The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2).
The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2).
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DOI：
10.1158/1078-0432.ccr-17-2289
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发表时间：
2018-03-01
期刊：
影响因子：
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通讯作者：
LCMC2 investigators
中科院分区：
文献类型：
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作者：
Aisner DL;Sholl LM;Berry LD;Rossi MR;Chen H;Fujimoto J;Moreira AL;Ramalingam SS;Villaruz LC;Otterson GA;Haura E;Politi K;Glisson B;Cetnar J;Garon EB;Schiller J;Waqar SN;Sequist LV;Brahmer J;Shyr Y;Kugler K;Wistuba II;Johnson BE;Minna JD;Kris MG;Bunn PA;Kwiatkowski DJ;LCMC2 investigators
多重基因组分析是晚期肺腺癌患者的标准治疗。肺癌突变联盟（LCMC）是一个多机构的努力，以确定和治疗肺腺癌患者的致癌驱动事件。16家美国机构在LCMC 2中招募了1367名肺癌患者; 904名患者被认为符合条件，并且使用经过验证的方法（包括基因分型，大规模平行测序和免疫组织化学）分析了14种癌症相关基因中的至少一种。与未接受靶向治疗的携带此类突变的患者相比，在携带EGFR、ERBB 2或BRAF p.V600E突变、ALK、ROS 1或RET重排或MET扩增的患者中使用靶向治疗可使生存期增加1.5年;与缺乏靶向驱动因素的患者相比，生存期增加1.0年。重要的是，60例有吸烟史的患者从EGFR/ALK/ROS 1改变的靶向治疗中获得了相似的生存获益，与75例具有相同改变的从不吸烟者相比。此外，在EGFR、ALK或ROS 1改变的患者中，共存的TP 53突变与生存期缩短相关。肺腺癌和致癌驱动突变患者接受有效的靶向治疗后生存期更长，无论既往是否有吸烟史。无论临床特征如何，对所有肺腺癌患者都应进行分子检测。大规模平行测序的常规使用使得能够检测可靶向驱动改变和肿瘤抑制基因以及对治疗选择具有潜在意义并作为治疗功效的预测标志物的其他改变。通过多重基因组分析多个突变来表征肺腺癌现在是护理标准。在这里，我们表明，靶向突变检测和定向治疗的生存效益是相似的，无论是从不吸烟者和当前和以前的吸烟者与肺腺癌。我们还证明，在EGFR、ALK或ROS 1改变的肺腺癌患者中，同时发生TP 53突变与较差的生存率相关。因此，常规使用大规模平行测序能够快速检测所有类型的临床显著序列变异，用于肺腺癌患者的护理，加速靶向治疗选择和预后评估。
Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas. Sixteen U.S. institutions enrolled 1367 lung cancer patients in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and immunohistochemistry. The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1 or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared to those with such mutations not receiving targeted therapy; and 1.0 year compared to those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared to 75 never smokers with the same alterations. In addition, co-existing TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations. Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Characterization of lung adenocarcinomas by multiplex genomic profiling for multiple mutations is now standard of care. Here we show that the survival benefit of targetable mutation detection and directed therapy is similar for both never smokers and current and former smokers with lung adenocarcinomas. We also demonstrate that concurrent TP53 mutation is associated with poorer survival among lung adenocarcinoma patients with EGFR, ALK, or ROS1 alterations. Hence, routine use of massively parallel sequencing enables rapid detection of all types of clinically significant sequence variants for the care of lung adenocarcinoma patients, accelerating both targeted therapy selection and prognostic assessment.