Analysis Of Prognostic Factors And Establishment Of Prognostic Model In Early Stage Lung Adenocarcinomas

Objective1)To investigate the prognostic factors in postoperative early stage lung adenocarcinoma;2)To investigate the clinicopathological and genetic features of early stage lung adenocarcinoma with high-risk factors of recurrence;3)To establish a quantified model estimating recurrence-free survival(RFS)in completely lobectomized lung adenocarcinoma and explore the high-risk population that would benefit from postoperative adjuvant chemotherapy(ACT).MethodsPatients who underwent surgery with diagnosis of early stage lung adenocarcinoma were retrospectively reviewed.Clinicopathological characteristics were collected and regular follow-up was performed.Second-generation sequencing technology was applied to test the genetic alterations of 68 genes.Pearson’s χ2 and Wilcoxon-Mann-Whitney test were used to compare the differences of continuous and categorical data among groups.Survival analysis was performed using Kaplan-Meier’s,Cox regression analysis,and competitive risk model analysis.Frequency of genetic alteration was compared by Fisher’s exact test.The nomogram predictive model was established based on the Cox regression results.Predictive ability of the model was evaluated by C-index and calibration curve.A smooth curve based on restricted cubic spline was used to exhibit the relationship between risk score and recurrence.The optimal cut-off point of the risk score was determined by X-tile analysis.Statistical significance was defined as P < 0.05.All statistical analyses were performed using SPSS24.0 software(SPSS Inc.,Chicago,IL,USA),R software(version 3.3.1),and Stata 14.0 software.Results:1)A total of 4606 completely lobectomized patients with pathological stage I lung adenocarcinoma were included.The mean age was 59.3±9.3years.The number of patients with stage IA and IB was 3192(69.3%)and1414(30.7%),respectively.The median follow-up was 40.4(2.6-107.0)months,with an average RFS of 89.4±0.6 months.The average RFS for stage IA and IB patients was 92.7±0.8 and 79.9±1.0 months,respectively.44.5% of patients had at least one high-risk factor.The proportion of patients with one,two,three,and four high-risk factors was 63.3%,29.8%,6.4% and0.4%,respectively.The most frequently observed combination pattern was solid/micropapillary subtype(98.3%)with poor differentiation,visceral pleural invasion(VPI)(43.8%)with poor differentiation,lymphovascular invasion(LVI)(53.6%)with poor differentiation,and LVI(36.6%)with VPI.A decreased RFS and overall survival(OS)was observed in patients with greater number of high-risk factors.The average PFS in patients without risk factors,with 1,2,3 and 4 risk factors was 93.91±0.72 m,84.57±1.01 m,71.39±1.80 m,64.69±4.12 m and 62.36±15.40 m,respectively(log-rank P< 0.0001).Patients with VPI can be subdivided into costal,interlobular pleural and mediastinal side according to the position of pleural invasion,with a 5-year RFS rate of 85.2%,79.6% and 54.2,respectively.The RFS was significantly shorter in patients with mediastinal VPI compared with those with costal or interlobular VPI.2)Early stage lung adenocarcinoma patients with genetic alterations(n=384)were included in the analysis,with 263 cases(68.4%)in stage I,20cases(5.2%)in stage Ⅱ,and 54 cases(14.1%)in stage Ⅲ.EGFR(70.6%),TP53(29.2%),ERBB2(8.1%),KRAS(7.0%),and RB1(5.2%)mutations were commonly seen.Patients with stage Ⅱ/Ⅲ were more likely to harbor AR,ERBB3,ROS1,and TP53 gene mutations while EGFR mutation was more commonly seen in stage I patients.Patients with solid/micropapillary pathological subtype had more genetic mutations in BRAF,CDK4,KRAS,NF1,NTRK2,and TP53.EGFR mutation was more frequently seen in patients with acinar/papillary subtypes.Patients with variant subtype had more KRAS mutation.Patients with VPI had a higher frequency in mutations of BRAF,PIK3 A,and SMAD4 genes than those without VPI.3)The 3-and 5-year RFS rates of patients with stage I lung adenocarcinoma were 91.0% and 83.6%,respectively.Age,gender,tumor size,pathological subtype,VPI,and LVI were independent prognostic factors affecting RFS.The established nomogram had a better predictive power for RFS than the 8th edition of TNM staging [C-index: 0.784(95%CI: 0.756-0.812)vs 0.719(95% CI: 0.689-0.749),P = 0.0017].Patients with a risk score of ≥245 were at high-risk of recurrence.Postoperative adjuvant chemotherapy improved RFS(P=0.0416)and disease-free survival(DFS)(P=0.0467)for patients with high-risk of recurrence.Conclusion1)The high-risk factor of postoperative recurrence in stage I lung adenocarcinoma were interrelated.A shorter RFS and OS was observed with the increased number of risk factors.2)Genetic alterations differed in lung adenocarcinoma with different stage.Stage I patients were more likely to harbor EGFR mutation while stage Ⅱ/Ⅲ patients were more likely to have mutations in AR,ERBB3,ROS1,and TP53.3)Patients with different pathological subtypes had distinctive genetic characteristics.Patients with solid/micropapillary subtype had more BRAF,CDK4,KRAS,NF1,NTRK2 and TP53 mutations.EGFR mutation was more frequently seen in patients with acinar/papillary subtype.KRAS mutations are more common in patients with variant subtype.4)For patients with stage I lung adenocarcinoma,those with mediastinal VPI were more likely to recur.BRAF,PIK3 A,and SMAD4 genetic mutations were related with VPI.5)Postoperative stage I adenocarcinoma patients with risk score of ≥245 were at high-risk of recurrence.ACT improved RFS and DFS in this high-risk population.