Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma

Tian, Yingying; Zhao, Jiuzhou; Ren, Pengfei; Wang, Bo; Zhao, Chengzhi; Shi, Chao; Wei, Bing; Ma, Jie; Guo, Yongjun

doi:10.1101/374710

Cited by 4 publications

(5 citation statements)

References 21 publications

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“…Since, EGFR p.T790M is still the most common mechanism of resistance to afatinib, similar to reversible EGFR TKI, a comparison of patients´prognosis and form of disease upon basis of the mutational profile should be made. Previously, patients were shown to have a better prognosis and more indolent form of disease progression upon the presence of an EGFR exon 19 deletion [31][32][33][34]. Matsuo and co-workers investigated whether there was an association of the (primary) EGFR driver mutation with the occurrence and frequency of EGFR p.T790M and the period of response to EGFR TKI.…”

Section: Discussionmentioning

confidence: 99%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

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Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1stgeneration (reversible) EGFR TKI and later the 2nd-generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. Methods: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification. Results: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib-vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M. Conclusions: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

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Section: Discussionmentioning

confidence: 99%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

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“…Recent clinical and laboratory findings-including those presented here-have shown that different EGFR exon 19 variants exhibit different inhibitor sensitivities 9,10,[12][13][14]16,17,19,[21][22][23]25,55 , arguing that they should not be treated as a single group in clinical decision making. Moreover, exon 19 variants can be associated with inhibitor responses that differ from those of other common EGFR mutations found in lung adenocarcinoma 32,38,55,56 .…”

Section: Discussionmentioning

confidence: 78%

“…1b) -which accounts for 75% in this database-has led current clinical recommendations to consider them all as a single group. Numerous studies have reported differential sensitivity of individual EGFR exon 19 variants to EGFR TKIs in clinical settings, however [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . For example, in a cohort of 202 patients with tumors harboring various exon 19 deletions, uncommon deletion variants were associated with significantly worse survival than the common ΔE746-A750 mutation with the first generation TKI gefitinib 24 .…”

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confidence: 99%

Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations

Rosenburgh

Grant

et al. 2022

Nat Commun

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Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low KM, ATP). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

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“…After regression analysis of the mutant patients, each exon mutation failed to associate with clinical or pathological features. In addition to the characteristics of the subtypes of EGFR mutations, different subtypes of EGFR mutations and expression of TTF-1 and Napsin A showed different levels of prognosis (27)(28)(29). The variable results may be due to the heterogeneity of EGFR mutations and relatively small samples with complex genetic background, demonstrating that the different mechanisms lead to a variety of EGFR mutations (26,30).…”

Section: Discussionmentioning

confidence: 99%

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients

Xiang¹,

Wen²,

Ren³

et al. 2022

J Thorac Dis

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Background: To evaluate the prompting value of thyroid transcription factor 1 (TTF-1) and Napsin A for the status of epidermal growth factor receptor (EGFR) mutations in an independent cohort of lung adenocarcinomas (LUADs) when genetic testing is unavailable.Methods: In this study, 976 untreated primary LUADs were retrospectively reviewed. The clinical and pathological data, including age, gender, smoking history, predictive values of TTF-1 and Napsin A, EGFR status, and tumor-node-metastasis (TNM) stage were obtained through medical records available in Shanxi Province Cancer Hospital. All patients were divided into 2 groups, a mutant group (n=362) and wild-type group (n=614), according to their EGFR status. The clinical data and the expression of TTF-1 and Napsin A were compared between the 2 groups. TTF-1 and Napsin A are detected by fully automated IHC.PCR was carried out to detect the EGFR mutation. Univariate and multivariate logistic regression analyses were undertaken to distinguish independent factors of EGFR mutations.Results: A total of 362 cases (37.1%) of EGFR mutations were detected, which were more frequent in females, never smokers, lymphatic metastasis, distant metastasis, and the positive expression of TTF-1 and Napsin A. Multivariate analysis indicated that females [odds ratio (OR), 1.950; 95% confidence interval (CI):

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Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma

Cited by 4 publications

References 21 publications

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients

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