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中华肺部疾病杂志(电子版)

中华肺部疾病杂志(电子版) ›› 2023, Vol. 16 ›› Issue (05) : 615 -623. doi: 10.3877/cma.j.issn.1674-6902.2023.05.003

论著

驱动基因阴性Ⅲ/Ⅳ期非小细胞肺癌BRCA1/2基因突变与含铂化疗疗效的关系
吴天秀, 徐瑜, 廖秀清, 姚伟, 王关嵩, 杨昱, 王斌, 郭亮, 张明周, 吴国明, 罗莉, 白莉, 王彦, 胡明冬, 徐智†()   
  1. 400037　重庆，陆军（第三）军医大学第二附属医院呼吸与危重症医学中心
    408099　重庆，重庆大学附属涪陵医院呼吸与危重症医学中心
    401120　重庆，重庆医科大学附属第三医院呼吸与危重症医学中心
  • 收稿日期:2023-09-07 出版日期:2023-10-25
  • 通信作者: 徐智
  • 基金资助:
    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)

Relationship between BRCA1/2 gene mutation and efficacy of platinum-base chemotherapy in driver mutation-negative stage Ⅲ/Ⅳ non-small cell lung cancer

Tianxiu Wu, Yu Xu, Xiuqing Liao, Wei Yao, Guansong Wang, Yu Yang, Bin Wang, Liang Guo, Mingzhou Zhang, Guoming Wu, Li Luo, Li Bai, Yan Wang, Mingdong Hu, Zhi Xu†()   

  1. Center for Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Army Military Medical University, Chongqing 400037, China
    Center of Respiratory and Critical Care Medicine, Fuling Hospital Affiliated to Chongqing University, Chongqing 408099, China
    Center of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
  • Received:2023-09-07 Published:2023-10-25
  • Corresponding author: Zhi Xu
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引用本文：

吴天秀, 徐瑜, 廖秀清, 姚伟, 王关嵩, 杨昱, 王斌, 郭亮, 张明周, 吴国明, 罗莉, 白莉, 王彦, 胡明冬, 徐智. 驱动基因阴性Ⅲ/Ⅳ期非小细胞肺癌BRCA1/2基因突变与含铂化疗疗效的关系[J]. 中华肺部疾病杂志(电子版), 2023, 16(05): 615-623.

Tianxiu Wu, Yu Xu, Xiuqing Liao, Wei Yao, Guansong Wang, Yu Yang, Bin Wang, Liang Guo, Mingzhou Zhang, Guoming Wu, Li Luo, Li Bai, Yan Wang, Mingdong Hu, Zhi Xu. Relationship between BRCA1/2 gene mutation and efficacy of platinum-base chemotherapy in driver mutation-negative stage Ⅲ/Ⅳ non-small cell lung cancer[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2023, 16(05): 615-623.

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。

关键词: DNA损伤修复基因, BRCA1/2基因, 驱动基因阴性, 非小细胞肺癌, 铂类化疗
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.

