非小细胞肺癌患者外周血表皮生长因子受体T790M检测与奥希替尼疗效的相关性研究
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摘要
[目的]评估非小细胞肺癌患者第一代表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)获得性耐药后外周血EGFR T790M突变的阳性率和用外周血T790M检测结果预测奥希替尼疗效的可靠性。[方法]回顾性分析2017年3月至2018年6月经第一代EGFR-TKI治疗后获得性耐药且使用超级扩增阻滞突变系统(ultraamplification refractory mutation system,Ultra-ARMS)进行外周血EGFR T790M检测的原发性非小细胞肺癌患者。评估血T790M阳性患者使用奥希替尼的疗效。[结果]共有103例符合标准的第一代EGFR-TKI获得性耐药患者,其中28例(27.2%,28/103)血T790M阳性,75例(72.8%,75/103)血T790M阴性。血T790M阳性患者中,接受奥希替尼治疗有23例:部分缓解(partial response,PR) 15例,疾病稳定(stable disease,SD)6例,疾病进展(progression of disease,PD) 2例。疾病控制率(disease control rate,DCR) 91.3%,客观有效率(objective response rate,ORR)65.2%。奥希替尼治疗的中位无进展生存时间(progression free survival,PFS) 12.5个月(95%CI:11.2～13.8)。有9例血T790M阴性患者后续进行了组织检测,3例在组织中检测到T790M突变。有6例血T790M阴性的患者虽未再行组织检测,但要求试用奥希替尼靶向治疗,1例患者获得了PR,1例SD(PFS超过5个月)。[结论]对第一代EGFR-TKI获得性耐药后未能再次行组织活检的非小细胞肺癌患者,Ultra-ARMS方法检测血T790M阳性可预测奥希替尼疗效。血T790M检测阴性的患者建议再次取组织进行T790M检测以排除假阴性。组织检测是T790M检测的金标准,血T790M检测可作为补充。
[Purpose] To detect epidermal growth factor receptor (EGFR) p.Thr790Met point mutation (T790M) in patients with non-small cell lung cancer (NSCLC) and to investigate the correlation between T790M detection and the efficacy of osimertinib. [Methods] One hundred and three NSCLC patients,who developed resistance to first generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) and admitted in Zhejiang Cancer Hospital from March 2017 to June 2018,were enrolled in the study. Plasma EGFR T790M was tested by ultra-amplification refractory mutation system (Ultra-ARMS). The efficacy of osimertinib in T790M-positive NSCLC patients was analyzed. [Results] Among 103 EGFR-TKI resistant NSCLC patients,plasma T790M was positive in 28 cases (27.2%) and negative in 75 cases (72.8%). In23 plasma T790M-positive patients receiving osimertinib treatment,there were partial response (PR) in15 cases,stable disease (SD) in 6 cases and progression of disease (PD) in 2 cases. The disease control rate (DCR) was 91.3%,and the objective response rate (ORR) was 65.2%. The median progression free survival (PFS) of osimertinib was 12.5 (95%CI:11.2～13.8) months. Nine plasma T790M-negative patients were subsequently examined with tissue specimens,and 3 of them were T790M-positive. Six plasma T790M-negative patients without tissue tests were treated with osimertinib,among whom 1achieved PR,and 1 achieved SD (PFS was longer than 5 months). [Conclusion] Plasma T790 M detection can predict the efficacy of osimeritinib in NSCLC patients with first-generation EGFR-TKI resistance. Patients with plasma negative T790 M are suggested to perform tissue T790 M test to exclude false negative results.
[Purpose] To detect epidermal growth factor receptor (EGFR) p.Thr790Met point mutation (T790M) in patients with non-small cell lung cancer (NSCLC) and to investigate the correlation between T790M detection and the efficacy of osimertinib. [Methods] One hundred and three NSCLC patients,who developed resistance to first generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) and admitted in Zhejiang Cancer Hospital from March 2017 to June 2018,were enrolled in the study. Plasma EGFR T790M was tested by ultra-amplification refractory mutation system (Ultra-ARMS). The efficacy of osimertinib in T790M-positive NSCLC patients was analyzed. [Results] Among 103 EGFR-TKI resistant NSCLC patients,plasma T790M was positive in 28 cases (27.2%) and negative in 75 cases (72.8%). In23 plasma T790M-positive patients receiving osimertinib treatment,there were partial response (PR) in15 cases,stable disease (SD) in 6 cases and progression of disease (PD) in 2 cases. The disease control rate (DCR) was 91.3%,and the objective response rate (ORR) was 65.2%. The median progression free survival (PFS) of osimertinib was 12.5 (95%CI:11.2～13.8) months. Nine plasma T790M-negative patients were subsequently examined with tissue specimens,and 3 of them were T790M-positive. Six plasma T790M-negative patients without tissue tests were treated with osimertinib,among whom 1achieved PR,and 1 achieved SD (PFS was longer than 5 months). [Conclusion] Plasma T790 M detection can predict the efficacy of osimeritinib in NSCLC patients with first-generation EGFR-TKI resistance. Patients with plasma negative T790 M are suggested to perform tissue T790 M test to exclude false negative results.
