Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non–Small-Cell Lung Cancer

Martin, Juliane; Lehmann, Annika; Klauschen, Frederick; Hummel, Michael; Lenze, Dido; Grohé, Christian; Tessmer, Antje; Gottschalk, Jack A.; Schmidt, Bernd; Pau, H. W.; Witt, Christian; Moegling, Stefan; Kromminga, Robert; Jöhrens, Korinna

doi:10.1016/j.cllc.2019.04.012

Cited by 13 publications

(7 citation statements)

References 109 publications

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“…In these reports, the incidence of EGFR compound mutations ranges from 4–6.7% to 26% of EGFR mutant cases ( Table 1 ) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In Caucasian populations, three large studies have been conducted, reporting ~5–7% compound EGFR mutations among EGFR -positive patients [ 15 , 16 , 17 ]. 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 ].…”

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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“…CDK6 CNV has been reported to correlate with first-generation EGFR TKI resistance and shorten PFS to osimeritinib ( 43 ). The clinical impact of rare and compound mutations of EGFR including EGFR D761N, EGFR Q791H, EGFR V843I has been mentioned in EGFR TKI treatment, however, without conclusions thus far ( 44 ). ERBB4 alterations have also been reported in NSCLC and found to be activated ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Wang

et al. 2021

Front. Oncol.

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PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

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“…Among patients receiving gefitinib or erlotinib, one achieved a PR, two achieved a SD, and nine others were nonresponders (i.e., PD). These patients achieved PD and SD experienced a short PFS from 0.9 to 8 months, with a median of 3 months (2,(8)(9)(10)(11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

“…Lung cancer, of which 80% -85% is classified as non-small-cell lung cancer (NSCLC), has the highest death rate of all cancers worldwide (1,2). Somatic activating mutations in the epidermal growth factor receptor (EGFR) are the most common oncogenic driver mutations in Asian NSCLC patients, with a prevalence of 47% (3).…”

Section: Introductionmentioning

confidence: 99%

A Lung Adenocarcinoma Patient With a Rare EGFR E709_T710delinsD Mutation Showed a Good Response to Afatinib Treatment: A Case Report and Literature Review

Cui²,

Guo³

et al. 2021

Front. Oncol.

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For advanced lung adenocarcinoma patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies, and achieve favorable responses. However, for the rare EGFR deletion-insertion mutation of exon 18, there is no evidence of the efficacy of EGFR TKIs. Herein, we report a lung adenocarcinoma patient harboring a rare EGFR E709_T710delinsD mutation who was treated with afatinib as the first-line therapy and achieved a progression-free survival of 23 months. After the disease progressed, the patient received almonertinib treatment and exhibited a stable disease. This case indicated that non-small cell lung cancer patients harboring the EGFR E709_T710delinsD mutation could benefit from afatinib treatment, followed with almonertinib treatment, as a potential therapeutic strategy.

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Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non–Small-Cell Lung Cancer

Cited by 13 publications

References 109 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

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

A Lung Adenocarcinoma Patient With a Rare EGFR E709_T710delinsD Mutation Showed a Good Response to Afatinib Treatment: A Case Report and Literature Review

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