Complex epidermal growth factor receptor mutations and their responses to tyrosine kinase inhibitors in previously untreated advanced lung adenocarcinomas

Zhang, Bo; Wang, Shuyuan; Qian, Jie; Yang, Weiguang; Qian, Fangfei; Lü, Jun; Zhang, Yanwei; Qiao, Rong; Han, Baohui

doi:10.1002/cncr.31329

Cited by 20 publications

(29 citation statements)

References 40 publications

(91 reference statements)

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“…The effectiveness of different EGFR TKIs in patients with complex EGFR mutations has not been fully elucidated. The incidence of complex EGFR mutations in lung adenocarcinoma has been reported to be 0.12–16.00% in all patients with EGFR mutations, 13 , 31 and the incidence in the current study was 5.1% (239 of 4714). Our cohort study comprised a comprehensive comparison of treatment effectiveness between different EGFR TKIs as first-line treatment in patients with complex EGFR mutations.…”

Section: Discussionsupporting

confidence: 44%

“…Although there have been a few studies on complex EGFR mutations and EGFR TKIs, the sample sizes of these published studies are very small and the conclusions were inconsistent. 13,16 Especially, the mechanism of acquired resistance to EGFR TKIs remains unclear in patients with complex EGFR mutations. In this study, we aim to clarify the effectiveness of different EGFR-TKIs as the first-line therapy in lung adenocarcinoma patients with complex EGFR mutations.…”

Section: Introductionmentioning

confidence: 99%

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The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

Yang

et al. 2020

Ther Adv Med Oncol

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Background and aims: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are effective against classical EGFR mutations in lung cancer. However, their effectiveness and the prognosis of lung cancer patients with complex EGFR mutations are not well delineated. Therefore, we aimed to investigate the treatment effectiveness of different EGFR TKIs in patients with complex EGFR mutations. Patients and methods: From 2005 to 2020, we collected lung adenocarcinoma tissue samples for EGFR mutation analysis using direct Sanger sequencing. Patients with EGFR mutations treated with EGFR TKIs as first-line treatment were enrolled. Clinical characteristics, EGFR mutation status, treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Among 2675 patients with EGFR mutations, 239 (8.9%) had complex EGFR mutations, of whom 125 received EGFR TKI treatment as first-line treatment. Multivariate analysis revealed that afatinib was a more favorable factor for PFS than gefitinib [hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.11–3.62] and erlotinib (HR, 2.61; 95% CI, 1.31–5.22), especially in patients with uncommon mutation patterns. Afatinib treatment as first-line treatment was also associated with longer OS compared with erlotinib (HR, 2.48; 95% CI, 1.20–5.12). Classical mutation pattern was associated with longer PFS ( p = 0.001) and OS ( p = 0.020). Secondary T790M was detected in 22 of 52 (42.3%) patients who had re-biopsied tissue samples after acquiring resistance to EGFR TKIs. There was no significant difference in secondary T790M formation after acquired resistance to the three EGFR TKIs ( p = 0.261). Furthermore, three (5.8%) patients had small-cell lung cancer transformation. Conclusion: Afatinib is an effective first-line treatment for patients with lung adenocarcinoma harboring complex EGFR mutations, especially those with uncommon mutation patterns.

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Section: Discussionsupporting

confidence: 44%

Section: Introductionmentioning

confidence: 99%

The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

Yang

et al. 2020

Ther Adv Med Oncol

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“…Occasionally, complex mutations occur, meaning a single tumor sample has two or more different EGFR mutations (45)(46)(47)(48)(49)(50). The frequency of complex mutations is 3-7% (25,26,(50)(51)(52)(53)(54). Theoretically, the introduction of an additional mutation could change the molecular conformation of the EGFR tyrosine kinase domain, leading to increased or decreased TKI affinity that subsequently affects the clinical outcome (55).…”

Section: Introductionmentioning

confidence: 99%

“…Theoretically, the introduction of an additional mutation could change the molecular conformation of the EGFR tyrosine kinase domain, leading to increased or decreased TKI affinity that subsequently affects the clinical outcome (55). Zhang et al (25) identified 187 patients with complex EGFR mutations out of 5898 EGFR-mutant NSCLC patients. Fifty-one of these patients had advanced lung adenocarcinoma and were treated with first-generation EGFR-TKIs as first-line therapy.…”

Section: Introductionmentioning

confidence: 99%

Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

et al. 2020

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

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“…For the rare compound mutations of EGFR , there have been some drug studies. For example, first-generation EGFR tyrosine kinase inhibitors (TKIs) are effective for G719X, 21L861Q and the compound mutations carrying sensitive mutations, but more data are needed for efficacy against 20S768I[ 2 , 3 ]. The second-generation EGFR-TKIs have a wider spectrum.…”

Section: Introductionmentioning

confidence: 99%

Lung adenocarcinoma harboring rare epidermal growth factor receptor L858R and V834L mutations treated with icotinib: A case report

Zhai

Yu²,

Gu³

et al. 2020

WJCC

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BACKGROUND Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations. However, patients with rare, even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors, which bring uncertainty to clinical treatment. CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain. Chest computed tomography revealed lung space-occupying lesions and multiple lymphadenectasis. Bronchoscopy and pathology suggested lung adenocarcinoma. Compound variation of EGFR gene (exon 21 L858R/V834L) was detected in both tissue and circulating tumor deoxyribonucleic acid samples. As a result of next-generation sequencing and her family’s wishes, the patient was given oral treatment with icotinib hydrochloride (125 mg/d, tid) from March 21, 2019 and has achieved stable disease for the last 1 year. CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858R/V834L was treated successfully with icotinib, and it may be a new medication treatment option.

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Complex epidermal growth factor receptor mutations and their responses to tyrosine kinase inhibitors in previously untreated advanced lung adenocarcinomas

Cited by 20 publications

References 40 publications

The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

Lung adenocarcinoma harboring rare epidermal growth factor receptor L858R and V834L mutations treated with icotinib: A case report

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