Abstract 2750: Detecting resistance mechanisms in patients on EGFR TKI treatment by liquid biopsy

2017 ◽  
Author(s):  
Laure Sorber ◽  
Karen Zwaenepoel ◽  
An Wouters ◽  
Janssens Annelies ◽  
Birgitta Hiddinga ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Resistance Mechanisms ◽  
Tki Treatment ◽  
Egfr Tki

Clonal evolution and osimertinib resistance mechanisms identified by whole exome and transcriptome sequencing in EGFR mutant NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9049-9049
Author(s):  
Nitin Roper ◽  
Anna-Leigh Brown ◽  
Sivasish Sindiri ◽  
Constance M. Cultraro ◽  
Shaojian Gao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Transcriptome Sequencing ◽  
Clonal Evolution ◽  
Resistance Mechanisms ◽  
Evolutionary Analysis ◽  
Whole Exome ◽  
Treatment Naïve ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

9049 Background: Osimertinib, a 3rd generation EGFR TKI, has been approved for treatment naïve patients (pts) with metastatic EGFR mutant NSCLC. Mechanisms of resistance to osimertinib are emerging from limited studies using targeted sequencing platforms. Methods: We performed whole exome (WES) and RNA-sequencing of osimertinib resistant tumors of EGFR-mutant NSCLC pts treated in a prospective clinical trial (NCT02759835). Treatment naïve EGFR mutant pts or pts with T790M-positive NSCLC after EGFR-TKI treatment receive osimertinib. Upon progression, pts with ≤5 progressing sites undergo local ablative therapy (LAT; surgery, radiation, RFA) and resume osimertinib. We analyzed paired pre-treatment and post-progression tumors in 10 patients and post-progression tumors in 3 additional patients and investigated intra- and inter-metastatic tumor heterogeneity using tumors procured from LAT surgeries and autopsies. Results: Acquired, focal copy number amplifications (CNA) of oncogenes occurred in the majority of patients (54%, n = 7/13) whereas acquired osimertinib resistance mutation EGFR C797S was less common (15%, n = 2/13). Early progression on osimertinib ( < 12 months PFS) in treatment naïve pts was associated with acquired, focal CNA. Despite pre-existing EGFR amplification, further amplification of the mutant allele of EGFR was the most common focal CNA (33%, n = 3/9). Other oncogenes amplified in resistant tumors include MET, KRAS, ERBB2 and YES1. CD274 (PD-L1) amplification occurred as the only putative mechanism of resistance in a pt without prior EGFR-TKI treatment. Using RNA-seq, we identified a pt who retained NSCLC histology, but upregulated genes associated with neuroendocrine differentiation upon osimertinib resistance. Clonal evolutionary analysis using WES of prospectively collected sensitive and resistant tumor tissue, including at autopsy is underway. Conclusions: Unbiased WES and transcriptome sequencing revealed heterogeneity, clonal evolution and novel osimertinib resistance mechanisms. Majority of pts had two or more resistance mechanisms suggesting the requirement of combination therapies to overcome resistance. Clinical trial information: NCT02759835.

Circulating tumor DNA profiling to reveal heterogeneity of EGFR-TKI resistance mechanisms in lung adenocarcinoma patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11527-11527
Author(s):  
Rongrong Chen ◽  
Jun Zhao ◽  
Xingsheng Hu ◽  
Pingping Dai ◽  
Yuting Yi ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Single Nucleotide Variants ◽  
Molecular Abnormalities ◽  
Activating Mutation ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Tumor Dna

