Spatial Tumor Heterogeneity in Lung Cancer with Acquired Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance: Targeting High-Level MET-Amplification.

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Spatial Tumor Heterogeneity in Lung Cancer with Acquired Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance: Targeting High-Level MET-Amplification and EGFR T790M Mutation Occurring at Different Sites in the Same Patient Matthias Scheffler, MD, Sabine Merkelbach-Bruse, PhD, Marc Bos, MD, Jana Fassunke, PhD, Masyar Gardizi, MD, Sebastian Michels, MD, Laura Groneck, MD, Anne M Schultheis, MD, Florian Malchers, PhD, Frauke Leenders, PhD, Carsten Kobe, MD, Katharina König, PhD, Lukas C. Heukamp, MB, PhD, Martin L. Sos, MD, Roman K. Thomas, MD, Reinhard Büttner, MD, Jürgen Wolf, MD Journal of Thoracic Oncology Volume 10, Issue 6, Pages e40-e43 (June 2015) DOI: 10.1097/JTO.0000000000000503 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Fluorodeoxyglucose (18F)-positron emission tomography–computed tomography results. A, October 2013: massive progression after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor resistance and chemotherapy (lung, myocardial infiltration, liver, and soft-tissue left arm). Rebiopsy left arm: EGFRL858R, high-level METamp, TP53C277*, and TP53R110C. B, November 2013: complete metabolic response of myocard-tissue, liver-tissue, and soft-tissue metastases after 8 days of crizotinib and erlotinib. C, December 2013: ongoing metabolic response of myocard-tissue, liver-tissue, and soft-tissue metastases under crizotinib and erlotinib. D, January 2014: ongoing metabolic response of liver-tissue and soft-tissue metastases. Metabolic progression of myocard infiltrating tumor and progressive pleural effusion left. Molecular analysis of pleural effusion: EGFRL858R, EGFRT790M, TP53R110C, and low-level METamp. Peripheral blood: EGFRL858R, EGFRT790M, and TP53R110C (MET status not assessable). Stop of crizotinib and erlotinib treatment, start of AZD9291. E, March 2014: stable metabolic disease in lung tumor, tumor progression in myocard- and liver metastases, tumor control of the soft-tissue metastasis in the arm. Stop of AZD9291, restart with crizotinib. F, April 2014: complete metabolic response of liver- and myocardial metastases, ongoing tumor control of the soft-tissue metastasis. Progress of pleural effusion. Patient died after 3 weeks of crizotinib treatment. Molecular analysis of pleural effusion: EGFRL858R, EGFRT790M, TP53R110C, and no METamp. Journal of Thoracic Oncology 2015 10, e40-e43DOI: (10.1097/JTO.0000000000000503) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Overview of the findings in the resistance setting after erlotinib treatment (November 2011–July 2012) and afatinib/cetuximab treatment (November 2012–June 2013) with intercurrent radiation/chemotherapy. Journal of Thoracic Oncology 2015 10, e40-e43DOI: (10.1097/JTO.0000000000000503) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Liquid biopsy reveals epidermal growth factor receptor (EGFR) and TP53 mutations: results of the peripheral blood analysis (January 2014). A, EGFRL858R mutation with an allele frequency of 13%. B, EGFRT790M mutation with an allele frequency of 10%. C, TP53R110C mutation with an allele frequency of 9%. All identified and illustrated by integrative genome viewer. Journal of Thoracic Oncology 2015 10, e40-e43DOI: (10.1097/JTO.0000000000000503) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions