MYC, v-myc avian myelocytomatosis viral oncogene homolog gene; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene; PD-L1, programmed death ligand 1 gene (also known as CD274 molecule); EML4, echinoderm microtubule associated protein like 4 gene; ALK, ALK receptor tyrosine kinase gene; RE, rearrangement. Journal of Thoracic Oncology 2019 14, 255-264DOI: (10.1016/j.jtho.2018.10.008) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions