行手术切除的肺腺鳞癌患者EGFR、KRAS基因突变情况和预后相关因素分析

Analysis of EGFR and KRAS mutation status and prognosis‐related factors in lung adenosquamous cell carcinoma patients with surgical resection

目的探讨可手术的肺腺鳞癌(LASC)患者的驱动基因突变状态和预后影响因素。方法回顾性病例系列研究。回顾性收集2008年1月至2018年12月在空军军医大学第二附属医院接受手术治疗的LASC患者的临床和病理资料,对患者手术切除标本均进行了表皮生长因子受体(EGFR)和Kirsten大鼠肉瘤(KRAS)基因测序。分析患者驱动基因EGFR、KRAS突变分布情况,比较各临床因素分层患者间基因突变分布差异;用Kaplan-Meier法分析各临床因素分层患者无病生存(DFS),比较采用log-rank检验。结果共纳入106例患者,其中男性64例(60.4%),女性42例(39.6%),年龄(58±10)岁。全组中EGFR、KRAS基因突变患者占38.7%(41/106),其中EGFR突变患者占33.0%(35/106),KRAS突变患者占5.7%(6/106);EGFR突变位点包括19del、L858R、L861Q和20in,KRAS突变位点包括G12A、G12D、G12C和G12V。年龄≤65岁、女性、病变位于左肺下叶、病理成分非鳞状细胞癌为主、吸烟指数<400年支患者中EGFR、KRAS基因突变的可能性大,但差异均无统计学意义(均P>0.05),各TNM分期、T分期、N分期患者间EGFR、KRAS基因突变患者占比差异亦均无统计学意义(均P>0.05)。中位随访51个月(范围:14~96个月)。不同N分期患者间DFS差异有统计学意义(P=0.002),N0期DFS均优于N1、N2、N3期,差异均有统计学意义(均P<0.05),其中N0、N1、N2期中位DFS时间分别为44.4、17.5、23.9个月,N3期仅1例,其DFS时间为8.7个月;而不同TNM分期患者间DFS有存在差异的趋势,但差异无统计学意义(P=0.060);不同病理成分患者间DFS差异无统计学意义(P=0.177);无胸膜侵犯患者DFS有优于有胸膜侵犯患者的趋势,但差异无统计学意义(P=0.252);驱动基因EGFR、KRAS是否突变患者DFS差异无统计学意义(P=0.809),进一步行亚组分析显示,突变患者中不同TNM分期患者DFS差异无统计学意义(P=0.684)。结论早期LASC患者驱动基因EGFR、KRAS突变较常见;DFS与TNM分期和N分期可能相关,但与EGFR、KRAS基因突变状态和病理类型、胸膜是否侵犯可能无关。

Objective To investigate the driver gene mutation status and prognostic influencing factors in patients with operable lung adenosquamous carcinoma(LASC).Methods A retrospective case series study was conducted.Clinical and pathologic data were retrospectively collected from patients with LASC who underwent surgical treatment at the Second Affiliated Hospital of Air Force Military Medical University from January 2008 to December 2018,and the patients'surgically resected specimens were sequenced for epidermal growth factor receptor(EGFR)and Kirsten rat sarcoma(KRAS)genes.The distribution of driver gene EGFR and KRAS mutations in patients was analyzed,and the differences in the distribution of mutations among patients stratified by clinical factors were compared;disease-free survival(DFS)of patients stratified by clinical factors was analyzed by the Kaplan-Meier method,and the comparison between groups was performed by the logrank test.Results A total of 106 patients were included,including 64(60.4%)males and 42(39.6%)females,aged(58±10)years old.Patients with EGFR and KRAS gene mutations accounted for 38.7%(41/106),of which 33.0%(35/106)were patients with EGFR mutations and 5.7%(6/106)were patients with KRAS mutations.The EGFR mutation loci included 19del,L858R,L861Q and 20in,and the KRAS mutation loci included G12A,G12D,G12C and G12V.Patients aged≤65 years old,female,with lesions in the lower lobe of the left lung,non-squamous cell carcinoma as the main pathological component,and with a smoking index of<400 were more likely to have EGFR and KRAS gene mutations,but the differences were not statistically significant(all P>0.05),and there was no statistically significant difference in the proportions of patients with EGFR and KRAS gene mutations among patients with different TNM stages,T stages and N stages(all P>0.05).The median follow-up time was 51 months(range:14-96 months).The difference in DFS among patients with different N stages was statistically significant(P=0.002),and the DFS of N0 stage was better than that of N1,N2 and N3 stages,and the differences were statistically significant(all P<0.05).The median DFS time of N0,N1 and N2 stages was 44.4,17.5 and 23.9 months,respectively,and the median DFS time of N3 stage(1 case)was 8.7 months.Patients with different TNM stages had a tendency to have differences in DFS,but the difference was not statistically significant(P=0.060);the difference in DFS between patients with different pathological components was not statistically significant(P=0.177);patients without pleural invasion had a tendency to have better DFS than patients with pleural invasion,but the difference was not statistically significant(P=0.252).The difference in DFS between patients with and without driver gene EGFR and KRAS mutations was not statistically significant(P=0.809),and further subgroup analysis showed that the difference in DFS among mutated patients with different TNM stages was not statistically significant(P=0.684).Conclusions The driver gene EGFR and KRAS mutations are more common in patients with early LASC;DFS may be related to TNM stage and N stage,but may not be related to the mutation status of EGFR and KRAS genes,the type of pathology,or whether or not the pleura is invaded.