Key words: DNA damage repair gene, BRCA1/2 gene, Driver mutation-negative, Non-small cell lung cancer, Platinum chemotherapy
表1 NSCLC患者基线临床特征[n(%)]
临床特征   BRCA1/2野生型(n＝82) BRCA1/2突变(n＝19) P值 BRCA2(n＝14) BRCA1(n＝6) P值
年龄 ≤60岁 51(62.2) 7(36.8) 0.07 5(35.7) 2(33.3) 0.676
  >60岁 31(37.8) 12(63.2) 0 9(64.3) 4(66.7)  
性别 男 71(86.6) 16(84.2) 0.72 12(85.7) 5(83.3) 0.650
  女 11(13.4) 3(15.8) 4 2(14.3) 1(16.7)  
吸烟史 有 67(81.7) 15(78.9) 0.75 11(78.6) 5(83.3) 0.701
  无 15(18.3) 4(21.1) 2 3(21.4) 1(16.7)  
病理类型 腺癌 38(46.3) 4(21.1) 0.06 3(21.4) 2(33.3) 0.650
  鳞癌 43(52.4) 15(78.9) 9 11(78.6) 4(66.7)  
TNM分期 Ⅲ期 35(42.7) 14(73.7) 0.02 11(78.6) 3(50.0) 0.299
  Ⅳ期 47(57.3) 5(26.3) 1 3(21.4) 3(50.0)  
ECOG评分 0 58(70.7) 9(47.3) 0.06 7(50.0) 2(33.3) 0.642
  1 24(29.3) 10(52.6) 3 7(50.0) 4(66.7)  
化疗方案 培美曲塞＋铂 36(43.9) 2(10.5) 0.00 2(14.3) 0 0.213
  吉西他滨＋铂 2(2.4) 2(10.5) 2 0 2(33.3)  
  紫杉醇类＋铂 41(50.0) 11(57.9)   9(64.3) 3(50.0)  
  多西他赛＋铂 3(3.7) 4(21.1)   3(21.4) 1(16.7)  
图1 19例NSCLC患者BRCA1/2基因突变信息。注：A：突变模式，包括错义突变(Missense Mutation)、无义突变(Nonsense Mutation)、框内插入(In_Frame_Ins)、移码缺失(Frame_Shift_Del)、移码插入(Frame_Shift_Ins)；B：突变类型，包括单核苷酸多态性(SNP)、插入(INS)、缺失(DEL)；C：SNP(点突变)中碱基突变分类和数量；D：19例突变数量与比例，纵坐标为突变数量，不同颜色占比表示不同突变比例；E：错义突变、无义突变、框内插入、移码缺失、移码插入突变数量的箱式图；F：BRCA1的基因突变包括错义突变、无义突变、框内插入、移码缺失4种类型，以错义突变为主，BRCA2基因突变包括错义突变、无义突变、框内插入、移码缺失、移码插入5种类型，以错义突变为主
表2 19例BRCA1/2突变NSCLC患者临床信息、突变位点与类型
编号 年龄(岁) 性别 病理类型 吸烟史 分期 ECOG评分 突变基因 HGVSc HGVSp 突变类型
1 54 男 鳞癌 无 ⅢC期 1 BRCA2 c.323A>G p.Asn108Ser SNP
2 69 女 腺癌 无 ⅣA期 1 BRCA1 c.3247A>G p.Met1083Val SNP
              BRCA1 c.2110_2111del p.Asn704CysfsTer7 DEL
3 58 男 鳞癌 有 ⅢB期 1 BRCA2 c.7380C>A p.Asn2460Lys SNP
4 46 男 鳞癌 有 ⅢB期 0 BRCA2 c.5683G>T p.Glu1895Ter SNP
5 68 男 鳞癌 有 ⅢA期 1 BRCA2 c.6100C>T p.Arg2034Cys SNP
6 61 男 鳞癌 有 ⅢB期 0 BRCA2 c.7070T>C p.Leu2357Pro SNP
7 63 女 腺癌 无 ⅢB期 0 BRCA2 c.8009C>T p.Ser2670Leu SNP
8 54 男 鳞癌 有 ⅢB期 0 BRCA1 c.5418_5419ins p.Leu1807LysfsTer12 INS
9 58 女 腺癌 无 ⅣA期 1 BRCA2 c.6121T>A p.Ser2041Thr SNP
10 51 男 鳞癌 有 ⅣA期 0 BRCA2 c.2808_2811del p.Ala938ProfsTer21 DEL
              BRCA2 c.4741G>A p.Glu1581Lys SNP
11 63 男 鳞癌 有 ⅢB期 1 BRCA1 c.1243G>A p.Val415Ile SNP
12 58 男 鳞癌 有 ⅣA期 1 BRCA1 c.514C>G p.Gln172Glu SNP
