Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network

Beau‐Faller, Michèle; Prim, Nathalie; Ruppert, Anne-Marie; Nanni-Metellus, Isabelle; Lacave, Roger; Lacroix, Ludovic; Escande, Fabienne; Lizard, Sarab; Prétet, Jean‐Luc; Rouquette, Isabelle; Crémoux, Patricia de; Solassol, Jérôme; Fraipont, Florence de; Bièche, Ivan; Cayre, Anne; Favre-Guillevin, E.; Tomasini, Pascale; Wislez, Marie; Besse, Benjamin; Legrain, M; Voegeli, Anne‐Claire; Baudrin, L.; Morin, Franck; Zalcman, Gérard; Quoix, Élisabeth; Blons, Hélène; Cadranel, Jacques

doi:10.1093/annonc/mdt418

Cited by 280 publications

(283 citation statements)

References 38 publications

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“…While we cannot identify any particular reason for this, it has been demonstrated that routine nationwide molecular profiling of NSCLC patients is feasible and provides immense benefit in terms of frequency of driver mutations and their specific type (39). Of special interest are NSCLC with uncommon EGFR mutations that occur in approximately 1.0% of NSCLC cases (40), or those with poor prognosis such as adenosquamous carcinoma (41), detected in 1.3% of our study patients, and EGFR-positive NSCLC metastasizing to the bone (42). The heterogeneous molecular profiles presented in these types need to be studied in detail in order to not only study the occurrence and pathological differences arising from various mutations but also to design specific therapies aimed at molecular targets (40).…”

Section: Discussionmentioning

confidence: 99%

“…Of special interest are NSCLC with uncommon EGFR mutations that occur in approximately 1.0% of NSCLC cases (40), or those with poor prognosis such as adenosquamous carcinoma (41), detected in 1.3% of our study patients, and EGFR-positive NSCLC metastasizing to the bone (42). The heterogeneous molecular profiles presented in these types need to be studied in detail in order to not only study the occurrence and pathological differences arising from various mutations but also to design specific therapies aimed at molecular targets (40). The database of the INSIGHT registry is the first of its kind for Poland in our knowledge and it provides robust data on sampling methods, molecular testing, frequency and types of EGFR mutations, treatment modalities, and prognostic factors related to Polish patients with EGFR-positive NSCLC.…”

Section: Discussionmentioning

confidence: 99%

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Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

et al. 2017

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Abstract. Targeted therapy of non-small cell lung cancer (NSCLC) patients with mutations in the epidermal growth factor receptor (EGFR) gene has been associated with improved prognosis. However, there is a shortage on data from real-world clinical practice in management of EGFR-positive NSCLC patients in Poland. The present study retrospectively analyzed data from the INSIGHT study to evaluate the incidence and clinical management of EGFR-positive NSCLC in Poland. The authors additionally aimed to identify predictors of the EGFR mutation and factors associated with clinical stage of the tumor at diagnosis. Incidence of EGFR mutations was 11.8% and the most common mutations were a deletion on exon 19 and an L858R substitution on exon 21. Mutations were strongly associated with female gender [male vs. female odds ratio (OR): 0.51; P=0.004] and never having smoked (current/past smoker vs. never smoked OR: 0.16; P<0.001), and advanced clinical stage (stage IV vs. stage I/II OR: 2.89; P=0.029). Patients with EGFR mutation were also observed to have a greater propensity to develop bone metastasis (OR: 11.62; P=0.008). Multivariate regression analysis demonstrated that patients with past or current smoking history or a poor performance on the Eastern Cooperative Oncology Group (ECOG) scale were less likely to have the EGFR mutation. Furthermore, EGFR-positive patients with greater ECOG scores and a tumor other than adenocarcinoma or squamous cell carcinoma were more likely to present advanced tumors. Early screening for EGFR mutation and the use of EGFR-targeting therapies as first-line agents may lead to better prognosis and successful clinical management of EGFR-positive NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

et al. 2017

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“…Due to the relative rarity of EGFR exon 20 mutations, clinical data concerning their associations with drug responsiveness are limited, and conflicting data exist regarding the sensitivity to EGFR-TKIs of tumors harboring p.S768I mutations (20,21). The literature review conducted for the present report revealed a limited number of cases involving p.S768I mutations (Table I), and conflicting data with regard to its clinical association with EGFR-TKI efficacy.…”