11527 Background: EGFR-TKI therapy has significantly improved prognosis of NSCLC patients with EGFR sensitive mutation. However, almost all patients ultimately develop PD while receiving TKI treatment. Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for comprehensive analysis of molecular abnormalities. Methods: A total of 254 advanced lung adenocarcinoma patients with signs of EGFR-TKI resistance were enrolled in the study. ctDNA was analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across 59 genes. Results: ctDNA profiling was possible for all patients, 172 patients had ≥ 1 ctDNA alteration(s). Median number of plasma somatic mutations was 2, predominantly located in EGFR and TP53, with MET, ERBB2 and PIK3CA followed. Of that, 30.6% of mutations detected in ctDNA were at a frequency below 1%. In exploring the mechanisms of TKI-resistance, we found TKI-sensitizing mutations were not detected in plasma of 138 patients (54.3%). Known mechanisms such as EGFR T790M/C797S mutation, activating mutations of PI3K- AKT- mTOR signaling, amplification of MET, activating mutation / amplification of ERBB2, activating mutation of KRAS, BRAF or mutations in EGFR EX20 other than T790M/C797S were identified in 59, 16, 8, 7, 3, 2, and 2 patients respectively. T790M/C797S was detected in 50.8% of patients with plasma positive for TKI-sensitizing mutations. Of note, C797S was only detected in patients treated with AZD9291. EGFR amplification were identified in 15 patients, though whether it would result in TKI-resistance was still controversial. Co-occurrence of resistance mechanisms were observed in 22 patients including 13 patients without TKI-sensitizing mutations. Conclusions: There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after EGFR TKI therapy. ctDNA can be used as a ‘liquid biopsy’ to facilitate the broad exploration of potential resistance mechanisms.

scholarly journals Next-generation sequencing of tissue and circulating tumor DNA: Resistance mechanisms to EGFR targeted therapy in a cohort of patients with advanced non-small cell lung cancer

2020 ◽  
Author(s):  
Yujun Zhang ◽  
Liwen Xiong ◽  
Fangfang Xie ◽  
Xiaoxuan Zheng ◽  
Ying Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Third Generation ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract Background Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has been considered as an effective treatment in epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC). However, most patients develop acquired resistance eventually. Here, we compared and analyzed the genetic alterations between tissue assay and circulating tumor DNA (ctDNA), and further explored the resistance mechanisms after EGFR-TKI treatment. Methods Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), Cobas® ARMS-PCR and next-generation sequencing (NGS) were performed on tissue samples after pathological diagnosis. Digital droplet PCR (ddPCR) and NGS were performed on plasma samples. The association between genetic alterations and clinical outcomes was analyzed retrospectively. Results Thirty-seven patients were included. The success rate of re-biopsy was 91.89% (34/37). The total detection rate of EGFR T790M was 62.16% (23/37) and the consistency between tissue and ctDNA was 78.26% (18/23). Thirty-four patients were analyzed retrospectively. Twenty-four patients harbored concomitant mutations. Moreover, tissue re-biopsy at resistance showed 21 patients (21/34, 61.76%) had concomitant T790M mutation, 4 with MET amplification and 4 with PIK3CA mutation. Patients with T790M mutation (p = 0.010 & p = 0.017) or third-generation EGFR-TKI treatment (p < 0.0001 & p = 0.073) showed better progression-free survival (PFS) and overall survival (OS). Interestingly, concomitant genetic alterations were significantly associated with a worse prognosis for patients with T790M mutation receiving third-generation EGFR-TKIs (p = 0.037). Conclusions Multi-platforms are feasible and highly consistent for re-biopsy after EGFR-TKI resistance. Concomitant genetic alterations may be associated with a poor prognosis for patients with T790M mutation after third-generation EGFR-TKIs. Trial Registration: The clinical trial registration was carried out on ClinicalTrials.gov. (NCT03309462), registered on September 1st 2017. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0007G1B&selectaction=Edit&uid=U0001WUU&ts=2&cx=frpicv

TKI-Resistenzen beim EGFR-positiven NSCLC

2019 ◽  
Vol 10 (05) ◽  
pp. 216-216
Author(s):  
Susanne Krome
Keyword(s):  
Liquid Biopsy ◽  
Invasives Monitoring ◽  
Egfr Tki

EGFR-Tyrosinkinase-Inhibitoren (EGFR-TKI) haben zu einem Paradigmenwechsel in der Behandlungsstrategie für nicht-kleinzellige Bronchialkarzinome (NSCLC) geführt und gehören inzwischen zum Standard. Dabei ist es auch wichtig, primäre und erworbene Resistenzen zu überwinden. Eine aktuelle Studie mit 116 Patienten ergab unterschiedliche Resistenz-Mechanismen für TKI der 1./2. und der 3. Generation. Die Liquid Biopsy ist nach Ansicht der Autoren eine Option für ein nicht-invasives Monitoring der molekularen Veränderungen unter der EGFR-Therapie. Ein Review beschäftigte sich mit den Resistenzmechanismen und der Liquid Biopsy als Instrument für die Therapieplanung und -monitoring.