13 63 男 鳞癌 有 ⅢC期 0 BRCA2 c.850G>A p.Gly284Arg SNP
              BRCA2 c.9392C>G p.Ser3131Cys SNP
14 62 男 鳞癌 有 ⅢB期 0 BRCA1 c.4249G>A p.Val1417Met SNP
15 67 男 鳞癌 有 ⅢC期 1 BRCA2 c.6422G>A p.Gly2141Asp SNP
16 62 男 鳞癌 有 ⅢC期 0 BRCA2 c.1015G>A p.Asp339Asn SNP
              BRCA2 c.4264G>C p.Glu1422Gln SNP
17 66 男 鳞癌 有 ⅢB期 0 BRCA2 c.580_581insC p.Trp194SerfsTer12 INS
              BRCA2 c.9154C>T p.Arg3052Trp SNP
18 67 男 腺癌 有 ⅣA期 1 BRCA2 c.2191G>T p.Glu731Ter SNP
              BRCA2 c.2196_2197ins p.Glu732_Val733ins INS
              BRCA2 c.3679_3680ins p.Lys1226_Leu1227ins INS
              BRCA2 c.6062A>T p.His2021Leu SNP
              BRCA1 c.1396_1397ins p.Tyr465_Arg466ins INS
19 65 男 鳞癌 有 ⅢB期 1 BRCA2 c.6172T>A p.Phe2058Ile SNP
              BRCA2 c.6926G>A p.Ser2309Asn SNP
图2 PFS森林图。注：PFS多因素Cox比例风险模型森林图，图中圆点是风险比率(HR)值
图3 OS森林图。注：OS多因素Cox比例风险模型森林图，图中圆点是风险比率(HR)值
图4 BRCA1/2基因突变状态与含铂化疗疗效相关性分析。注：A：BRCA1/2突变组客观缓解率68.4%，其中CR1例，PR12例；B：BRCA1/2野生型组客观缓解率36.59%，其中PR30例；C：BRCA1/2基因突变组的客观缓解率(ORR)高于野生型组(P＝0.019)；D：BRCA1/2基因突变组的疾病控制率(DCR)高于与野生型组(P＝0.020)；E：BRCA1/2基因突变组CR1例、PR12例、SD6例、PD0例，ORR68.4%；F：BRCA1/2野生型组CR0例、PR30例、SD33例、PD19例，ORR36.6%；G：BRCA1/2基因突变组与野生型组PFS生存曲线。BRCA1/2基因突变组mPFS＝8.0个月，BRCA1/2基因野生型组mPFS＝4.6个月(P＝0.009)。H：BRCA1/2基因突变组与野生型组OS生存曲线。BRCA1/2基因突变组mOS＝19.4个月，BRCA1/2基因野生型组mOS＝16.4(P＝0.631)
表3 BRCA1/2基因突变状态与含铂化疗疗效[n(%)]
疗效评估(n＝101) BRCA1/2突变(n＝19) BRCA1/2野生型(n＝82) P值
CR＋PR 13/19(68.4) 30/82(36.6) －
SD 6/19(31.6) 33/82(40.2) －
PD 0 19/82(23.2) －
ORR 13/19(68.4) 30/82(36.6) 0.019
DCR 19/19(100) 63/82(76.8) 0.020
中位PFS(月) 8.0 4.6 0.009
中位OS(月) 19.4 16.4 0.631
图5 BRCA1、BRCA2基因含铂双药化疗疗效图。注：A：客观缓解率(ORR)条形图。BRCA1基因组客观缓解率66.7%，其中CR1例，PR3例；BRCA2基因组客观缓解率64.3%，其中PR9例，两组间ORR无显著统计学差异(P＝0.567)。B：BRCA1、BRCA2基因突变肿瘤治疗后主病灶变化最佳长径瀑布图，绿色表示BRCA1基因突变5例，粉红色表示同时有BRCA1、BRCA2基因突变1例，蓝色表示BRCA2基因突变13例。C：BRCA1基因组、BRCA2基因组PFS生存曲线(P＝0.145)。D. BRCA1基因组、BRCA2基因组OS生存曲线(P＝0.142)
表4 BRCA1、BRCA2基因与含铂双药化疗疗效(%)
疗效评估(n＝19) BRCA1/2 BRCA2 BRCA1
CR＋PR 13/19(68.4) 9/14(64.3) 4/6(66.7)
SD 6/19(31.6) 5/14(35.7) 2/6(33.3)
PD 0 0 0
ORR 13/19(68.4) 9/14(64.3) 4/6(66.7)
中位PFS(月) 8.0 7.8 13.7
中位OS(月) 19.4 14.4 24.0
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