引文
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[12]Kuang Y,Rogers A,Yeap BY,et al.Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant nonsmall cell lung cancer[J].Clin Cancer Res,2009,15:2630-2636.
[13]Takahama T,Sakai K,Takeda M,et al.Detection of the T790M mutation of EGFR in plasma of advanced nonsmall cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors(West Japan Oncology Group8014LTR Study)[J].Oncotarget,2016,7:58492-58499.
[14]Bosc C,Ferretti GR,Cadranel J,et al.Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC[J].Target Oncol,2015,10:247-253.
[15]Hata A,Katakami N,Yoshioka H,et al.T790M heterogeneity in individual patients with EGFR-mutant non-small-cell lung cancer after acquired resistance to EGFR-TKI[J].JThorac Oncol,2015,10:1553-1559.
[16]Marchetti A,Palma JF,Felicioni L,et al.Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of nsclc patients[J].J Thorac Oncol,2015,10:1437-1443.
[17]Sorensen BS,Wu L,Wei W,et al.Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib[J].Cancer,2014,120:3896-3901.
[18]Murtaza M,Dawson SJ,Pogrebniak K,et al.Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer[J].Nat Commun,2015,6:8760.
[19]Remon J,Caramella C,Jovelet C,et al.Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA[J].Ann Oncol,2017,28:784-790.
[20]Yang JC,Ahn MJ,Kim DW,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURA study phaseⅡextension component[J].J Clin Oncol,2017,35:1288-1296.
[2]Maemondo M,Inoue A,Kobayashi K,et al.Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J].N Engl J Med,2010,362:2380-2388.
[3]Mok TS,Wu YL,Thongprasert S,et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma[J].N Engl J Med,2009,361:947-957.
[4]Wu YL,Zhou C,Hu CP,et al.Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations(LUX-Lung 6):an open-label,randomised phase 3 trial[J].Lancet Oncol,2014,15:213-222.
[5]Arcila ME,Oxnard GR,Nafa K,et al.Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay[J].Clin Cancer Res,2011,17:1169-1180.
[6]Yu HA,Arcila ME,Rekhtman N,et al.Analysis of tumor specimens at the time of acquired resistance to EGFR-TKItherapy in 155 patients with EGFR-mutant lung cancers[J].Clin Cancer Res,2013,19:2240-2247.
[7]Cross DA,Ashton SE,Ghiorghiu S,et al.AZD9291,an irreversible EGFR TKI,overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer[J].Cancer Discov,2014,4:1046-1061.
[8]Remon J,Menis J,Hasan B,et al.The APPLE trial:feasibility and activity of AZD9291(osimertinib)treatment on positive plasma T790M in EGFR-mutant NSCLC patients[J].Clin Lung Cancer,2017,18:583-588.
[9]Jovelet C,Ileana E,Le Deley MC,et al.Circulating cellfree tumor DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO trial[J].Clin Cancer Res,2016,22:2960-2968.
[10]Jenkins S,Yang JC,Ramalingam SS,et al.Plasma ctDNAanalysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer[J].JThorac Oncol,2017,12:1061-1070.
[11]Oxnard GR,Thress KS,Alden RS,et al.Association between plasma genotyping and outcomes of treat ment with osimertinib(AZD9291)in advanced non-small-cell lung cancer[J].J Clin Oncol,2016,34:3375-3382.
[12]Kuang Y,Rogers A,Yeap BY,et al.Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant nonsmall cell lung cancer[J].Clin Cancer Res,2009,15:2630-2636.
[13]Takahama T,Sakai K,Takeda M,et al.Detection of the T790M mutation of EGFR in plasma of advanced nonsmall cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors(West Japan Oncology Group8014LTR Study)[J].Oncotarget,2016,7:58492-58499.
[14]Bosc C,Ferretti GR,Cadranel J,et al.Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC[J].Target Oncol,2015,10:247-253.
[15]Hata A,Katakami N,Yoshioka H,et al.T790M heterogeneity in individual patients with EGFR-mutant non-small-cell lung cancer after acquired resistance to EGFR-TKI[J].JThorac Oncol,2015,10:1553-1559.
[16]Marchetti A,Palma JF,Felicioni L,et al.Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of nsclc patients[J].J Thorac Oncol,2015,10:1437-1443.
[17]Sorensen BS,Wu L,Wei W,et al.Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib[J].Cancer,2014,120:3896-3901.
[18]Murtaza M,Dawson SJ,Pogrebniak K,et al.Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer[J].Nat Commun,2015,6:8760.
[19]Remon J,Caramella C,Jovelet C,et al.Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA[J].Ann Oncol,2017,28:784-790.
[20]Yang JC,Ahn MJ,Kim DW,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURA study phaseⅡextension component[J].J Clin Oncol,2017,35:1288-1296.