非小细胞肺癌EGFR罕见突变及其靶向与免疫治疗策略

doi:10.3969/j.issn.1009-976X.2021.04.023

摘要/Abstract

摘要： 表皮生长因子受体（EGFR）基因的激活突变包括经典突变和罕见突变。罕见突变病人数量少,不同突变类型对不同的EGFR酪氨酸激酶抑制剂的敏感性差异较大。本文将对各种罕见突变进行系统回顾,总结针对罕见突变的临床前研究和临床研究,为临床治疗决策提供依据。

关键词: 非小细胞肺癌, EGFR突变, 罕见突变, 靶向治疗, 免疫治疗

Abstract: Two types of activation mutations were found in epidermal growth factor receptor （EGFR）： classical mutation and rare mutation, with diverse response to EGFR-TKI treatment or immuno-therapy. It was systemically reviewed the pre-clinical and clinical studies on rare mutations of EGFR of non-small cell lung cancer in this paper.

Key words: non-small cell lung cancer, EGFR mutation, rare mutation, targeted therapy, immunetherapy

中图分类号:

R734.2

冯惠仪, 吴明玮. 非小细胞肺癌EGFR罕见突变及其靶向与免疫治疗策略[J]. 岭南现代临床外科, 2021, 21(04): 482-488.

FENG Hui-yi, WU Ming-wei. Targeted therapy and immuno-therapy of non-small cell lung cancer harboring rare mutation in EGFR[J]. Lingnan Modern Clinics In Surgery, 2021, 21(04): 482-488.

参考文献

[1] D′Angelo SP, Pietanza MC, Johnson ML, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas[J]. J Clin Oncol, 2011, 29(15): 2066-2070.
[2] Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma[J]. Nature, 2014, 511(7511): 543-550.
[3] Shi Y, Au JS, Thongprasert S, et al.A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol,2014, 9(2): 154-162.
[4] Gazdar AF.Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors[J]. Oncogene, 2009, 28(Suppl 1): S24-31.
[5] Kobayashi Y, Mitsudomi T.Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy[J]. Cancer Sci, 2016, 107(9): 1179-1186.
[6] Heigener DF, Schumann C, Sebastian M, et al.Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors[J]. Oncologist, 2015, 20(10): 1167-1174.
[7] Kobayashi Y, Togashi Y, Yatabe Y, et al.EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs[J]. Clin Cancer Res, 2015, 21(23):5305-5313.
[8] Chiu CH, Yang CT, Shih JY, et al.Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations[J]. J Thorac Oncol, 2015, 10(5):793-799.
[9] Cho JH, Lim SH, An HJ, et al.Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09)[J]. J Clin Oncol,2020, 38(5):488-495.
[10] Yasuda H, Park E, Yun CH, et al. Structural, biochemical,clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer [J]. Sci Transl Med, 2013, 5(216):216ra177.
[11] Oxnard GR, Lo PC, Nishino M, et al.Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions[J]. J Thorac Oncol, 2013, 8(2):179-184.
[12] Robichaux JP, Elamin YY, Tan Z, et al.Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer[J]. Nat Med, 2018, 24(5):638-646.
[13] Robichaux JP, Elamin YY, Tan Z, et al.Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer[J]. Nat Med, 2018, 24(5):638-646.
[14] Banno E, Togashi Y, Nakamura Y, et al.Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor?[J]. Cancer Sci, 2016, 107(8):1134-1140.
[15] Leventakos K, Kipp BR, Rumilla KM, et al.S768I Mutation in EGFR in Patients with Lung Cancer[J]. J Thorac Oncol, 2016, 11(10):1798-1801.
[16] Yun CH, Boggon TJ, Li Y, et al.Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity[J]. Cancer Cell, 2007, 11(3):217-227.
[17] Roengvoraphoj M, Tsongalis GJ, Dragnev KH, et al.Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: Focus on epidermal growth factor receptor mutation testing and mutation-positive patients[J]. Cancer Treat Rev, 2013, 39(8): 839-850.
[18] Sharma N, Graziano S.Overview of the LUX-Lung clinical trial program of afatinib for non-small cell lung cancer[J]. Cancer Treat Rev, 2018, 69: 143-151.
[19] Wang J, Li X, Xue X, et al.Clinical outcomes of EGFR kinase domain duplication to targeted therapies in NSCLC[J]. Int J Cancer, 2019, 144(11): 2677-2682.
[20] Costa DB.Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements[J]. Transl Lung Cancer Res, 2016, 5(3): 331-337.
[21] Gallant JN, Sheehan JH, Shaver TM, et al.EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib[J]. Cancer Discov, 2015, 5(11):1155-1163.
[22] Baik CS, Wu D, Smith C, et al.Durable Response to Tyrosine Kinase Inhibitor Therapy in a Lung Cancer Patient Harboring Epidermal Growth Factor Receptor Tandem Kinase Domain Duplication[J]. J Thorac Oncol, 2015, 10(10):e97-99.
[23] Liu Y, Wu BQ, Zhong HH, et al.Screening for EGFR and KRAS mutations in non-small cell lung carcinomas using DNA extraction by hydrothermal pressure coupled with PCR-based direct sequencing[J]. Int J Clin Exp Pathol, 2013, 6(9):1880-1889.
[24] Peng L, Song ZG, Jiao SC.Efficacy analysis of tyrosine kinase inhibitors on rare non-small cell lung cancer patients harboring complex EGFR mutations[J]. Sci Rep, 2014, 4:6104.
[25] Kohsaka S, Nagano M, Ueno T, et al. A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer [J]. Sci Transl Med, 2017, 9(416):eaan6566.
[26] Xu J, Jin B, Chu T, et al.EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China[J]. Lung Cancer, 2016, 96:87-92.
[27] Baek JH, Sun JM, Min YJ, et al.Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer except both exon 19 deletion and exon 21 L858R: a retrospective analysis in Korea[J]. Lung Cancer, 2015, 87(2):148-154.
[28] Yoshida H, Kim YH, Ozasa H, et al.Nivolumab in non-small-cell lung cancer with EGFR mutation[J]. Ann Oncol, 2018, 29(3):777-778.
[29] Yamada T, Hirai S, Katayama Y, et al.Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer[J]. Cancer Med, 2019, 8(4): 1521-1529.
[30] Taniguchi Y, Takeda M, Tamiya A, et al.Programmed death-ligand 1 expression in uncommon epidermal growth factor receptor mutation-positive non-small-cell lung cancer[J]. Ann Oncol, 2018, 29(11): 2262-2263.
[31] Gettinger S, Horn L, Jackman D, et al.Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: Results From the CA209-003 Study[J]. J Clin Oncol, 2018, 36(17):1675-1684.
[32] Dominguez C, Tsang KY, Palena C.Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies[J]. Cell Death Dis, 2016, 7(9):e2380.
[33] Moya-Horno I, Viteri S, Karachaliou N, Rosell R.Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC)[J]. Ther Adv Med Oncol, 2018, 10:1758834017745012.
[34] Ahn MJ, Sun JM, Lee SH, et al.EGFR TKI combination with immunotherapy in non-small cell lung cancer[J]. Expert Opin Drug Saf, 2017, 16(4): 465-469.