Detection and Clinical Significance of Intratumoral EGFR Mutational Heterogeneity in Chinese Patients with Advanced Non-Small Cell Lung Cancer

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.

High concordance of ALK rearrangement between primary tumor and paired metastatic lymph node in patients with lung adenocarcinoma

“…and poses a significant challenge to personalized cancer medicine. It was reported that activating EGFR mutations were found to display intratumor heterogeneity and spatial discordance in 6.3-30% of cases in lung cancer (25,26). However, intratumor heterogeneity of ALK rearrangement was rarely evaluated.…”

Comparison of Epidermal Growth Factor Receptor Mutations between Primary Tumors and Lymph Nodes in Non-small Cell Lung Cancer: a Review and Meta-analysis of Published Data

“…However, some studies have shown that the heterogeneous distribution of EGFR mutations is extremely rare (Yatabe et al, 2011). A combination of EGFR-mutated and wild-type cells was detected with DHPLC and ARMS by Hua (Bai et al, 2013), who reported that approximately 30% Chinese patients with advanced NSCLC presented intratumoral EGFR mutational heterogeneity, indicating a difference in the frequency of EGFR mutation between the two ethnic groups. Of course, a more sensitive method for detecting EGFR mutations is needed.…”

Analysis of EGFR mutation status in tissue and plasma for predicting response to EGFR-TKIs in advanced non-small-cell lung cancer

“…Due to therapeutic selective pressure, mutated cellular clones could proliferate and release ctDNA into the peripheral blood, resulting in positive detection of EGFR mutations in plasma DNA. In addition, tumor tissue heterogeneity may result in missed detection of EGFR mutations in some tumor samples (23), which can be supplemented by ctDNA from a different region of the tumor.…”