Abstract
BackgroundDespite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations.MethodsAmong patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry.ResultsTwenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis.ConclusionThe mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.
Highlights
Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops
Amplification of the MET gene has been reported to contribute to resistance in approximately 5–20% of cases [6,7,8] and increased AXL expression was recently discovered to occur in almost 20% of patients [9] phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutation, epithelial-to-mesenchymal transition (EMT) and small cell lung cancer (SCLC) transformation are associated with acquired resistance [6]
Our study is the first to present data regarding EGFR-TKI resistance mechanisms and their frequency in a Korean population
Summary
Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Recent advances with targeted therapies, such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), have resulted in marked benefit to subsets of lung cancer patients whose tumors have specific genetic mutations. Amplification of the MET gene has been reported to contribute to resistance in approximately 5–20% of cases [6,7,8] and increased AXL expression was recently discovered to occur in almost 20% of patients [9] phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) mutation, epithelial-to-mesenchymal transition (EMT) and small cell lung cancer (SCLC) transformation are associated with acquired resistance [6]. The aim of this study was to analyze the mechanisms of acquired resistance to EGFR-TKI and its frequency in Korean patients with lung cancer
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