Objective:To explore the prognostic value of epidermal growth factor receptor (EGFR) co-mutation status in patients with advanced lung adenocarcinoma.Methods:Clinical data of patients with stage ⅢB-Ⅳ lung adenocarcinoma who were first diagnosed in the Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Hebei North University from January 2019 to December 2022 were collected prospectively. Patients were divided into EGFR mutation group ( n=82) and EGFR co-mutation group ( n=74) according to whether EGFR was combined with other gene mutations. The level of circulating tumor DNA (ctDNA) in peripheral blood was measured by real time fluorescence quantitative PCR. Objective response rate (ORR), disease control rate (DCR), the levels of ctDNA in peripheral blood, and progression-free survival (PFS) were compared between two groups of patients before and after 1 month of treatment. The univariate and multivariate analyses were conducted by Cox proportional hazards regression model. Results:In the EGFR mutation group, there were 45 cases of EGFR19 deletion mutation and 37 cases of EGFR21 mutation. In the EGFR co-mutation group, there were 41 cases of EGFR19 deletion mutation, 33 cases of EGFR21 mutation, 46 cases of TP53 mutation, 16 cases of RB1 mutation, 6 cases of PTEN mutation, 2 cases of MET amplification, 1 case of ERBB2 mutation, 1 case of KRAS mutation, 1 case of RET rearrangement, and 1 case of ALK rearrangement. There were statistically significant differences between the EGFR mutation group and the EGFR co-mutation group in the maximum tumor diameter ( χ2=5.04, P=0.025) and stage ( χ2=3.92, P=0.048). The ORRs of the two groups were 64.63% (53/82) and 37.84% (28/74), respectively, with a statistically significant difference ( χ2=11.19, P<0.001). The DCRs were 96.34% (79/82) and 86.49% (64/74), respectively, with a statistically significant difference ( χ2=4.95, P=0.026). The ctDNA levels in the EGFR mutation group and EGFR co-mutation group after one month of treatment decreased compared to before treatment[2.63 (1.83, 3.30) ng/μl vs. 4.73 (3.92, 5.49) ng/μl, Z=-7.06, P<0.001; 4.26 (2.26, 6.07) ng/μl vs. 5.28 (4.37, 6.09) ng/μl, Z=-5.15, P<0.001], the ctDNA levels in the EGFR co-mutation group were higher than those in the EGFR mutation group before treatment and after 1 month of treatment ( Z=-2.47, P=0.013; Z=-4.29, P<0.001). In the EGFR co-mutation group, the ctDNA levels in peripheral blood of patients who were effectively treated with targeted therapy decreased after 1 month of treatment compared to before treatment [(2.03±0.63) ng/μl vs. (3.92±0.82) ng/μl, t=42.94, P<0.001], the levels of ctDNA in peripheral blood of ineffectively treated patients before and after 1 month of treatment were higher than those of effectively treated patients [(5.84±0.57) ng/μl vs. (3.92±0.82) ng/μl, t=-11.91, P<0.001; (5.87±1.64) ng/μl vs. (2.03±0.63) ng/μl, t=-14.43, P<0.001]. The median PFS of the EGFR mutation group and the EGFR co-mutation group of patients were 10.4 and 8.3 months, respectively, with a statistically significant difference ( χ2=22.28, P<0.001). Univariate analysis suggested that the maximum tumor diameter ( HR=0.10, 95% CI: 0.06-0.16, P<0.001), performance status (PS) score ( HR=0.09, 95% CI: 0.06-0.15, P<0.001), stage ( HR=0.09, 95% CI: 0.05-0.14, P<0.001), pre-treatment ctDNA level ( HR=12.04, 95% CI: 8.21-17.65, P<0.001), ctDNA level after 1 month of treatment ( HR=3.75, 95% CI: 3.10-4.54, P<0.001) and EGFR co-mutations ( HR=2.21, 95% CI: 1.57-3.12, P<0.001) were found to be significant factors affecting the PFS of stage ⅢB-Ⅳ lung adenocarcinoma patients receiving targeted therapy; Multivariate analysis demonstrated that PS score ( HR=0.25, 95% CI: 0.14-0.47, P<0.001), stage ( HR=0.49, 95% CI: 0.24-0.98, P=0.044), pre-treatment ctDNA level ( HR=4.73, 95% CI: 3.08-7.28, P<0.001), ctDNA level after 1 month of treatment ( HR=2.15, 95% CI: 1.65-2.80, P<0.001), and EGFR gene co-mutation ( HR=2.26, 95% CI: 1.40-3.64, P<0.001) were independent risk factors for PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients receiving targeted therapy. Conclusion:Both the EGFR mutation group and EGFR co-mutation group show a decrease in ctDNA levels after targeted therapy for one month compared to before treatment. The median PFS of EGFR co-mutation patients is shorter than that of patients with a single EGFR mutation. PS score, stage, ctDNA levels before and after treatment, and EGFR gene co-mutation are all independent factors affecting PFS in stage ⅢB-Ⅳ lung adenocarcinoma patients after targeted therapy.

