Abstract
PurposeThis study evaluated occurrence and potential clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with non-small cell lung cancer (NSCLC).Materials and MethodsEighty-five stage IIIa-IV NSCLC patients who had undergone palliative surgical resection were included in this study. Of these, 45 patients carried EGFR mutations (group-M) and 40 patients were wild-type (group-W). Each tumor sample was microdissected to yield 28–34 tumor foci and Intratumoral EGFR mutation were determined using Denaturing High Performance Liquid Chromatography (DHPLC) and Amplification Refractory Mutation System (ARMS). EGFR copy numbers were measured using fluorescence in situ hybridization (FISH).ResultsMicrodissection yielded 1,431 tumor foci from EGFR mutant patients (group-M) and 1,238 foci from wild-type patients (group-W). The EGFR mutant frequencies in group-M were 80.6% (1,154/1,431) and 87.1% (1,247/1,431) using DHPLC and ARMS, respectively. A combination of EGFR-mutated and wild-type cells was detected in 32.9% (28/85) of samples by DHPLC and 28.2% (24/85) by ARMS, supporting the occurrence of intratumoral heterogeneity. Thirty-one patients (36.5%) were identified as EGFR FISH-positive. Patients harboring intratumoral mutational heterogeneity possessed lower EGFR copy numbers than those tumors contained mutant cells alone (16.7% vs. 71.0%, P<0.05). Among 26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher in patients showing partial response (86.1%) or stable disease (48.7%) compared with patients experiencing progressive disease (6.0%) (P = 0.001). There also showed relationship between progression-free survival (PFS) and different content of EGFR mutation groups (pure wild type EGFR, EGFR mutation with heterogeneity and pure mutated EGFR) (P = 0.001).ConclusionApproximately 30% of patients presented intratumoral EGFR mutational heterogeneity, accompanying with relatively low EGFR copy number. EGFR mutant content was correlated with the response and prognosis of EGFR-TKIs.
Highlights
Epithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib had been applied broadly to the treatment of non-small cell lung cancer (NSCLC)
A combination of EGFR-mutated and wild-type cells was detected in 32.9% (28/85) of samples by Denaturing High Performance Liquid Chromatography (DHPLC) and 28.2% (24/85) by Amplification Refractory Mutation System (ARMS), supporting the occurrence of intratumoral heterogeneity
Among 26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher in patients showing partial response (86.1%) or stable disease (48.7%) compared with patients experiencing progressive disease (6.0%) (P = 0.001)
Summary
Epithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib had been applied broadly to the treatment of non-small cell lung cancer (NSCLC). Several reports have suggested that patients treated with EGFRTKIs exhibit improved treatment efficacy and survival times when they carry activating mutations in EGFR [1,2,3,4,5,6]. There exist EGFR-mutated NSCLC patients who exhibit poor responses to EGFR-TKIs or who relapse following a period of disease control, suggesting that there are additional factors mediating the response to EGFR-TKIs. Secondary mutation (T790M) in exon 20 of EGFR as well as other genetic aberrances of EGFR related bypass and downstream pathways, such as, C-MET amplification [8,9,10], IGF-1R mutation [11] had been identified relative to TKIs drug resistance. Intratumoral heterogeneity of EGFR mutations has garnered attention as a potential source of treatment failure and drug resistance to EGFR-TKIs [12,13]
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