Clinicopathological characteristics of lung adenocarcinoma with compound EGFR mutations

Hayashi, Takuo; Takamochi, Kazuya; Hara, Kieko; Kishikawa, Satsuki; Sano, Kei; Takahashi, Fumiyuki; Suehara, Yoshiyuki; Saito, Tsuyoshi; Takahashi, Kazuhisa; Suzuki, Kenji; Yao, Takashi

doi:10.1016/j.humpath.2020.07.007

Cited by 7 publications

(10 citation statements)

References 34 publications

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“…The impact of ethnicity, and also possibly environmental factors, clearly emerges from a relevant study conducted on 2146 NSCLC in Southwest China: in the rural Qujing area, the incidence of compound EGFR mutations was 43.6% compared to 10.4% in the non-Qujing region ( p < 0.0001), with patients’ occupation (farmer vs. non-farmer) being independently associated with an increased rate of EGFR compound mutations [ 12 ]. The incidence rate of compound mutations with respect to single EGFR mutations appears not to be affected by clinic-pathological features such as sex, smoking status or histology [ 18 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients’ subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novoEGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40–80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20–70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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“…LADs with no expression of NKX2-1/TTF-1 exon 1 were significantly associated with older age (p = 0.0006), no TTF-1 immunoreactivity (p = 0.0009), and EGFR wild-type tumours (p = 0.0009). However, there was no significant correlation between expression of NKX2-1/TTF-1 exon 1 and LAD histological features, such as micropapillary or cribriform 369 TSS-level expression of NKX2-1/TTF-1 isoforms in LAD patterns, that are unfavourable prognostic factors in LAD [24]. Furthermore, 49 (79%) and 51 (82%) LADs with no NKX2-1/TTF-1 exon 1 expression exhibited an EGFR and KRAS wild-type genotype, respectively.…”

Section: Lad Clinicopathological Characteristics Of Nkx2-1/ Ttf-1 Exon 1 Expressionmentioning

confidence: 81%

“…Pathological diagnoses were based on the 2015 World Health Organization classification [23]. For immunohistochemical analyses of TTF-1 (clone 8G7G3/1; DAKO, Glostrup, Denmark), tumours were assembled into tissue microarrays (TMAs), using 1.5-2.0 mm cores sampled from one or two different representative areas of each FFPE tissue block (Pathology Institute Corp., Toyama, Japan), as previously described [24]. TTF-1 was considered positive if 1% or greater of tumour cells were stained.…”

Section: Histological and Immunohistochemical Analysesmentioning

confidence: 99%

Transcription start site‐level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance

Sano

Hayashi

Suehara

et al. 2021

The Journal of Pathology CR

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There are multiple transcription start sites (TSSs) in agreement with multiple transcript variants encoding different isoforms of NKX2-1/TTF-1 (thyroid transcription factor 1); however, the clinicopathological significance of each transcript isoform of NKX2-1/TTF-1 in lung adenocarcinoma (LAD) is unknown. Herein, TSS-level expression of NKX2-1/TTF-1 isoforms was evaluated in 71 LADs using bioinformatic analysis of cap analysis of gene expression (CAGE)-sequencing data, which provides genome-wide expression levels of the 5'-untranslated regions and the TSSs of different isoforms. Results of CAGE were further validated in 664 LADs using in situ hybridisation. Fourteen of 17 TSSs in NKX2-1/TTF-1 (80% of known TSSs in FANTOM5, an atlas of mammalian promoters) were identified in LADs, including TSSs 1-13 and 15; four isoforms of NKX2-1/TTF-1 transcripts (NKX2-1_001, NKX2-1_002, NKX2-1_004, and NKX2-1_005) were expressed in LADs, although NKX2-1_005 did not contain a homeodomain. Among those, six TSSs regulated NKX2-1_004 and NKX2-1_005, both of which contain exon 1. LADs with low expression of isoforms from TSS region 11 regulating exon 1 were significantly associated with poor prognosis in the CAGE data set. In the validation set, 62 tumours (9.3%) showed no expression of NKX2-1/TTF-1 exon 1; such tumours were significantly associated with older age, EGFR wild-type tumours, and poor prognosis. In contrast, 94 tumours, including 22 of 30 pulmonary invasive mucinous adenocarcinomas (IMAs) exhibited exon 1 expression without immunohistochemical TTF-1 protein expression. Furthermore, IMAs commonly exhibited higher exon 1 expression relative to that of exon 4/5, which contained a homeodomain in comparison with EGFR-mutated LADs. These transcriptome and clinicopathological results reveal that LAD use at least 80% of NKX2-1 TSSs and expression of the NKX2-1/TTF-1 transcript isoform without exon 1 (NKX2-1_004 and NKX2-1_005) defines a distinct subset of LAD characterised by aggressive behaviour in elder patients. Moreover, usage of alternative TSSs regions regulating NKX2-1_005 may occur in subsets of LADs.

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“…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 ). The response rate of those tumors with compound mutations to EGFR-TKIs compared with those with single mutations is contested.…”

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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Clinicopathological characteristics of lung adenocarcinoma with compound EGFR mutations

Cited by 7 publications

References 34 publications

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

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

Transcription start site‐level expression of thyroid transcription factor 1 isoforms in lung adenocarcinoma and its clinicopathological significance

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

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