Dynamic Monitoring Of Lymphocyte Subpopulation During The EGFR-TKI Therapy For Predicting The Efficacy And Resistance Of EGFR-TKI In EGFR Mutated Lung Cancer Patients

Objective:To evaluate the peripheral blood cytological markers in patients with non-small cell lung cancer(NSCLC)sensitive to epidermal growth factor receptor(EGFR)before and after treatment with EGFR tyrosine kinase inhibitor(EGFR-TKI)Dynamic monitoring to explore the precise therapeutic effect prediction of EGFR-TKIs and the immunological markers of early drug resistance.Methods: Patients with advanced lung adenocarcinoma with EGFR-sensitive mutations in the first-line EGFR-TKI treatment were prospectively included since January 1,2015.Prior to EGFR-TKI treatment,and every 2 months after treatment,10 mL of patient peripheral blood samples were collected.Flow cytometry was used to detect immune lymphocyte subpopulations in peripheral blood.The items included absolute lymphocyte counts,total T cell absolute counts(CD3+),T helper cell absolute counts(CD3+CD4+),and absolute T cell suppression cell counts(CD3).+CD8+),absolute B cell absolute count(CD19+),NK cell absolute count(CD16+CD56+),and CD4+/CD8+(Th/Ts)changes.Patients were enrolled in the following criteria:(1)Patients with relapsed or metastatic NSCLC at the first diagnosis of stage IV or later were diagnosed with lung adenocarcinoma by histopathology;(2)tumor tissue or plasma free DNA(cfDNA)was detected for EGFR E19 del or E21 L858 R mutations.Exclusion criteria:(1)lung cancer patients with unknown tissue types or other non-adenocarcinoma components;(2)other EGFR mutation types or non-sensitive mutation types;(3)patients who have received EGFR-TKI.Follow-up was performed every 2 months.Efficacy was evaluated according to RECIST 1.1 criteria.Progressive disease(PD)was secondary to EGFR-TKI resistance.Univariate and multivariate analyses correlated the correlation between immune-related markers and other clinicopathological factors with first-resistance(ie,PFS)of EGFR-TKI.The difference of each test variable before and after treatment was analyzed by paired t-test,Kaplan-Meier method for univariate survival analysis,PFS comparison by Log-rank test,ROC curve to determine Cut off value,and Cox multivariate regression analysis of each variable for prognosis survival influences Results: As of December 31,2017,20 patients with first-line EGFR-TKI-treated EGFR-sensitive late-stage lung adenocarcinoma were enrolled in the study.The median progression-free survival(mPFS)was 12 months(95% CI: 0.5-23.5)..Of the14 patients who completed the treatment and every 2 months after treatment,dynamic immune cell tests were performed for 12 months(95% CI: 4.1-20.0).Univariate analysis showed EGFR mutation types,absolute CD3+ counts before treatment,changes in CD3+CD4+ before and after treatment(? CD3+CD4+),absolute CD16+CD56+ counts before treatment,absolute CD3+CD8+ counts before treatment,and CD3+CD8+ after treatment Absolute counts and PLT counts before treatment were all associated with PFS(P<0.05).Multivariate analysis showed that EGFR mutation type,absolute CD3+ count before treatment,change of CD3+CD4+ before and after treatment(?CD3+CD4+),absolute count of CD16+CD56+ before treatment,absolute count of CD3+CD8+ before treatment,and count of pre-treatment PLT Patients were associated with PFS(HR values were 0.143,0.809,0.879,1.051,1.15,0.872,respectively).mPFS were E19 del vs E21 L858R: 18.3 months vs 7 months;before treatment CD3+ ? 1080 vs <1080: 17.2 months vs 6.4 months;?CD3+CD4+ ? 78.66% vs <78.66%: 17.2 months vs 8.1 months;treatment Pre-CD16+CD56+?211 vs <211:18.3 months vs 5.2 months;CD3+CD8+?278 vs<278:12 months vs 3 months before treatment;PLT?210*10^9g/L vs <210*10^9g/L before treatment: 13.3 months vs 5.2 months;P values are all less than 0.05.The CD3+ absolute count,changes in CD3+ before and after treatment,CD3+CD8+absolute counts after treatment,and changes in lymphocyte counts before treatment had no significant effect on the early resistance to EGFR-TKI in NSCLC patients.Conclusion: Before treatment,CD3+,CD3+CD4+,CD16+CD56+,CD3+CD8+,and PLT were independent prognostic factors for secondary resistance to EGFR-TKI.Increasing the dynamic detection of these immune lymphocyte subsets in EGFR-sensitive NSCLC patients can better predict the efficacy of EGFR-TKI and the emergence of early drug resistance.We need to expand the sample for further verification.