Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring &lt;em&gt;EGFR&lt;/em&gt; exon 20 mutations

Chen, Dan; Song, Zhengbo; Cheng, Guoping

doi:10.2147/ott.s108242

Cited by 65 publications

(61 citation statements)

References 27 publications

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“…The G719X, S768I and L861Q carriers contributed most primary resistance patients in our study. Robust evidence has shown the poor response to the first‐generation TKI in G719X/S768I/L861Q carriers . Therefore, second generation TKI, such as afatinib, have been recommended to treat these patients .…”

Section: Discussionmentioning

confidence: 99%

Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study

Lei

Wang

Zhu³

et al. 2020

Cancer Science

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The incidence of epidermal growth factor receptor uncommon mutation (EGFRum) is relatively low and patients harboring EGFRum are resistant to the first-generation tyrosine kinase inhibitors (TKI). However, the mechanism of primary resistance remains unclear. Medical records of 98 patients who had never been treated by TKI and who accepted icotinib treatment were collected and followed. The circulating tumor DNA (ctDNA) were detected and analyzed using the next-generation sequencing (NGS) platform after progression on icotinib. The potential primary resistance mechanism of icotinib was explored. A total of 21 (21.4%) and 48 (49%) patients developed primary and acquired resistance to icotinib, respectively. The median progression-free survival (PFS) of primary resistance patients was 1.8 months (0.5-2.3, 95% CI = 1.50-2.10). Before treatment, 52.4% (11/21) of patients carried S768I, 23.8% (5/21) L861Q, 14.3% (3/21) G719X and 14.3% (3/21) exon 20-ins mutations. Approximately 23.8%(5/21) of patients harbored the combined pattern mutations and 76.2% (16/21) of patients harbored the single pattern mutations. The combined pattern with EGFR classical mutation (EGFRcm) had worse PFS than the combined with EGFRum and single pattern (P < .05). There were 6 (28.57%) patients with acquired EGFR extracellular domain mutation, 5 (23.81%) with BCL2L11 loss (BIM deletion polymorphism), 3 (14.29%) with MET amplification, 1 (4.76%) with ERBB2 amplification, 1 (4.76%) with MYC amplification, 1 (4.76%) with PTEN mutation, 1 (4.76%) with PIK3CA mutation and 3 (14.29%) with unknown status. EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN and PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in patients with advanced

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Section: Discussionmentioning

confidence: 99%

Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study

Lei

Wang

Zhu³

et al. 2020

Cancer Science

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“…The difference of treatment effect and prognosis may be due to the existence of genetic heterogeneity, such as the different mutation status of EGFR and KRAS genes. Researches showed that after applying Gefitinib and Erlotinib on behalf of TKI therapy, the remission rate of NSCLC patients with EGFR exon 19 deletion and exon 21 L858R point mutation was significantly higher than that of EGFR wild-type patients [20]. However, similar to chemotherapy, TKI therapy also inevitably faced the issue of drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Association of EGFR and KRAS mutations with expression of p-AKT, DR5 and DcR1 in non-small cell lung cancer

Zhao¹,

Deng²,

Lu³

et al. 2017

neo

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The activation of AKT is one of the causes of resistance to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combines with related receptors to trigger apoptosis or protect the cells against TRAIL apoptosis. This research focused on the association of EGFR and KRAS mutations with expression of AKT, p-AKT, DR5 and DcR1 in non-small cell lung cancer. 82 NSCLC patients were included in the study. xTAG liquichip techonolgy (xTAG-LCT) was applied to investigate the genetic mutation of EGFR and KRAS, Quantitative Real-time PCR was used to test the mRNA expression of AKT, DR5 and DcR1 and Western Blot was applied to test the protein expression of AKT, p-AKT, DR5, and DcR1. We found that of 82 patients, 31 cases had EGFR-activating mutations, more common in female, adenocarcinoma, and non-smoker patients; 9 cases had KRAS mutations, frequently found in patients with smoking history. The expression of AKT and p-AKT correlated with staging, tumor differentiation, and lymph node metastasis. The expression of DR5 in phase III and low differentiation tumor was significantly higher than that in phase I+II and high and median differentiation tumor; the expression of DcR1 in phase III and low differentiation tumor was significantly lower than that in phase I+II and high and median differentiation tumor. Compared with EGFR and KRAS wild type, in NSCLC tissue with EGFR and KRAS mutations, the expression of AKT and p-AKT was significantly higher. These results suggest that EGFR and KRAS mutation status was associated with the expression of AKT and p-AKT. AKT, p-AKT, DR5, and DcR1 all took part in the occurrence and development of NSCLC, and may become a reference index to evaluate the prognosis of NSCLC.

