The Exploratory Research Of NSCLC With Concomitant EGFR Mutations And ALK Rearrangements

Objective: Epidermal growth factor receptor(EGFR)mutations and anaplastic lymphoma kinase(ALK)rearrangements are two driver alterations and are generally considered mutually exclusive in non-small cell lung cancer(NSCLC).The prevalence of EGFR/ALK co-mutation in patients with NSCLC is low(accounted for 0.1-1.6%according to published studies).The clinicopathological characteristics of these patients are still unclear,and till now the standard treatments are controversial.This retrospective case series study aimed to analyse the clinicopathological characteristics and the efficacy of different targeted therapies to these NSCLC patients with co-mutation of EGFR/ALK.Methods: By searching the hospital information system,we summarized cases of NSCLC harboring both EGFR mutations and ALK rearrangements from Janurary 2014 to Janurary 2019 in the Department of Oncology,the Affiliated Hospital of Qingdao University.The co-mutation cases with detailed clinical information were collected by searching literarure databases of PUBMED,EMBASE and MEDLINE.We explored association between the efficacy of target therapies and possible efficacy relevant factors,such as gender,age,ethnicity,smoking history,clinical stage,central nervous system metastasis and EGFR mutations.The PFS curves were estimated using the Kaplan-Meier product-limit method with the distributions of PFS compared via Log-Rank test.The COX proportional hazard model was used for multivariate analysis.Bioinformatics data used to analyze its possible molecular mechanisms.Results:(1)A total of 93 NSCLC cases with both EGFR mutations and ALK rearrangements were collected in this study,of which 3 ptients were diagnosed in the Department of Oncology,Affiliated Hospital of Qingdao University,and 90 cases were from literature searching.According to our study,the co-mutation tended to occur in female,non-smoker,Asian origin,adenocarcinoma.(2)The survival analysis indicated the objective response ration(ORR)and disease control rate(DCR)of EGFR tyrosine kinase inhibitors(TKIs)and ALK-TKIs as the first targeted therapy was 40.81%,67.35%and 66.67%,83.33%,respectively;ALK-TKIs showed prolonged median PFS(m PFS)than EGFR-TKIs(m PFS: 15.1 vs.7.2 months,HR: 0.48,95% confidence interval(CI):0.24-0.96,P=0.03).Patients with central nervous system(CNS)metastasis significantly associated shorter m PFS(m PFS: 4.00 vs.10.00 months,HR: 3.01,95%CI: 1.07-8.50,P<0.01).And uncommon EGFR mutation was also as a negative factor to prognosis(m PFS: uncommon mutations 3.00 months vs.19 exon deletion 12.00 months,HR: 3.82,95%CI: 0.90-16.17,P<0.01;m PFS uncommon mutations 3.00 months vs.exon 21 L858R11.20 months,HR: 2.73,95%CI: 0.76-9.78,P =0.03)in our study.(3)A correlation analysis based on TCGA database,and found that the correlation coefficients of Pearson and Soearman in the three data sets are all less than 0.1,but the P values are greater than0.05.GCBI database analysis showed both EGFR and ALK signaling pathways could be regulated by transcription factors such as JUN,SOX2,SOX10,FOXO1.We guessed these protein expressions may be potentially associated with co-mutations of EGFR and ALK,and further experimental verification was needed.Conclusion and significance: NSCLC patients both with EGFR mutations and ALK rearrangements recieved ALK-TKIs as the first target therapy showed prolonged m PFS than patients treated with EGFR-TKIs.For patients with both EGFR mutations and ALK rearrangements,ALK-TKIs seemed to associated with better prognosis than EGFR-TKIs in the first treatment option of target therapy.