Heterogeneity Of EGFR Mutation/ALK Fusion In 97 Cases Of Synchronous Multifocal Lung Adenocarcinomas

Objective Through the adequate detection of the driving genes EGFR and EML4-ALK in patients with synchronous multifocal lung adenocarcinoma,we aim to investigate the heterogeneity of EGFRmutations/ALK fusions and provide strong evidence for accurate treatment of patients with multifocal lung adenocarcinomas..Methods A total of 1059 patients with lung adenocarcinoma who underwent surgical resection were collected,and patients with pathologically confirmed adenocarcinoma of the lung with at least 2 lesions were enrolled.The status of EGFR mutation and ALK fusion in each of the lesions was identified by ARMS-PCR and IHC/FISH detection platforms.Unifocal cases were simultaneously tested for EGFRmutation/ALK fusion status and participated in the study as a control group.Follow-up was performed on cases in which EGFR mutations and ALK fusion occurred simultaneously.Results A total of 97 patients with multifocal lung adenocarcinoma were screened in 1059 patients with lung adenocarcinoma.Among them,the proportion of EGFR mutation or EML4-ALK fusion in at least one tumor was 62.89%(61/97).and 14.43%(14/97).The ratio of EGFR and EML4-ALK co-alteration was 4.12%(4/97).In 962 patients with unifocal lung adenocarcinoma,EGFR mutation,EML4-ALK fusion and EGFR/ALK co-alteration respectively were 59.25%(570/962),6.44%(62/962),and 0.83%(8/962).Obviously,compared with unifocal lung adenocarcinoma,EML4-ALK fusion has a higher expression rate in multifocal lung adenocarcinoma(14.43% vs 6.44%,P=0.004),while EGFR mutation was no significant difference(62.89% vs 59.25%,P=0.487).At the same time,we were surprised to find that the incidence of EGFR/ALK co-alteration in synchronous multifocal lung adenocarcinoma was much higher than that in patients with unifocal lung adenocarcinoma(4.12% vs 0.83%,P=0.008).In addition,the inconsistent rates of EGFR/ALK expression in different lesions of multifocal lung adenocarcinoma were 65.57%(40/61)and 21.43%(3/14),respectively.Four patients with multifocal lung adenocarcinoma with simultaneous EGFR/ALK co-alternation were followed up and showed different disease-free survival.Conclusion The synchronous multifocal lung adenocarcinomas showed stronger oncogene-driven heterogeneity.Multifocal lesions require extensive driver mutation profiling and pathological evaluation,which have a profound influence on diagnostic and therapeutic strategies.