摘要
目的:分析BRCA1/2基因在驱动基因阴性Ⅲ/Ⅳ期非小细胞肺癌(non-small cell lung cancer, NSCLC)中的突变频率、突变类型及与含铂化疗疗效的关系。方法:选择2018年5月至2021年9月在陆军(第三)军医大学第二附属医院呼吸与危重症医学中心、重庆大学附属涪陵医院呼吸与危重症医学中心、重庆医科大学附属第三医院呼吸与危重症医学中心诊治且肺癌驱动基因阴性，一线接受含铂双药化疗的Ⅲ~Ⅳ期NSCLC患者101例。采集肿瘤组织或血液标本，采用二代测序(next-generation sequencing, NGS)检测BRCA1/2基因突变。按RECIST1.1标准评估疗效，主要终点客观缓解率(ORR)、无进展生存期(PFS)，次要终点疾病控制率(DCR)、总生存期(OS)。分析BRCA1/2基因突变与含铂化疗疗效的关系。结果:驱动基因阴性Ⅲ/Ⅳ期NSCLC 101例中19例(18.8%)BRCA1/2基因突变。BRCA1/2基因突变类型包括单核苷酸多态性、插入、缺失。突变模式有错义突变、无义突变、框内插入、移码缺失、移码插入。BRCA1/2基因突变组和BRCA1/2基因野生型组在人口学基线特征上无统计学差异。经4~6个周期标准一线含铂双药化疗治疗后，与BRCA1/2野生型组相比，BRCA1/2基因突变组ORR(68.4% vs. 36.6%，P＝0.019)和DCR(100% vs. 76.8%，P＝0.020)佳，中位无进展生存期(mPFS)显著延长(8.0个月vs. 4.6个月，P＝0.009)，中位总生存期(mOS)有延长趋势(19.4个月vs. 16.4个月，P＝0.631)。BRCA1基因突变组与BRCA2基因突变组ORR( 66.7% vs. 64.3%，P＝0.567)、PFS(13.7个月vs. 7.8个月，P＝0.145)和OS(24.0个月vs. 14.4个月，P＝0.142)无统计学差异。结论:BRCA1/2基因突变在驱动基因阴性Ⅲ/Ⅳ期NSCLC中的突变频率约18.8%。BRCA1/2基因突变最常见类型是单核苷酸多态性，最常见突变模式是错义突变。伴有BRCA1/2基因突变的驱动基因阴性Ⅲ/Ⅳ期NSCLC可能更易从一线含铂双药化疗中获益。
Abstract
Objective:To explore the BRCA1/2 gene mutation frequency, the mutation types and the relationship between RCA1/2 gene mutation and efficacy of platinum-base chemotherapy in driver mutation-negative stage Ⅲ/Ⅳ non-small cell lung cancer.Methods:All of 101patients with driver mutation-negative stage Ⅲ/Ⅳ NSCLC who were initially diagnosed and received platinum containing dual drug chemotherapy at the Respiratory and Critical Care Medical Center of the Second Affiliated Hospital Army Medical University, Fuling Hospital Affiliated to Chongqing University, Third Affiliated Hospital of Chongqing Medical University. BRCA1/2 gene mutations in tumor tissue/blood samples were detcted by Next Generation Sequencing (NGS). The treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The primary endpoint was ORR, PFS, The secondary endpoints DCR, OS. The relationships between BRCA1/2 gene mutations and the efficacy of platinum containing chemotherapy were analyzed by medical statistics.Results:All of 101 driver mutation-negative stage Ⅲ/Ⅳ NSCLC patients were enrolled in this study. 19(18.8%) of 101 patients had BRCA1/2 gene mutations. The mutation types of BRCA1/2 include single nucleotide polymorphism, insertion and deletion; The mutation pattern include missense mutation, nonsense mutation, inframe insertion, frameshift deletion, and frameshift insertion. BRCA1/2 gene mutation group and BRCA1/2 gene wild-type group was no statistical difference in demographic baseline characteristics. After receiving 4-6 cycles of standard first-line platinum-base dual drug chemotherapy, the objective response rate (ORR 68.4% vs. 36.6%, P=0.019) and disease control rate (DCR 100% vs. 76.8%, P=0.020) of the BRCA1/2 gene mutation group was significantly higher than that of the BRCA1/2 gene wild type group. In contrast to the BRCA1/2 gene wild type group, the BRCA1/2 gene mutation group has longer median PFS(mPFS, 8.0 months vs. 4.6 months, P=0.009, HR 0.537, 95%CI: 0.351-0.821), while the median OS(mOS)just has lengthen tendency but no significantly different (19.4 months vs. 16.4 months, P=0.631, HR 0.866, 95%CI 0.491-1.528). In the subgroups of BRCA1 and BRCA2 gene mutations, there was no statistically significant difference in ORR (66.7% vs. 64.3%, P=0.567), PFS (13.7 months vs. 7.8 months, P=0.145) and OS (24.0 months vs. 14.4 months, P=0.142).Conclusions:BRCA1/2 gene mutations frequency is about 18.8% in driver mutation-negative stage Ⅲ/Ⅳ NSCLC. The most common mutation types of BRCA1/2 gene is single nucleotide polymorphism and the most common mutation pattern is missense mutation. Driver mutation-negative stage Ⅲ/Ⅳ NSCLC patients with BRCA1/2 gene mutations may be more easy benefit from first-line platinum containing dual drug chemotherapy.
基金项目
2018年陆军卫生保健专项科研项目(18BJZ02)
陆军军医大学第二附属医院(新桥医院)临床研究重点项目(2016YLC02)
陆军军医大学重点支持对象培养项目(2019R025)
万方数据