Non-invasive and quantitative analysis for EGFR T790M mutation in the patients with advanced non-small cell lung cancer received EGFR-TKI therapy.

e19101 Background: Approximately 50% of advanced non-small cell lung cancer (A-NSCLC) patients with EGFR sensitive mutation who develop acquired resistance to EGFR-TKIs reportedly have a secondary EGFR T790M mutation. Establishing a dynamical, quantitative and noninvasive detection system of EGFR T790M mutation in process of disease therapy for NSCLC is critical to personalized targeted therapy. Methods: 135 A-NSCLC patients with EGFR mutation who received EGFR-TKIs and presented acquired resistance (PFS≥6 months) were included into this study. All patients provided the plasma samples for molecular analysis when disease progressed. 109 patients of them had matched TKI-naive plasma. T790M mutation was measured qualitatively and quantitatively by ARMS and Digital PCR (DggPCR), respectively. Association of T790M mutation with clinical charateristics were evaluated. Results: DgPCR was more sensitive than ARMs to detect T790M mutation in plasma [pre-treatment 29.4% (32/109) VS 5.5% (6/109); post-treatment: 43.0% (58/135) VS 25.2% (34/135)]. 32 patients with pre-treatment T790M mutation predicted shorter PFS and OS compared with 77 T790 M negative patients (PFS, F 12.7 VS 9.2 months, P=0.004, GOS, F 27.0 VS 18.8 months, P=0.002). Patients with or without post-treatment T790M mutation have no significantly different PFS and OS. However, quantified the ratio of copy number of mutant T790M to wild-type by DgPCR, patients were divided into high-frequency groups (≥5%), low-frequency group (0%-5%) and wild-group (0%) according to the number of positive signals observed from DgPCR results. 12 patients in high-frequency group showed shorter PFS and OS compared with wild group and low-frequency group (PFS 9.5 VS 11.9 months, P=0.033, G9.5 VS 13.6 months, P=0.028, GOS, F 18.5 VS 21.2 months, P=0.044, 18.5 VS 28.8 months, P=0.001). Conclusions: Non-invisive and quantitative detection of T790m mutation by digital PCR is feasible in clinical practice. High contents of T790M when disease progression after EGFR-TKIs therapy predicted poor prognosis.

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Abstract 1596: Feasibility of liquid biopsy using extracellular vesicle-derived DNA isolated from bronchoalveolar lavage fluid and plasma in addition to tissue rebiopsy to detect T790M mutation in NSCLC patients with acquired resistance to EGFR-TKIs

10.1158/1538-7445.am2018-1596 ◽

2018 ◽

Author(s):

Jong Sik Lee ◽

Hee Joung Kim ◽

In Ae Kim ◽

Jae Young Hur ◽

Kye Young Lee

Keyword(s):

Bronchoalveolar Lavage ◽

Liquid Biopsy ◽

Bronchoalveolar Lavage Fluid ◽

Acquired Resistance ◽

Lavage Fluid ◽

Extracellular Vesicle ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tkis

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Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Cancers ◽

10.3390/cancers11030365 ◽

2019 ◽

Vol 11 (3) ◽

pp. 365 ◽

Cited By ~ 2

Author(s):

Akihiro Yoshimura ◽

Tadaaki Yamada ◽

Naoko Okura ◽

Takayuki Takeda ◽

Kazuki Hirose ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr T790m ◽

Egfr Tkis

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

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3075 Association between clinical outcome of first EGFR-TKIs and T790M mutation in NSCLC patients harboring EGFR mutation with acquired resistance to EGFR-TKIs

European Journal of Cancer ◽

10.1016/s0959-8049(16)31716-6 ◽

2015 ◽

Vol 51 ◽

pp. S622

Author(s):

Y. Oya

Keyword(s):

Clinical Outcome ◽

Egfr Mutation ◽

Acquired Resistance ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tkis

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P1.01-32 Bronchoalveolar Lavage as an Alternative to Rebiopsy for Detection of T790M Mutation in NSCLC Patients with Acquired Resistance to EGFR-TKIs

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.08.747 ◽

2019 ◽

Vol 14 (10) ◽

pp. S368

Author(s):

H. Kim ◽

J.Y. Hur ◽

I.A. Kim ◽

S. Lee ◽

W.S. Kim ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Acquired Resistance ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tkis

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A digital PCR assay development to detect EGFR T790M mutation in NSCLC patients

Frontiers in Laboratory Medicine ◽

10.1016/j.flm.2018.08.002 ◽

2018 ◽

Vol 2 (3) ◽

pp. 89-96 ◽

Cited By ~ 2

Author(s):

Ruifeng Zhou ◽

Yiran Cai ◽

Zhaoliang Li ◽

Shuangye Shen ◽

Mozhou Sha ◽

...

