Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer.
Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer.
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同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
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发表时间：
2018-01-15
期刊：
影响因子：
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通讯作者：
Riely GJ
中科院分区：
文献类型：
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作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
大约25%的非小细胞肺癌（NSCLC）患者发生KRAS突变。尽管KRAS突变的存在是一致的，但KRAS突变的NSCLC患者的临床病程可能不同。由于共发生突变的模式可以描述kras突变型肺腺癌患者的不同生物学亚群，因此我们探讨了共发生突变对患者预后和治疗反应的影响。我们确定了晚期kras突变NSCLC患者，并评估了最常见的共发生基因组改变。进行多变量分析，纳入最常见的共突变和临床特征，以评估与总生存期的关系以及对铂-培美曲塞化疗和免疫检查点抑制剂的反应。在330例晚期kras突变型肺癌患者中，最常见的共突变是TP53（42%）、STK11（29%）和KEAP1/NFE2L2（27%）。在多变量分析中，KEAP1/NFE2L2共突变患者的生存期明显缩短（HR 1.96, 95%CI 1.33-2.92, p=<0.001）。STK11 （HR1.3, p=0.22）和TP53 （HR 1.11, p= 0.58）共突变状态与生存无关。KEAP1/NFE2L2共突变还与初始化疗时间较短（风险比1.64,95% CI 1.04-2.59, p=0.03）和免疫治疗开始后的总生存期较短（风险比3.54,95% CI 1.55-8.11, p=0.003）相关。在kras突变的晚期NSCLC患者中，TP53、STK11和KEAP1/NFE2L2是最常见的共同发生的体细胞基因组改变。KRAS和KEAP1/ NFE2L2的共突变是一个独立的预后因素，预测更短的生存期，对初始铂类化疗的反应时间，以及从免疫治疗开始的生存期。
KRAS mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of KRAS mutations, patients with KRAS-mutant NSCLC can have a heterogeneous clinical course. Since the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. We identified patients with advanced KRAS-mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum-pemetrexed chemotherapy and immune checkpoint inhibitors. Among 330 patients with advanced KRAS-mutant lung cancers, the most frequent co-mutations were found in TP53 (42%), STK11 (29%), and KEAP1/NFE2L2 (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in KEAP1/NFE2L2 (HR 1.96, 95%CI 1.33–2.92, p=<0.001). STK11 (HR1.3, p=0.22) and TP53 (HR 1.11, p= 0.58) co-mutation status were not associated with survival. Co-mutation in KEAP1/NFE2L2 was also associated with shorter duration of initial chemotherapy (HR 1.64, 95% CI 1.04–2.59, p=0.03) and shorter overall survival from initiation of immune therapy (HR 3.54, 95% CI 1.55–8.11, p=0.003). Among people with KRAS-mutant advanced NSCLC, TP53, STK11, and KEAP1/NFE2L2 are the most commonly co-occurring somatic genomic alterations. Co-mutation of KRAS and KEAP1/ NFE2L2 is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum based chemotherapy, and survival from start of immune therapy.