| Objective:Some EGFR-positive advanced NSCLC patients show poor efficacy or primary resistance to EGFR-TKI,and previous studies have shown that concurrent genetic alterations may play an important role in predicting the efficacy and response to EGFR-TKI.The aim of this study was to observe the co-mutation gene profiles of EGFR-positive advanced NSCLC in some regions of China in the real world,and also to analyze the effects of diverse concurrent genetic alterations on the prognosis of targeted therapy in EGFR-positive NSCLC.Methods:The CAPTRA-Lung(NCT03334864)database was used to retrieve 307 patients with advanced EGFR mutant NSCLC with genetic test results between January 1,2018 and January 1,2022 in our hospital,among them,103 patients were sequenced by NGS and the results showed that other concurrent genetic alterations.The basic information of these patients included sex,age,ECOG score,pathological type,clinical stage,distant metastasis,smoking history,family history of tumor,EGFR mutation types,concurrent genetic alterations,first-line treatment and tumor progression,the follow-up deadline was October1,2022.We divided them into two cohorts,where those with NGS test results at baseline were included in cohort 1,and those who received NGS test after progression to first-line therapy were included in cohort 2.The concurrent gene alterations profiles were observed by heatmap using R software version 4.1.2,and the survival curves were plotted by Kaplan-Meier method,the effects of different concurrent genetic alterations on PFS were analyzed by Log-rank test.Cox proportional hazard regression model was used for multivariate analysis to analyze the independent risk factors affecting prognosis.Results:1.Baseline clinical characteristicsIn the whole cohort,most of them were females(n=63;61.2%)and non-smokers(n=69;67.0%),with an average age of 59.52 ± 9.118 years old.92.2% of the patients(95/103)were already in stage IV at the time of diagnosis,the most common metastatic sites at the time of diagnosis were bone(n=39,37.9%),brain(n=21,20.4%)and pleura(n=14,13.6%).The most common subtypes of EGFR mutations were EGFR 19 del mutations(45.6%),followed by 21L858 R point mutations(42.7%),and other patients had EGFR rare mutations or compound mutations.The vast majority of patients(n=94,91.3%)received EGFR-TKI targeted therapy in the first line,of which 57 patients were treated with the first-generation EGFR-TKI,32 patients were treated with the third-generation EGFR-TKI and 5 patients were treated with the second-generation EGFR-TKI.2.Distribution of TP53,KRAS and PIK3 CA mutation subtypes in the whole cohortIn the whole cohort,the most frequency alterations discerned were in the following genes: TP53 mutation(n=64,62.14%),EGFR amplification(n=14,13.59%),KRAS mutation(n=13,12.62%),PIK3 CA mutation(n=13,12.62%)and DNMT3 A mutation(n=13,12.62%).Most TP53 mutations were located in exon 5(16/64),exon 6(9/64),exon7(10/64)and exon 8(9/64);for KRAS mutations,G12V(4/13)and G12S(3/13)were the most common mutations types;E545K(5/13)and H1047R(2/13)were the most common mutation types in PIK3 CA.3.Baseline clinical characteristics and co-mutations predict the survival outcomes of EGFR-TKI in cohort 1Cohort 1 included 68 patients(mean age 60.93 ±9.051 years old;female accounted for 55.9%).Univariate analysis found no the correlation between baseline clinical characteristics and survival outcomes(P>0.05).TP53 mutation was associated with significantly worse PFS(8 versus 10 months;P=0.007).ATM mutation was significantly associated with worse(median PFS,5 versus 9 months;P=0.008).LRP1 B mutation was associated with significantly worse PFS(6 versus 9 months;P=0.011).MET amplification was associated with worse PFS(7 versus 9 months;P=0.038).Multivariate analysis revealed that alterations in TP53(HR: 1.946;95% CI: 1.112–3.403;P=0.020)and MET(HR: 3.581;95% CI: 1.070–11.992;P=0.039)were independently associated with worse PFS.4.Baseline clinical characteristics and co-mutations predict the survival outcomes of EGFR-TKI in cohort 2Cohort 2 included 35 patients(mean age 56.80 ±8.741 years old;female accounted for 71.4%).Univariate analysis found no the correlation between baseline clinical characteristics and survival outcomes(P>0.05).Survival analysis suggested that the TP53 mutation was associated with a trend toward a shorter PFS as compared with wild-type TP53(8 versus 12 months,P=0.029),and RB1 mutation was associated with significantly worse PFS(4 versus 10 months,P=0.001).Multifactorial analysis showed that TP53 mutation(HR: 2.198,95% CI: 1.006-4.803,P=0.048)and RB1 mutation(HR:8.798,95% CI: 1.604-48.269,P=0.012)were independent risk factors for PFS with first-line targeted therapy.Conclusion:1.The study further confirmed that concurrent genetic alterations were associated with the clinical outcomes with advanced NSCLC treated with first-line EGFR-TKI and could predict the efficacy and prognosis of EGFR-TKI.TP53 mutation,MET amplification,and RB1 mutation were independent prognostic risk factors for PFS in EGFR mutant advanced NSCLC treated with first-line targeted therapy.2.Based on the advantage of NGS high-throughput sequencing,more and more co-mutations have been detected.Early large panel NGS sequencing has a certain significance for predicting the efficacy and prognosis of EGFR-TKI. |
