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

Abstract

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...

Detection of Epidermal Growth Factor Receptor (EGFR) Gene Mutation in Formalin Fixed Paraffin Embedded Tissue by Polymerase Chain Reaction-Single Strand Conformational Polymorphism (PCR-SSCP) in Non-Small Cell Lung Cancer in the Northeastern Region of Thailand

“…From previous studies, a mutation in the EGFR at 2235_2249 delggaattaagagaagc (Del E746-A750) in exon 19 (Marchetti et al, 2005;Jorge et al, 2014) and a new insertion at 2313_2314insCAC position (771_772insHis) in exon 20 have been found. The database showed a correlation between the pattern from the PCR-SSCP and that from the control that was confirmed by DNA sequencing, which previous studies have not reported (Arcila et al, 2013;Improta et al, 2016;Zupa et al, 2012).…”

Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma

“…p.S768I has been categorized as a primary resistant EGFR mutation[40], although there are conflicting opinions from other studies with small case numbers [41, 42]. The largest cohort study showed TKIs were less effective in 7 patients with p.S768I mutation [43].…”

Molecular Pathology of Lung Cancer

“…Ekzon 20 üzerinde saptanan mutasyonlar genellikle tedaviye dirençli değişikliklerdir (5). Bu durumun istisnası ekzon 20 üzerinde pozisyon 768 ve öncesindeki insersiyonlardır (6,7). EGFR tirozin kinaz inhibitörleriyle tedavi olan hastaların çok büyük bir kısmında tedavinin bir noktasında ilaca karşı gelişen direnç nedeniyle relaps görülür.…”