Keyword(s):

Digital Pcr ◽

Assay Development ◽

Pcr Assay ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr T790m

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Large Cell Neuroendocrine Carcinoma Transformation and EGFR -T790M Mutation as Coexisting Mechanisms of Acquired Resistance to EGFR-TKIs in Lung Cancer

Mayo Clinic Proceedings ◽

10.1016/j.mayocp.2017.03.022 ◽

2017 ◽

Vol 92 (8) ◽

pp. 1304-1311 ◽

Cited By ~ 7

Author(s):

Sara Baglivo ◽

Vienna Ludovini ◽

Angelo Sidoni ◽

Giulio Metro ◽

Biagio Ricciuti ◽

...

Keyword(s):

Lung Cancer ◽

Neuroendocrine Carcinoma ◽

Acquired Resistance ◽

Large Cell ◽

Large Cell Neuroendocrine Carcinoma ◽

T790m Mutation ◽

Egfr T790m ◽

Egfr Tkis

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Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20576 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20576-e20576

Author(s):

Ying Jin ◽

Jianjun Zhang ◽

Ming Chen ◽

Yang Shao ◽

Xun Shi ◽

...

Keyword(s):

First Generation ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Resistance Mechanisms ◽

Egfr Mutations ◽

T790m Mutation ◽

Targeted Next Generation Sequencing ◽

Egfr Tyrosine Kinase Inhibitors ◽

Nsclc Patients ◽

Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

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Detect T790M in cell free tumor DNA of Chinese advanced non-small cell lung cancer adenocarcinoma patients by different platforms and evaluate clinical outcomes of T790M positive patients with osimertinib monotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps9104 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS9104-TPS9104

Author(s):

Zhiyong Liang ◽

Ying Cheng ◽

Yuan Chen ◽

Weiping Liu ◽

You Lu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Digital Pcr ◽

Small Cell ◽

Small Cell Lung ◽

T790m Mutation ◽

Nsclc Patients ◽

Egfr Tki ◽

Tumor Dna ◽

Egfr T790m

TPS9104 Background: EGFR T790M mutation occurs in approximately 50-60% of non-small cell lung cancer adenocarcinoma (NSCLC) patients with acquired EGFR-TKI resistance, based on tumor re-biopsies using an invasive clinical procedure. Recently, Cell free tumor DNA (ctDNA) has emerged as a specific and sensitive blood-based biomarker and studies have demonstrated ctDNA as a feasible and minimally invasive alternative to tissue biopsy. Data on different technology platforms used for EGFR T790M detection in blood in China is limited. We aim to compare the methods currently available in hospital practise, including cobas EGFR Mutation Test (Roche Molecular Systems), super-ARMS, digital PCR and NGS, to compare each platform and clinically validate each as companion diagnostic to osimertinib. Methods: This is an open-label, multi-center study in 250 locally advanced or metastatic NSCLC patients with documented EGFR sensitizing mutation and progression on previous EGFR-TKI. T790M mutation in plasma ctDNA will be tested by four methods: cobas, super-ARMS, digital PCR and NGS in order to evaluate the concordance, sensitivity and specificity of T790M testing in plasma between the cobas test and the other platforms. T790M positive patients by any of the four platforms will receive osimertinib treatment (administered orally as one 80 mg tablet once a day in ASTRIS study, NCT02474355) and the clinical outcomes (PFS, ORR, OS) will be followed. Patients will continue to receive osimertinib until disease progression (PD), as assessed by investigators. Digital PCR and NGS will be used to monitor the molecular evolution of T790M and C797S in plasma from NSCLC patients during osimertinib treatment. NGS will also be used to explore acquired resistance mechanisms before osimertinib treatment and after PD. 23 of planned 250 patients have been enrolled in the study as of January 2017. Clinical trial information: NCT02997501.

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