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“…nity k ATP, vazebná afinita k TKI je tedy v těchto případech podobná nemutovanému EGFR a výsledkem je primární rezistence k současně používaným TKI [37]. Je k dispozici řada retrospektivních studií hodnotících menší soubory pacientů léčených TKI 1. a 2. generace [52][53][54]. Jediná prospektivní data vyplývají z post hoc analýzy studií Lux-Lung 2, Lux-Lung 3 a Lux-Lung 6, která ukázala, že u 23 pacientů s ins20 genu EGFR byla ORR na afatinib pouze 8,7 %, medián času do progrese (mPFS) 2,7 měsíce a medián celkového přežití (mOS) 9,2 měsíce.…”

Section: S9unclassified

“…V retrospektivních studiích s TKI 1. generace byla zaznamenána částečná odpověď s ORR 20-33 % v případě samostatného výskytu S768I, výrazně lepší výsledky byly u komplexních mutací. Chen et al uvádějí mPFS 2,7 měsíce [60,61]. V post hoc analýze Lux-Lung 2, Lux--Lung 3 a Lux-Lung 6 byla zaznamenána 100% odpověď na léčbu afatinibem, PFS 14,7 měsíce, avšak u 7 z 8 pacientů byla zachycena komplexní mutace s L858R a G719X [55].…”

Section: Bodové Mutace Exonu 20unclassified

Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment

Bílek¹,

Holánek²,

Berkovcová³

et al. 2019

Klin Onkol

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Východiska: Mutace genu pro receptor epidermálního růstového faktoru (epidermal growth factor receptor-EGFR) hrají důležitou roli v patogenezi nemalobuněčného karcinomu plic. Protože se jedná o alterace často ovlivnitelné cílenou léčbou, představuje jejich detekce součást běžné klinické praxe. U pacientů s aktivačními mutacemi EGFR bylo dosaženo výrazného zlepšení léčebných výsledků pomocí cílené léčby tyrozinkinázovými inhibitory. Dia gnostickým standardem mutací EGFR jsou v současné době metody založené na polymerázové řetězové reakci, zejména kvantitativní polymerázová řetězová reakce v reálném čase. V posledních letech roste význam sekvenování nové generace. EGFR obsahuje čtyři domény: extracelulární s vazebným místem ligandu, transmembránovou doménu, cytoplazmatickou tyrozinkinázovou katalytickou doménu a C-terminální doménu. Klíčové struktury tyrozinkinázové domény zodpovědné za aktivaci a přenos signálu jsou kódovány v rámci exonů 18-21 na 7. chromozomu. Mutace EGFR jsou vysoce heterogenní. Asi 90 % mutací EGFR tvoří delece exonu 19 a bodová mutace L858R v exonu 21. Jsou označovány za "klasické" mutace. Přibližně 10% podíl z celkového počtu mutací připadá na méně časté alterace genu pro EGFR. Vzhledem k nízké incidenci nemalobuněčného karcinomu plic s méně častými mutacemi je stále třeba nových informací o jejich prediktivním významu. Většinu dosavadních dat o méně častých mutacích tvoří retrospektivní analýzy a hodnocení menších souborů. Cíl: Cílem tohoto přehledového článku je shrnout možnosti dia gnostiky a léčby nemalobuněčného karcinomu plic s méně častými mutacemi EGFR. Klíčová slova nemalobuněčný karcinom plic-receptor pro epidermální růstový faktor-tyrozinkinázové inhibitory-cílená léčba-mutace EGFR Práce byla podpořena MŠMT-NPU I-LO1413 a MZ ČR-RVO (MOÚ, 00209805). This work was supported by the MEYS-NPS I-LO1413 and MH CR-DRO (MMCI, 00209805). 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.

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Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring <em>EGFR</em> exon 20 mutations

Cited by 65 publications

References 27 publications

Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study

Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study

Association of EGFR and KRAS mutations with expression of p-AKT, DR5 and DcR1 in non-small cell lung cancer

Uncommon EGFR Mutations in Non-Small Cell Lung Cancer and Their Impact on the Treatment

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