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《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2023年05期

页码:

615-623

栏目:

论著

出版日期:

2023-10-20

文章信息/Info

Title:

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

作者:

吴天秀¹; 徐 瑜¹; 廖秀清²; 姚 伟³; 王关嵩¹; 杨 昱¹; 王 斌¹; 郭 亮¹; 张明周¹; 吴国明¹; 罗 莉¹; 白 莉¹; 王 彦¹; 胡明冬¹; 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¹
408099 重庆,重庆大学附属涪陵医院呼吸与危重症医学中心²
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³

Author(s):

Wu Tianxiu¹;  Xu Yu¹;  Liao Xiuqing²;  Yao Wei³;  Wang Guansong¹;  Yang Yu¹;  Wang Bin¹;  Guo Liang¹;  Zhang Mingzhou¹;  Wu Guoming¹;  Luo Li¹;  Bai Li¹;  Wang Yan¹;  Hu Mingdong¹;  Xu Zhi¹.

¹Center for Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Army Military Medical University, Chongqing 400037, China; ²Center of Respiratory and Critical Care Medicine, Fuling Hospital Affiliated to Chongqing University, Chongqing 408099, China; ³Center of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China

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

Keywords:

DNA damage repair gene;  BRCA1/2 gene;  Driver mutation-negative;  Non-small cell lung cancer;  Platinum chemotherapy

分类号:

R734.2

DOI:

10.3877/cma.j.issn.1674-6902.2023.05.003

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.

参考文献/References:

1 Nasser Hanna, David Johnson, Sarah Temin, et al. Systemic therapy for stage Ⅳ non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update Summary[J]. J Oncol Pract, 2017, 13(12): 832-837.
2 Planchard D, Popat S, Kerr K, et al. Correction to: “Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”[J]. Ann Oncol, 2019, 30(5): 863-870.
3 Kathryn C Arbour, Gregory J Riely. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: A review[J]. JAMA, 2019, 322(8): 764-774.
4 Basel Abdelazeem, Kirellos Said Abbas, Fatma Labieb, et al. The role of immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for advanced non-small cell lung cancer: an updated systematic review and meta-analysis of randomized controlled trials[J]. Expert Rev Anticancer Ther, 2022, 22(10): 1127-1140.
5 Eugenia Cella, Lodovica Zullo, Silvia Marconi, et al. Immunotherapy-chemotherapy combinations for non-small cell lung cancer: current trends and future perspectives[J]. Expert Opin Biol Ther, 2022, 22(10): 1259-1273.
6 Griesinger F, Korol EE, Kayaniyil S, et al. Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: A meta-analysis[J]. Lung Cancer, 2019, 135: 196-204.
7 Narjust Duma, Rafael Santana-Davila, Julian R Molina. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment[J]. Mayo Clin Proc, 2019, 94(8): 1623-1640.
8 重庆市医学会肿瘤学分会化疗学组. 肺癌化疗原则专家共识[J]. 中国医院用药评价与分析, 2022, 22(12): 1428-1438.
9 Robert Pirker. Chemotherapy remains a cornerstone in the treatment of nonsmall cell lung cancer[J]. Curr Opin Oncol, 2020, 32(1): 63-67.
10 Theo AK, Wang LH, Michael TZ, et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas[J]. Cell Rep, 2018, 23(1): 239-254.
11 Chai Y, Chen YJ, Zhang D, et al. Homologous recombination deficiency(HRD) and BRCA 1/2 gene mutation for predicting the effect of platinum-based neoadjuvant chemotherapy of early-stage triple-negative breast cancer(TNBC): A systematic review and Meta-analysis[J]. J Pers Med, 2022, 12(2): 323.
12 Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group[J]. J Clin Oncol, 2012, 30: 2654-2663.
13 Mark MP, Sandor S, Li Jia, et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer[J]. Cancer, 2017, 123(18): 3532-3539.
14 Teo MY, Seier K, Ostrovnaya I, et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers[J]. J Clin Oncol, 2018, 36: 1685-1694.
15 Biagio R, Gonzalo R, Liam FS, et al. Impact of DNA damage response and repair(DDR)gene mutations on efficacy of PD-(L)1 immune checkpoint inhibition in non-small cell lung cancer[J]. Clin Cancer Res, 2020, 26(15): 4135-4142.
16 Xingsheng Hu, Dongyong Yang, Yalun Li, et al. Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non-small cell lung cancer patients[J]. Cancer Biol Med, 2019, 16(3): 556-564.
17 Linlin Zhang, Shasha Guan, Fanlu Meng, et al. Next-generation sequencing of homologous recombination genes could predict efficacy of platinum-based chemotherapy in non-small cell lung cancer[J]. Front Oncol, 2022, 12: 1035808.
18 Bokang Yan, Bin Xie, Meiyuan Huang, et al. Mutations and expressions of breast cancer 1/2 in lung cancer[J]. Thorac Cancer, 2023, 14(18): 1753-1763.
19 Xianqi Gao, Xiyan Nan, Yilan Liu, et al. Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients[J]. Hum Mutat, 2020, 41(3): 696-708.
20 Peter MS, Rachel Palmieri Weber, Edwin SI, et al. A cross-cancer genetic association analysis of the DNA repair and DNA damage signaling pathways for lung, ovary, prostate, breast, and colorectal cancer[J]. Cancer Epidemiol Biomarkers Prev, 2016, 25(1): 193-200.
21 Dasari S, Bernard TP. Cisplatin in cancer therapy: molecular mechanisms of action[J]. Eur J Pharmacol, 2014, 740: 364-378.
22 Zeng C, Fan WD, Zhang XQ. RRMI expression is associated with the outcome of gemcitabine-based treatment of non-small cell lung cancer patients-a short report[J]. Cell Oncol, 2015, 38(4): 319-325.
23 Shane O'Grady, Stephen P Finn, Sinead Cuffe, et al. The role of DNA repair pathways in cisplatin resistant lung cancer[J]. Cancer Treat Rev, 2014, 40(10): 1161-1170.
24 Dilruba S, Kalayda GV. Platinum-based drugs: past, present and future[J]. Cancer Chemother Pharmacol, 2016, 77(6): 1103-1124.
25 Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas[J]. Clin Cancer Res an Off J Am Assoc Cancer Res, 2014, 20(3): 764-775.
26 Kadouri L, Rottenberg Y, Zick A, et al. Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization[J]. Lung Cancer, 2019, 137: 48-51.
27 Owen DH, Williams TM, Bertino EM, et al. Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer[J]. Lung Cancer, 2019, 134: 167-173.
28 Diossy M, Sztupinszki Z, Borcsok J, et al. A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures[J]. NPJ Precis Oncol, 2021, 5(1): 55.

备注/Memo

备注/Memo:

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)
通信作者: 徐 智, Email: xu_zhi999@163.com

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更新日期/Last Update: 2023-10-20