High-throughput sequencing reveals distinct genetic features and clinical implications of NSCLC with de novo and acquired EGFR T790M mutation

Tian, Panwen; Wang, Ye; Wang, Weiya; Li, Yalun; Wang, Ke; Cheng, Xiaowei; Tang, Yuan; Han‐Zhang, Han; Ye, Junyi; Chuai, Shannon; Liu, Weimin

doi:10.1016/j.lungcan.2018.08.014

Cited by 21 publications

(24 citation statements)

References 29 publications

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“…Furthermore, large-scale prospective studies are warranted to elucidate the efficacy and prognostic factors of different EGFR TKIs in patients with different rare or compound mutations. Osimertinib, a 3rd generation EGFR TKI, has been used to treat the de novo T790M mutation [ 28 ], and several case reports have demonstrated that it may be effective in some patients harboring uncommon mutations [ 29 , 30 ]. However, more evidence is still needed.…”

Section: Discussionmentioning

confidence: 99%

Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Tsai

Hung

Lee

et al. 2018

Cancers

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Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

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Section: Discussionmentioning

confidence: 99%

Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Tsai

Hung

Lee

et al. 2018

Cancers

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“…The frequency of de novo T790M was 4.2% among 437 assessable patients in the randomized pan-Asian phase III IPASS trial [2], while it accounted for 2% (16/800) of all identified EGFR -mutant cases in a large Chinese cohort of 1903 resected NSCLCs [60] and was estimated to be <3% in Caucasians using Sanger sequencing [1]. Recently, two Chinese and one Italian NGS-based studies identified a de novo T790M co-mutation in 5.8%, 14%, and 6.8% of TKI-naïve patients concomitantly carrying sensitizing EGFR -mutations, respectively [52,53,61]. These data not only indicate that combined mutations may impact the occurrence of specific resistant EGFR -mutations such as T790M, but also that the higher sensitivity of NGS panels compared to previous DNA-sequencig methods may increase the frequency of T790M co-mutation.…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

127

126

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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“…Uncommon EGFR mutations, which commonly deemed as mutations other than 19del and L858R are highly heterogeneous and display various sensitivity to EGFR-TKIs. For example, exon 20 insertion [14] and de novo T790M [15] are resistant to early generation EGFR-TKIs. However, other "common" uncommon EGFR mutations include G719X (2-6 % of all EGFR mutations), L861Q (1.3-3.2 %) and S768I (1.3-3 %) [16][17][18][19][20] have been demonstrated sensitive to EGFR-TKIs [18,21,22].…”

Section: Introductionmentioning

confidence: 99%

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Yang

Mao

et al. 2020

Lung Cancer

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High-throughput sequencing reveals distinct genetic features and clinical implications of NSCLC with de novo and acquired EGFR T790M mutation

Cited by 21 publications

References 29 publications

Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

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