Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC

Knebel, Franciele Hinterholz; Bettoni, Fabiana; Shimada, Andrea Kazumi; Cruz, Manoel; Alessi, Joao; Negrão, Marcelo V.; Reis, Luiz F. L.; Katz, Artur; Camargo, Anamaria A.

doi:10.1016/j.lungcan.2017.04.004

Cited by 64 publications

(51 citation statements)

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“…After a median of 9.6–11.0 months' remission with osimertinib treatment, tumors will inevitably have progress. Although a lot of studies had been done, the molecular mechanisms of resistance are not yet fully understood [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Nie¹,

Jiang

Zhang

et al. 2018

BioMed Research International

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Purpose To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results A total of 9 Chinese patients were studied, 5 females and 4 males, age 51–89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

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Section: Introductionmentioning

confidence: 99%

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Nie¹,

Jiang

Zhang

et al. 2018

BioMed Research International

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“…Problé-mem léčby je, stejně jako u předchozích generací EGFR-TKI, postupně se rozvíje-jící rezistence k léčbě, která může mít ně-kolik důvodů [6]. Dle dosavadních poznatků se může jednat o různé bypass cesty (HER2 amplifikace, MET amplifikace, KRAS či BRAF mutace), tak i amplifikaci původní delece exonu 19 či nové EGFR mutace (především dále popsána mutace C797S) [10][11][12][13]. Byl popsán i výskyt několika nových EGFR mutací současně [11].…”

Section: Obr 3 Parciální Regrese Nálezu Na Ct Při Terapii Osimertinunclassified

Patient with Three EGFR Mutations – Gradual Development of Resistance to Previous Targeted Treatment

Svatoň¹,

Pešek²,

Baxa³

et al. 2018

Klin Onkol

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SouhrnVýchodiska: Pa cienti se senzitivními EGFR mutacemi jsou již standardně léčeni tyrozinkinázo-vými inhibitory (TKI) 1. a 2. generace. Nicméně na tyto preparáty vzniká po čase rezistence, která je u více než poloviny případů zapříčiněna EGFR rezistentní mutací T790M. Osimertinib je nová léčebná možnost, jak ji překonat. Bohužel i na tento preparát po několika měsících léčby vzniká rezistence. Jednou z jejích příčin je EGFR mutace C797S, o které pojednává naše kazuistika. Případ: Naše kazuistické sdělení přináší průkaz postupného vývoje rezistence k EGFR-TKI u pa cientky s delecí na exonu 19 genu EGFR. Nejprve na základě získané mutace T790M při léčbě afatinibem a posléze na podkladě mutace C797S při terapii osimertinibem. Též se věnujeme úvahám o překonání této rezistentní mutace jak pomocí EGFR-TKI 4. generace, tak i případnými alternativními postupy (chemoterapie, imunoterapie, kombinace EGFR-TKI starších generací). Rovněž zmiňujeme vzácný případ nemocné s metastázami na peritoneu po předchozí léčbě osimertinibem. Tento nepříznivý stav jsme se vzhledem k již zhoršenému výkonnostnímu stavu nemocné pokusili ovlivnit erlotinibem, který neumožňoval podání chemoterapie. Jsou doložené případy, kdy erlotinibem byli úspěšně léčeni pa cienti s peritoneálními metastázami a též nemocní s EGFR mutací C797S po progresi na afatinibu. To však v našem případě nenastalo, patrně pro přetrvávající EGFR mutaci T790M. Závěr: V naší kazuistice erlotinib nejevil účinnost po progresi na osimertinibu. Jedinou možnou léčbou se v tomto případě prozatím jeví chemoterapie u pa cientů v dobrém klinickém stavu. TKI nové generace procházejí nadějným vývojem. Klíčová slovaEGFR -delece na exonu 19 -mutace T790M -mutace C797S -afatinib -osimertinib Projekt byl podpořen grantem AZV 17-30748A. Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. MUDr. Martin Svatoň KazuistikaDvaačtyřicetiletá žena, exkuřačka (celkem cca 10 krabičkoroků), vyjma kožní formy psoriázy vážněji nestonající, se dostavila v září 2015 na Kliniku pneumologie a ftizeologie FN Plzeň pro náma-hovou dušnost, subfebrilie, kašel s mír-nou hemoptýzou a bolestí na pravém boku. Vzhledem k elevaci zánětlivých parametrů a vstupnímu skiagramu plic bylo zprvu uzavíráno jako oboustranná pneumonie s pravostranným výpotkem. Ten byl punktován a byla zahájena empirická antibio tická terapie, též byla nastavena symp tomatická léčba přidružených obtíží. Nález na skiagramu plic se však nelepšil, v mezidobí byly z výpotku charakteru exsudátu cytologicky určeny atypické buňky, kdy k vyloučení malignity bylo doporučeno provedení cytobloku. Pro recidivující výpotek byla následně provedena hrudní drenáž. V cytobloku byl popsán aden...

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“…It is noteworthy that the diagnosis of the origin of some metastases occurring from an initially unknown lung cancer and finally from an adenocarcinoma of the lung can be made exceptionally in the absence of any tissue biopsy examination, if an EGFR mutation is detected with circulating DNA extracted from plasma [ 40 ]. Different mechanisms of secondary resistance can occur in patients treated with osimertinib and may be detected with a LB, such as the emergence of a small tumor cell subpopulation carrying the EGFR -C797S mutation, an additional subpopulation carrying amplified copies of EGFR -exon19del or other genomic alterations [ 10 , 41 ]. The different mechanisms of resistance occurring in patients receiving osimertinib and detected with a LB can be observed in patients receiving this TKI as second but also as first-line treatment of EGFR mutation positive [ 17 , 42 , 43 ].…”

Section: Mutations In Egfr: the Main Therapeutic Target Examined Imentioning

confidence: 99%

Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology

Hofman

2017

Cancers

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The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed with plasma DNA and have been approved as companion diagnostic test for patients treated with tyrosine kinase inhibitors. ALK is another important target in lung cancer since it leads to treatment of patients who are positive for a rearrangement in ALK identified with tumor tissue. By analogy with EGFR, LB for detection of genomic alterations in ALK (rearrangements or mutations) has been rapidly adopted in the clinic. However, this promising approach has some limitations and has not yet been disseminated as much as the blood test targeting EGFR. In addition to these two therapeutic targets LB can be used for evaluation of the genomic status of other genes of interest of patients with lung cancer (ROS1, RET, NTRK MET, BRAF, HER2, etc.). LB can be performed to evaluate a specific target or for a more or less complex panel of genes. Considering the number of potential targets for clinical trials, techniques of next-generation sequencing of circulating DNA are on the rise. This review will provide an update on the contribution of LB to care of patients with metastatic lung cancer, including the present limits of this approach, and will consider certain perspectives.

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Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC

Cited by 64 publications

References 10 publications

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients

Patient with Three EGFR Mutations – Gradual Development of Resistance to Previous Targeted Treatment

Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology

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