Objective To explore the value of peripheral blood circulating DNA in predicting the efficacy and prognosis of immunotherapy for advanced non-small cell lung cancer.Method A retrospective study was conducted on 78 NSCLC patients who were admitted to the Respiratory and Critical Care Medicine Department of the First Affiliated Hospital of Hebei North University and were treated with tirelizumab for advanced driver gene negativity from January 2021 to December 2021.After 2 cycles of immunotherapy,the efficacy was evaluated according to the Solid Tumor Efficacy Evaluation Criteria(RECIST 1.1),including complete remission,partial remission,disease stability,and disease progression.CR and PR patients were defined as the experimental group(n=48)Other patients were defined as the control group(n=30),and the ctDNA levels in peripheral blood were measured before and after treatment in both groups.ROC curves were used to analyze the predictive value of periph-eral blood ctDNA levels for achieving objective remission after immunotherapy.All patients were followed up and their progression free survival were calcutated.Using univariate and multivariate regression analysis identified the factors affecting the prognosis of patients after immunotherapy.Using Spearman correlation coefficient analyzed the correlation between ctDNA levels and PFS.Kalplan Meier survival curve were used for survival analysis.Result The peripheral blood ctDNA levels before and after treatment in the experimental group were(4.47±1.21)ng/μL and(2.65±1.14)ng/μL,respectively(t=7.559,P<0.001),while those in the control group were(4.54±1.15)ng/mL and(4.29±1.57)ng/μL,respectively(t=0.699,P=0.487).There was no statistically significant difference in peripheral blood ctDNA levels between the two groups before treatment(t=-0.25,P=0.801).The peripheral blood ctDNA levels in the experimental group decreased compared to the control group after treatment(t=-5.35,P<0.001).The ROC curve analysis showed that the area under the curve for predicting objective remission after immunotherapy based on peripheral blood ctDNA levels was 0.819,with a sensitivity of 81.3%and specificity of 80%.Peripheral blood ctDNA levels were negatively correlated with progression free survival(r=-0.784,P=0.000).Single factor COX regression was used to analyze the clinical and pathological characteristics and ctDNA levels of enrolled patients,and the results showed that the maximum tumor diameter was greater than 5 cm(HR=0.501,95%CI:6.731～35.567)Tumor stage IV(HR=0.392,95%CI:0.227～0.677),treatment approach(HR=15.473,95%CI:6.731～35.567),and ctDNA levels(HR=4.657,95%CI:3.182～6.555)are all influencing factors for PFS in advanced NSCLC patients after immunotherapy.Multiple factor analysis was conducted on the appeal indicators with statistical differences,and the results showed that treatment approach(HR=2.981,95%CI:1.019～8.722)and peripheral blood ctDNA levels(HR=3.918,95%CI:2.619～5.861)It is an independent influencing factor of PFS in advanced NSCLC patients.The Kalplan Meier survival curve was used for analysis,and the results showed that the median PFS of the treatment effective group was 8.4 months,while the median PFS of the control group was 5.4 months.(χ2=49.277,P=0.000).Conclusion Immunotherapy combined with chemotherapy can enhance the ability to kill tumor cells,and peripheral blood ctDNA levels can evaluate the efficacy and prognosis of immunotherapy,which can be used to guide immunotherapy in advanced NSCLC patients.