Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Attili, Ilaria; Passaro, Antonio; Pisapia, Pasquale; Malapelle, Umberto; Marinis, Filippo de

doi:10.3390/curroncol29010024

Cited by 35 publications

(37 citation statements)

References 52 publications

(69 reference statements)

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“…Uncommon EGFR mutations can occur alone or coexist with either common or other uncommon EGFR mutations, including complex or compound mutations. The incidence of complex EGFR mutations varies among different study populations and detection methods, ranging from 4% to 26% of all EGFR mutations ( 15 ). Data regarding the effect of EGFR -TKIs on complex EGFR mutations are even fewer, and the results based on a relatively small number of cases were highly heterogeneous ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

“…The incidence of complex EGFR mutations varies among different study populations and detection methods, ranging from 4% to 26% of all EGFR mutations ( 15 ). Data regarding the effect of EGFR -TKIs on complex EGFR mutations are even fewer, and the results based on a relatively small number of cases were highly heterogeneous ( 15 ). Generally, the result in patients carrying complex mutations is similar to that in patients with single uncommon mutations and is less favorable than that in patients with common mutations ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…Data regarding the effect of EGFR -TKIs on complex EGFR mutations are even fewer, and the results based on a relatively small number of cases were highly heterogeneous ( 15 ). Generally, the result in patients carrying complex mutations is similar to that in patients with single uncommon mutations and is less favorable than that in patients with common mutations ( 15 , 16 ). Nevertheless, the characteristics of NSCLC patients with complex EGFR mutations are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation

Shie²,

Wang³

et al. 2022

Front. Immunol.

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IntroductionUncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear.MethodsThis retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database.ResultsBetween 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively).ConclusionsOur study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation

Shie²,

Wang³

et al. 2022

Front. Immunol.

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“…Compound mutations indicate the presence of more than one EGFR mutation, either common or uncommon, within the same tumor. Attili et al ( 98 ) found high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), with the variance possibly due to the different testing methods adopted, and the specific mutations considered. In various combinations, compound EGFR mutations containing either exon 21 p. L858R or exon 19 deletions were common ( 99 ).…”

Section: Drug Resistance Mechanisms and Progress In The Use Of First-...mentioning

confidence: 99%

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

et al. 2022

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According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

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“…(Melosky et al, 2022). A classic or common EGFR alterations mainly comprise an in-frame deletion in exon 19 and L858R missense mutation in exon 21, accounting for about 80%-90% of EGFR alterations in NSCLC (Attili et al, 2022). Approximately 10% of patients with NSCLC harbor uncommon EGFR alterations including major uncommon mutation G719X, L861Q and S768I (Figure 1), de novo T790M mutation and exon 20 insertions, or their compound forms including the co-existence of common or uncommon mutation (Russo et al, 2019;Zhang et al, 2019;Gristina et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors

Gao

Liu

et al. 2022

Front. Pharmacol.

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Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) harbor uncommon epidermal growth factor receptor (EGFR) alterations. This study aims to investigate the therapeutic responses and predict the binding activity of different tyrosine kinase inhibitors (TKIs) for EGFR uncommon alterations.Methods: Between May 2014 and June 2021, clinical outcomes of NSCLC patients harboring EGFR uncommon alterations who received diverse treatment modalities: first-generation (1G) EGFR-TKI, second-generation (2G) EGFR-TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed, and structural analysis for the binding activity of major uncommon subtypes G719A, S768I, and L861Q to different TKIs were predicted.Results: A total of 102 NSCLC patients harboring EGFR uncommon alterations with treatment and survival outcomes were included and analyzed. The majority of patients presented compound mutations (54.9%), and G719X plus S768I was the predominant subtype (n = 33, 32.3%). There was a significant difference in median progression-free survival (mPFS) between therapeutic patterns (p = 0.015) and EGFR alteration subtypes (p = 0.017). Rather than almonertinib and furmonertinib, afatinib, dacomitinib and osimertinib revealed favorable binding activity to G719A mutation. In contrast, S768I and L861Q mutation indicated an unaffected binding activity to these diverse kinds of EGFR TKIs.Conclusion: Together with afatinib, 1G-TKIs combined with chemotherapy might be another effective option for NSCLC patients harboring EGFR uncommon alterations. Based on computational findings, afatinib, dacomitinib, and osimertinib might confer favorable activity to G719A, S768I, and L861Q, whereas almonertinib and furmonertinib revealed less activity to G719A.

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Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Cited by 35 publications

References 52 publications

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

EGFR uncommon alterations in advanced non-small cell lung cancer and structural insights into sensitivity to diverse tyrosine kinase inhibitors

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