Freitas Helano C, Torrezan Giovana Tardin, da Cunha Isabela Werneck, Macedo Mariana Petaccia, Karen de Sá Vanessa, Corassa Marcelo, Ferreira Elisa Napolitano E, Saito Augusto Obuti, Dal Molin Graziela Zibetti, Cordeiro de Lima Vladmir C, Carraro Dirce Maria
Medical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil.
Genomics and Molecular Biology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil.
Front Oncol. 2020 Jul 2;10:1068. doi: 10.3389/fonc.2020.01068. eCollection 2020.
Approximately 60% of lung adenocarcinomas (LAs) carry mutations that can guide treatment with tyrosine-kinase inhibitors (TKI) and other targeted therapies. Data on activating mutations in and other tyrosine-kinase receptor (TKR) genes in highly admixed populations, such as that of Brazil, are scarce. In this study, we comprehensively analyzed the actionable alteration profile of LA in Brazilian patients. driver mutation data were collected from a large Brazilian LA cohort covering an 8-year period of molecular testing in a single institution. Tests were performed using three distinct methods, and demographic and histopathological data were analyzed. For a subset of patients, driver mutations in , and and gene fusions involving TKR genes (before TKI treatment) and T790M (after TKI treatment) were assessed. mutations were detected in 25% of 1,316 LAs evaluated, with exon 19 deletions and exon 21 L858R TKI sensitizing mutations representing 72.5% of all mutations. Mutation rates were higher in women and non-smokers ( < 0.001). Next-generation sequencing was very sensitive, with a lower rate of inconclusive results compared with Sanger sequencing and pyrosequencing. hotspot gene panels were applied in 495 LA cases and detected oncogenic mutations in 51.3% of samples, most frequently in (22.4%) and (26.9%). In subgroups of 36 and 35 patients, gene fusions were detected in 11.1% of tumors and T790M resistance mutations were detected in 59% of plasma samples from patients previously treated with TKI, respectively. This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations in and other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.
大约60%的肺腺癌（LA）携带可指导使用酪氨酸激酶抑制剂（TKI）和其他靶向疗法进行治疗的突变。在高度混合的人群中，如巴西人群，关于表皮生长因子受体（EGFR）和其他酪氨酸激酶受体（TKR）基因激活突变的数据很少。在本研究中，我们全面分析了巴西患者LA中可指导治疗的改变谱。驱动突变数据来自巴西一个大型LA队列，该队列涵盖了一个机构8年的分子检测。使用三种不同方法进行检测，并分析人口统计学和组织病理学数据。对于一部分患者，评估了EGFR、KRAS和NRAS中的驱动突变以及涉及TKR基因的基因融合（TKI治疗前）和T790M（TKI治疗后）。在评估的1316例LA中，25%检测到EGFR突变，外显子19缺失和外显子21 L858R TKI敏感突变占所有突变的72.5%。女性和非吸烟者的突变率更高（P<0.001）。与桑格测序和焦磷酸测序相比，二代测序非常敏感，不确定结果的发生率更低。在495例LA病例中应用热点基因检测板，51.3%的样本检测到致癌突变，最常见于EGFR（22.4%）和KRAS（26.9%）。在36例和35例患者的亚组中，分别在11.1%的肿瘤中检测到基因融合，在先前接受TKI治疗的患者的59%的血浆样本中检测到T790M耐药突变。本报告提供了巴西LA中首个全面的可指导治疗的改变情况。LA中EGFR和其他驱动基因的高可指导治疗改变率强化了将分子诊断指导的TKI纳入公共和私立医疗系统患者临床常规的必要性。