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confidence: 85%

Epidermal growth factor receptor exon 20 p.S768I mutation in non-small cell lung carcinoma: A case report combined with a review of the literature and investigation of clinical significance

et al. 2015

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Abstract. Epidermal growth factor receptor (EGFR) plays a significant role in non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer worldwide. Therefore, EGFR may be a useful molecular target for personalized therapy utilizing tyrosine kinase inhibitors (TKIs). Somatic activating EGFR mutations may be used to identify tumors sensitive to the effects of small-molecule EGFR-TKIs (gefitinib and erlotinib), and alternative, less frequently observed mutations, including the majority of mutations identified within exon 20, may be associated with a lack of response to TKIs. However, due to the comparative rarity of EGFR exon 20 mutations, clinical information concerning the association between EGFR exon 20 mutations and responsiveness to TKIs has been limited within the relevant literature, particularly for certain rare mutations, including p.S768I. The current study reports the case of a patient with NSCLC harboring a p.S768I mutation in the EGFR gene [a substitution at codon 768 of exon 20 (c.2303G>T, p.S768I)], as well as a mutation at codon 719, exon 18 (p.G719A). The relevant literature concerning this rare EGFR somatic mutation is also reviewed. IntroductionLung cancer is the most common cause of cancer-associated mortality in a number of developed countries (1), and non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer worldwide, accounting for 85% of all lung cancer cases (2,3). Epidermal growth factor receptor (EGFR) may play a significant role in NSCLC, and is thus a potential molecular target for personalized therapy with tyrosine kinase inhibitors (TKIs) (4).Somatic activating EGFR mutations, which are clustered within the tyrosine kinase domain, most commonly occur in the form of deletions in exon 19 or p.L858R mutations in exon 21. These somatic activating mutations account for ~85% of all EGFR mutations, and may indicate the likely sensitivity of tumors to the effects of small-molecule inhibitors (such as gefitinib and erlotinib) (4-6). Other, less prevalent EGFR mutations, including exon 18 p.G719X mutations (3% of all EGFR mutations) (7) and exon 21 p.L861Q (2% of all EGFR mutations) have been associated with enhanced efficacy of EGFR-TKIs (8). By contrast, alternative classes of EGFR mutations may be associated with a lack of response to TKIs, and this is the case for the majority of exon 20 mutations, which account for ~5% of all EGFR mutations (9).EGFR exon 20 mutations occur in patients with clinicopathological features similar to those of patients with classical EGFR mutations (women, non-smokers, adenocarcinomas). Exon 20 mutations encompass the area surrounding amino acid positions Glu762 to Cys775, located in the N-lobe of the kinase domain of EGFR following the C-helix. These mutations induce a pattern of in vitro and in vivo resistance to EGFR-TKIs (9). A number of mutations in EGFR exon 20 are thought to increase the affinity of EGFR for adenosine triphosphate (ATP), thus decreasing the efficacy of TKI inhibition (10). However, due to the comparati...

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“…Molecular tests based on real-time PCR techniques detect several rare EGFR mutations, including: Different substitutions in codons 709 and 719 in exon 18, substitutions and insertions in exon 20, as well as different substitutions in codons 858 and 861 in exon 21 (9). Such tests have confirmed that rare EGFR mutations occur more frequently than previously thought Results from the French National Cancer Institute network (ERMETIC-IFCT) indicated that ~10% of EGFR-mutated NSCLC patients may have rare EGFR gene mutations (10). Similarly, in our recent multicenter study in Poland, we showed that 14.77% of patients with EGFR-mutated NSCLC had rare mutations (11).…”

Section: Introductionmentioning

confidence: 91%

“…Beau-Faller et al recently proved that rare EGFR gene mutations could be associated with resistance to EGFR-TKIs treatment (distal exon 20 insertions) or sensitivity to EGFR-TKIs treatment (exon 18 substitution or complex EGFR mutations) in Caucasian NSCLC patients (10). When investigating 50 NSCLC patients with rare EGFR gene mutations treated with EGFR-TKIs, they found that primary resistance to EGFR-TKIs was diagnosed in 54% of patients with exon 20 mutations, in 66% of patients with exon 18 substitutions, and in 14% of patients with more complex EGFR mutations (10).…”

Section: Univariate Analysis Multivariate Analysis Median Pfs -------mentioning

confidence: 99%

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

et al. 2017

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Abstract. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of EGFR-TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare EGFR mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) EGFR mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. EGFR mutations were determined using RT-PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression-free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of EGFR mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare EGFR gene mutations (P=0.013). Patients with common EGFR mutations showed significantly longer median PFS than those with rare EGFR mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare EGFR mutations. When undergoing EGFR-TKI treatment, patients with rare EGFR mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare EGFR mutations and EGFR-TKIs treatment outcomes is required.

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Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network

Cited by 280 publications

References 38 publications

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland

Epidermal growth factor receptor exon 20 p.S768I mutation in non-small cell lung carcinoma: A case report combined with a review of the literature and investigation of clinical significance

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations

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