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Subclonal Therapy by Two EGFR TKIs Guided by Sequential Plasma Cell-free DNA in EGFR-Mutated Lung Cancer  Nir Peled, MD, PhD, Laila C. Roisman, PhD, Benjamin.

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Presentation on theme: "Subclonal Therapy by Two EGFR TKIs Guided by Sequential Plasma Cell-free DNA in EGFR-Mutated Lung Cancer  Nir Peled, MD, PhD, Laila C. Roisman, PhD, Benjamin."— Presentation transcript:

1 Subclonal Therapy by Two EGFR TKIs Guided by Sequential Plasma Cell-free DNA in EGFR-Mutated Lung Cancer  Nir Peled, MD, PhD, Laila C. Roisman, PhD, Benjamin Miron, MD, Raphael Pfeffer, MD, Richard B. Lanman, MD, Maya Ilouze, PhD, Addie Dvir, Lior Soussan-Gutman, Fabrice Barlesi, MD, PhD, Gabi Tarcic, PhD, Oded Edelheit, PhD, David Gandara, MD, Yehiel Elkabetz, PhD  Journal of Thoracic Oncology  Volume 12, Issue 7, Pages e81-e84 (July 2017) DOI: /j.jtho Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

2 Figure 1 Response to treatment through positron emission tomography scan. Fludeoxyglucose F 18 positron emission tomography scans along the treatment journey, showing a rapid decrease in fludeoxyglucose F 18 uptake in most of the bone lesions within 2 weeks after initiation of osimertinib therapy. The liver lesion (red arrow), which was T790M negative, did not respond; a partial response to the drug combination and subsequent severe progression followed. Journal of Thoracic Oncology  , e81-e84DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

3 Figure 2 Cell-free DNA tumor response. Cell-free DNA analysis of total somatic alteration burden detected over five time points and the EGFR variant–specific results over time reflect responses to changes in matched therapy. TP53, tumor protein p53. Journal of Thoracic Oncology  , e81-e84DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

4 Figure 3 Functional analysis of EGFR alterations identified from cell-free DNA. Oncogenic activity of EGFR mutations was measured by using signaling pathways reporter for the nuclear factor kappa B subunit 1 (NFkB) pathway (RelA). Activation levels of the EGFR mutation G724S alone and in combination with E746-S752>V (exon 19) were significantly greater than wild-type (WT) activation (p < 0.05) and comparable to a known activating oncogenic mutation in EGFR (L861Q) (A). NFkB activation is represented in both graphs by the median nuclear-to-cytoplasmic ratio (NCR) for each condition. NCR values were measured by using a fluorescent microscope and an accompanying image analysis algorithm that is able to identify and segment the nuclei and cell border of the imaged cells. NCR is a ratio of the measured fluorescent reporter (RelA) in the nuclear (active) state versus in the cytoplasm. Presented is a representative segmented microscopy image with relevant labels (B). NFkB activation of the EGFR double-mutant E746-S752>V/G724S NCR was also measured after incubation with increasing concentrations of afatinib (in nmol). At baseline, activation by the EGFR double-mutant E746-S752>V/G724S was significantly greater than by the WT (p < 0.05). NFkB activation was inhibited to WT levels with 2.5 nmol afatinib, which persisted with escalating doses (C). Functional analysis of EGFR activity was characterized by using an in vitro platform. The analyzed mutations were synthesized on a WT expression vector backbone and transfected into HeLa cells along with signaling pathway reporters. Presented in both panels is one representative experiment with multiple repeats. Significance was calculated by Student's t test and is indicated with an asterisk accompanied by SE bars. The number of the cells analyzed is shown on the graph (A) at the base of each bar. Journal of Thoracic Oncology  , e81-e84DOI: ( /j.jtho ) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

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