Demographic Characteristics Of Chinese Lung Adenocarcinoma Patients With EGFR Mutation And Primary Resistant Mechanisms To EGFR-TKIs

BackgroundEpidermal growth factor receptor is one of the most important driving genes of advanced lung cancer.Although there have been severalstudies on EGFR mutation epidemiology,There are mostly small sample size studies or only research on the early or advanced stage.Although several primary resistant mechanisms of first generation epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)that have been reported,most patients with EGFR mutations in clinical practice have no response to EGFR-TKIs treatment but cannot be explained by the resistance mechanism that already reported.Chapterl:Demographic Characteristics of Chinese Lung AdenocarcinomaPatients with EGFR Mutation ObjectiveTo explore the distribution and epidemiological characteristics of EGFR mutation in chinese lung adenocarcinoma patients.MethodsWe retrospectively collected the patients who were diagnosed with adenocarcinoma,treatment naive and received EGFR mutation test from May 2014 to May 2016 in Guangdong General Hospital.All patients were divided into two groups.Early stage group was defined as pathology stage IA to IIIA after surgery and advanced stage group was defined as stage IIIB without chance to receive curative treatment or stage IV by clinical examination.Tumor stage was categorized according to the 7th version American Joint Committee on Cancer Staging Manual.ResultsTotally 1699 patients were enrolledin this study,750 of 1699 patients were enrolled in early-stage group and the other 949 patients in advanced-stage group.In the general population,male was 56.7%and female was 43.3%.Smoker was 45.3%and non-smoker was 54.7%.The EGFR mutation rate was 52.4%,EGFR19deletion(23%),L858R(24.1%),de-novoT790(1.2%),double mutation(0.9%),uncommon mutation(3%).There was same EGFR mutation rate and spectrum in early stage and advanced-stage group(53.6%vs 51.4%,p=0.379).For different EGFR mutation subtypes,there were no significant differences between two groups.EGFRmutation rate range from 32.4%(12/37,stage IIB)to 60.2%(171/284,stage IA).We further explored the EGFR mutation rates in different lymph node metastasis status(N0,N1 and N2),and the EGFR mutation rate was similar in three groups(N0:55.2%,N1:45.5%,N2:44.8%,p=0.391).ConclusionEGFR mutation rate was 52.4%.Comparing to advanced-stage,early staged lung adenocarcinoma patients have similar EGFR mutation frequency and mutant types.There was no significant correlation between EGFR mutation status and lymph node metastasis.Chapter2:Primary resistance to first-generation EGFR-TKIs in NSCLCpatients harbouring sensitive EGFR mutationsObjectiveTo explore the potentialprimary resistant mechanisms of first generationEGFR-TKIsMethodsAdvanced NSCLC patients harbouring the EGFR sensitive mutation,and who received first-generation EGFR-TKIsat Guangdong General Hospital from January 2012 to April 2014,were included in this study.WES was performed on tumor samples and white blood cells from EGFR-TKI primary resistant patients and matched EGFR-TKI-high sensitivity patients with similar clinical characteristics,ResultsIn total of 271 patients enrolled in this study.23 of 273(8.5%)primary resistant patients were enrolled in primary resistance group and another 248 patients enrolled in sensitive group.Based on the similar characteristics,five patients in the resistant group and five patients in the high sensitivity group were enrolled in the WES analysis.The mutation burden of five patients in the resistant group was higher than their matched sensitive patients.The mean number of non-synonymous single nucleotide variations(SNVs)per sample was 195(range:97-348)for the TKI-resistant group versus 84(range:60-101)for the TKI-sensitive group(p=0.059).The resistant group shared a similar abundance to that of the sensitive group(p=0.611)and no T790M mutation was detected.The somatic mutations and copy numbervariations that may be associated with EGFR-TKI resistance including FAT4,RBM10 mutationand KRAS,MET,BRAFamplification.ConclusionIn conclusion,our study suggests that potential primary resistance mechanisms of first-generation EGFR-TKIs are highly heterogeneous.At the macroscopic level,the mutation burden is related to primary resistance.At the molecular level,somatic mutations and copy number variations may be associated with EGFR-TKI primary resistance.More research on larger cohorts is warranted to further explore these potential mechanisms.