scholarly journals Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

2021 ◽  
Vol 22 (2) ◽  
pp. 792
Author(s):  
Tohru Ohmori ◽  
Toshimitsu Yamaoka ◽  
Koichi Ando ◽  
Sojiro Kusumoto ◽  
Yasunari Kishino ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tyrosine Kinase ◽  
Performance Status ◽  
Cytotoxic Agents ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Chronic Obstructive ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

scholarly journals Osimertinib versus afatinib in patients with T790M-positive, non-small-cell lung cancer and multiple central nervous system metastases after failure of initial EGFR-TKI treatment

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Yang ◽  
Qilong Liu ◽  
Lei Cao ◽  
Wei Sun ◽  
Xiaowei Gu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Central Nervous System ◽  
Nervous System ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Tki Treatment ◽  
Egfr Tki

Abstract Background The purpose of this study was to compare the efficacy of osimertinib (OSI) versus afatinib (AFA) in patients with T790M-positive, non-small-cell lung cancer (NSCLC) and multiple central nervous system (CNS) metastases after failure of initial epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Methods Consecutive patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment were retrospectively identified from our medical institution during 2016–2018 and underwent either oral 80 daily OSI or oral 40 daily AFA every 3 weeks for up to 6 cycles, until disease progression, intolerable adverse events (AEs), or death. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS). Results The cohort consisted of 124 patients (OSI: n = 60, mean age = 64.24 years [SD: 12.33]; AFA: n = 64, mean age = 64.13 years [SD: 13.72]). After a median follow-up of 24 months (range, 3 to 28), a significant improvement in OS was detected (hazard ratio [HR] 0.59, 95% confidence interval [CI], 0.39–0.91; p = 0.0160; median, 13.7 months [95% CI, 11.1–14.8] for OSI vs 9.6 months [95% CI, 8.4–10.2] for AFA). The median duration of PFS was significantly longer with OSI than with AFA (HR 0.62; 95% CI, 0.41–0.91; p = 0.014; median, 4.5 months [95% CI, 3.5–5.7] vs 3.9 months [95% CI, 3.1–4.8]). The proportion of grade 3 or higher adverse events (AEs) was lower with OSI (22.4%) than with AFA (39.4%). Conclusions In patients with T790M-positive NSCLC and multiple CNS metastases after failure of initial EGFR-TKI treatment, OSI may be associated with significantly improved survival benefit compared with AFA, with a controllable tolerability profile.

scholarly journals Clinical Characteristics and Survival Outcomes for Non-Small-Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Double Mutations

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Min Peng ◽  
Yi Ming Weng ◽  
Hua Li Liu ◽  
Gui Fang Yang ◽  
Yi Yao ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

Multiple randomized clinical trials have demonstrated that epidermal growth factor receptor (EGFR) exon 19 deletion (19Del) and exon 21 L858R mutation (L858R) are highly correlated with sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC). A mutation in exon 20 (T790M) is reportedly associated with resistance to EGFR-TKIs. However, few studies have focused on patients harboring double mutations in these 3 mutation sites. In this retrospective study, forty-five patients (45/2546, 1.7%) harbored double mutations of 19Del, L858R, and T790M. Twenty-four patients with EGFR double mutations received EGFR-TKI therapy. Clinical characteristics of these patients, including the response to EGFR-TKIs and progression-free survival outcome for EGFR-TKI treatment (PFS-TKI), were analyzed. Patients with EGFR double mutations were more likely to be nonsmokers, have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1, have adenocarcinoma, and be at stage III-IV. The ORR, DCR, and median PFS-TKI in patients harboring EGFR double mutations were lower than in patients with a single EGFR-activating mutation. The differences in ORR and DCR were statistically insignificant between the 3 groups. Patients with double mutations of 19Del and T790M had longer PFS-TKIs than patients in the other 2 groups.

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