A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer

Tu, Hai‐Yan; Ke, E-E; Yang, Jing; Sun, Yue‐Li; Yan, Hong‐Hong; Zheng, Ming-Ying; Bai, Xiaoyan; Wang, Zhen; Su, Jian; Chen, Zhihong; Zhang, Xuchao; Dong, Zhong‐Yi; Wu, Si-Pei; Jiang, Ben‐Yuan; Chen, Hua-Jun; Wang, Bin-Chao; Xu, Chong-Rui; Zhou, Qing; Mei, Ping; Luo, Dong-Hua; Zhong, Wen‐Zhao; Yang, Xue‐Ning; Wu, Yi‐Long

doi:10.1016/j.lungcan.2017.11.005

Cited by 157 publications

(166 citation statements)

References 27 publications

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“…The mutation rate of NSCLC in this TCGA cohort appeared consistent with the previous report that these two mutations accounted for 85% to 90% of all EGFR-mutated NSCLC tumors [38,39]. For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34,[40][41][42]. It is clear that different EGFR mutations have very different implications, and only those resulting in destabilization of the equi-librium between the active and inactive states of EGFR kinase activity may benefit from EGFR targeted therapy [43,44].…”

Section: Discussionsupporting

confidence: 87%

Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan‐cancer analysis

Liu

Zhang

Sun

2020

Cancer Communications

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Background Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations. Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available. This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications. Methods The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene. Mutation frequency, genomic location distribution, functional impact, and clinical targeted therapy implication were compared among different cancer types, and their associations with patient survival were analyzed. Results EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types. The overall mutation frequency in all cancers combined was relatively low. Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain. Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin‐like domain where targeted therapy was less effective. Low‐grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome. Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival. Squamous cell carcinoma regardless of their sites (the head and neck, lung, or esophagus) exhibited similar characteristics with an alteration frequency of about 5.0%, was dominated by gene amplification, and had increased EGFR expression generally associated with short patient survival. DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers. Conclusions EGFR aberration type, frequency, distribution in functional domains, and expression vary from cancer to cancer. While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR‐driven tumors.

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Section: Discussionsupporting

confidence: 87%

Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan‐cancer analysis

Liu

Zhang

Sun

2020

Cancer Communications

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“…Our results indicated that patients with uncommon EGFR mutations, G719X and exon 20 insertions, had significantly better response, PFS, and TTF than those in patients with common EGFR mutations, such as exon 19 deletions and L858R in exon 21, consistent with findings reported previously . These findings suggested that patients with uncommon EGFR mutations might associate with more specific characteristics of smokers than patients with common EGFR mutations, although our study could not indicate the significant relationship between smoking history and the efficacy of ICIs . As it was reported as a controversial finding, smoking history might be an inadequate and confounding factor in the outcomes of ICIs in EGFR ‐mutated NSCLC.…”

Section: Discussionsupporting

confidence: 85%

Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR‐mutated non‐small cell lung cancer

et al. 2019

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Background Treatment with epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR‐mutated non‐small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. Patients and Methods We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR‐TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. Results We enrolled 27 patients who harbored EGFR‐activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression‐free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). Conclusion Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR‐mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations.

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“…In our study, 154 uncommon EGFR mutations in 108 patients, which accounted for 18.9% of EGFR ‐mutant patients, were identified. Two previous studies reported that approximately 6.5% of uncommon EGFR ‐mutant patients were detected in Chinese patients with NSCLC by Sanger sequencing or amplification refractory mutation system (ARMS) technologies . Uncommon EGFR mutations that co‐occurred with sensitizing mutations were identified in 7.4% of EGFR ‐mutant patients, and 11.6% of EGFR ‐mutant patients harbored only uncommon mutations.…”

Section: Resultsmentioning

confidence: 99%

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

Dai

Wang

et al. 2019

The Oncologist

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Background Non‐small cell lung cancer (NSCLC) is one of the most common human malignancies and the leading cause of cancer‐related death. Over the past few decades, genomic alterations of cancer driver genes have been identified in NSCLC, and molecular testing and targeted therapies have become standard care for lung cancer patients. Here we studied the unique genomic profile of driver genes in Chinese patients with NSCLC by next‐generation sequencing (NGS) assay. Materials and Methods A total of 1,200 Chinese patients with NSCLC were enrolled in this study. The median age was 60 years (range: 26–89), and 83% cases were adenocarcinoma. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples and matched blood. Results Approximately 73.9% of patients with NSCLC harbored at least one actionable alteration recommended by the National Comprehensive Cancer Network guideline, including epidermal growth factor receptor (EGFR), ALK, ERBB2, MET, BRAF, RET, and ROS1. Twenty‐seven patients (2.2%) harbored inherited germline mutations of cancer susceptibility genes. The frequencies of EGFR genomic alterations (both mutations and amplification) and ALK rearrangement were identified as 50.1% and 7.8% in Chinese NSCLC populations, respectively, and significantly higher than the Western population. Fifty‐six distinct uncommon EGFR mutations other than L858R, exon19del, exon20ins, or T790M were identified in 18.9% of patients with EGFR‐mutant NSCLC. About 7.4% of patients harbored both sensitizing and uncommon mutations, and 11.6% of patients harbored only uncommon EGFR mutations. The uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. In patients <40 years of age, the ALK‐positive percentage was up to 28.2%. Moreover, 3.2% of ALK‐positive patients harbored multi ALK rearrangements, and seven new partner genes were identified. Conclusion More unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that NGS technology is more feasible and necessary than other molecular testing methods, and suggested that the special strategies are needed for drug development and targeted therapy for Chinese patients with NSCLC. Implications for Practice Molecular targeted therapy is now the standard first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC). Samples of 1,200 Chinese patients with NSCLC were analyzed through next‐generation sequencing to characterize the unique feature of uncommon EGFR mutations and ALK fusion. The results showed that 7.4% of EGFR‐mutant patients harbored both sensitizing and uncommon mutations and 11.6% harbored only uncommon mutations. Uncommon EGFR mutations more frequently combined with the genomic alterations of ALK, CDKN2A, NTRK3, TSC2, and KRAS. ALK fusion was more common in younger patients, and the frequency decreased monotonically with age. 3.2% of ALK‐positive patien...

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A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer

Cited by 157 publications

References 27 publications

Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan‐cancer analysis

Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan‐cancer analysis

Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR‐mutated non‐small cell lung cancer

Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer

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