非小细胞肺癌Kras基因突变相关因素及其与一线同步放化疗疗效相关性研究

目的鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,Kras)突变是影响非小细胞肺癌(non-small cell lung cancer,NSCLC)患者化疗及靶向药物治疗疗效的不良预后因素,但Kras基因状态和同步放化疗疗效及预后的关系目前尚不明确。本研究旨在探讨Kras基因突变人群的特征及基因状态与NSCLC患者同步放化疗疗效及预后之间的关系,为NSCLC临床治疗决策提供依据。方法收集2010-01-20-2018-06-30武警河南省总队医院收治的局部晚期NSCLC一线行同期放化疗患者246例临床资料,所有患者均经病理学和影像学确诊。随访至2018-09-30,失访16例,对230例纳入临床研究,ⅢA期77例,ⅢB期153例。一线选择同步放化疗,化疗方案为以铂类为基础的双药联合且同步放化后巩固化疗>2个周期,放疗技术采用三维适形或调强放疗,肿瘤剂量60~65Gy,2.0Gy/次,5次/周;按照实体瘤RECIST 1.1版,治疗前后均采用CT等影像学检查评价疗效,并计算患者的客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)和疾病无进展生存期(progression free surivival,PFS),入组患者治疗前均进行Kras基因状态检测,分析Kras基因状态及特征和同步放化疗临床疗效之间的关系。采用SPSS 20.0对数据进行统计学分析,生存分析采用Kaplan-Meier曲线法,多因素分析比较采用Cox回归法。结果 230例NSCLC患者Kras基因突变发生率有吸烟史者为19.8%(18/91),无吸烟史者为12.2%(17/139),差异有统计学意义,χ~2=6.026,P=0.021;男性为21.2%(25/118),女性为8.9%(10/112),差异有统计学意义,χ~2=6.691,P=0.019。230例患者ORR为81.7%(188/230),DCR为92.6%(213/230),中位PFS为10.6个月。其中Kras突变型患者ORR为82.9%(29/35),DCR为94.3%(33/35),中位PFS为8.2个月;野生型患者ORR为81.5%(159/195),DCR为92.3%(180/195),中位PFS为12.5个月。两者相比在ORR(χ~2=1.272,P=0.261)和DCR(χ~2=1.767,P=0.146),差异均无统计学意义。两者中位PFS相比,Kras野生型患者12.5个月高于突变型患者8.2个月,差异有统计学意义,χ~2=5.613,P=0.037。Cox多因素分析显示,Kras基因状态是影响NSCLC同步放化疗PFS的独立预后影响因子,HR=1.412,95%CI为1.076~1.182,P=0.016。结论 Kras基因突变在吸烟和男性患者中高发,与PFS呈负相关系。Kras基因突变是影响局部晚期NSCLC患者一线同步放、化疗效的不良预后因素。

Efficacy of Kras mutation status on the first-line concurrent chemoradiation in the treatment of non-small cell lung cancer

OBJECTIVE Kirsten rat sarcoma viral oncogene(Kras)was a risk factor for poor prognosis in the chemotherapy and target-treatment of non-small cell lung cancer(NSCLC)patients,the realationship of Kras mutation status and concurrent chemoradiation was uncertainty.The aim of this study was to investigate the mutation feature and efficacy,prognosis of Kras mutation status on the first-line concurrent chemoradiation in the treatment of locally advanced NSCLC,the purpose was to offer the basise for making therapy policy of NSCLC patients.METHODS The clinical data of 230 cases locally advanced non-small cell lung cancer patients who diagnosed by histopathology from 2010-1-20 to 2018-06-30 in the HeNan Amed Police Corps Hospital were collected.Until 2018-09-30,16 patients who were lost to follow-up were excluded,230 Patients were suitable for the study(stageⅢA were 77 cases,stageⅢB were 153 casse).First-line selection was the concurrent radiochemotherapy for NSCLC patients,the therapy was platinum based chemotherapy.The consolidated treatment was to select more than two weeks of chemotherapy after the concurrent radiochemotherapy,the radiation method was to select 3-dimensional conformal radiotherapy or intensity modulated radiation therapy,tumor dose was 60-65 Gy,2.0 Gy/time,5 times/week;According to the standard of Response Evaluation Criteria in Solid Tumors(1.1 edition),the treatment effectiveness evaluation was used by CT or other image examination after or before therapy;the Objective Response Rate(ORR),the Disease Control Rate(DCR)and the Progression Free Surivival(PFS)were calculated,the Kras mutation status of all patients were detected before therapy,to study the realationship between the Kras mutation status and the clinical efficacy of concurrent radiochemotherapy.SPSS 20.0 was used to study statistics data,the Kaplan-Meier was used to study survival rate and the Cox Multiple factors analysis was used.RESULTS All of the 230 patients Kras status were determined,the incidence of Kras mutations with smoking history was 19.8%(18/91),without smoking history was 12.2%(17/139)(χ~2=6.026,P=0.021);in male was 21.2%(25/118),in femal was 8.9%(10/112)(χ~2=6.691,P=0.019);230 patients received first-line concurrent chemoradiation,the ORR was 81.7%(188/230),DCR was 92.6%(213/230),medium-PFS was 10.6 months,and the patients with harboring Kras mutation:ORR was 82.9%(29/35),DCR was 94.3%(33/35),medium-PFS was 8.2 months;the patients with Kras wild-typs:ORR was 81.5%(159/195),DCR was 92.3%(180/195),medium-PFS was 12.5 months,when compared the ORR(χ~2=1.272,P=0.261)and DCR(χ~2=1.767,P=0.146)between various Kras mutations subtypes,there was no statistically significant difference;the medium-PFS in patients with harbored Kras wild-type(12.5 months)was higher than that patients with Kras-activating-mutations(8.2 months),there was statistically significant difference compared the resultants(χ~2=5.613,P=0.037);the resultant of the Cox Multiple factors analysis was that the Kras mutation status was a independent prognostic factors for concurrent radiochemotherapy of NSCLC patients(HR=1.412,95%CI:1.076-1.182,P=0.016).CONCLUSIONS The rate of occurrcnce of Kras mutations was high in the patients with smoking history and male.The relationships was negative factor between Kras mutations and PFS,the Kras mutations was a risk factor and poor prognosis in the first-line concurrent radiochemotherapy of locally advanced non-small cell lung cancer(NSCLC)patients.