Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy
Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy
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DOI：
10.1200/jco.2012.48.1390
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发表时间：
2013-06-10
影响因子：
45.3
通讯作者：
Tsao, Ming-Sound
中科院分区：
文献类型：
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作者：
Shepherd, Frances A.;Domerg, Caroline;Tsao, Ming-Sound
PurposeWe进行了这项分析KRAS突变的辅助化疗（ACT）与观察（OBS）的四个试验，以澄清预后/预测作用KRAS在非小细胞肺癌（NSCLC）。进行了探索性分析，以表征突变状态和亚型和生存结局之间的关系，使用多变量考克斯model.ResultsAmong 1,543例（763 OBS，780 ACT），300 KRAS突变（密码子12，n = 275;密码子13，n = 24;密码子14，n = 1）。在OBS患者中，密码子12（突变与野生型[WT]风险比[HR] = 1.04; 95% CI，0.77至1.40）或密码子13（HR = 1.01; 95% CI，0.47至2.17）突变的总生存期无预后差异。对于WT-KRAS，未观察到ACT的显著获益（ACT vs OBS HR = 0.89; 95% CI，0.76 - 1.04; P = 0.15）或密码子-12突变（HR = 0.95; 95% CI，0.67至1.35; P = 0.77）;密码子-13突变，ACT是有害的（HR = 5.78; 95% CI，2.06至16.2; P <0.001;相互作用P = 0.002）。特异性密码子-12氨基酸取代对预后无影响。ACT的效果在密码子12突变的患者中是可变的：G12 A或G12 R（HR = 0.66; P = 0.48），G12 C或G12 V（HR = 0.94; P = 0.77）和G12 D或G12 S（HR = 1.39; P = 0.48;四种HR的比较，包括WT，相互作用P = 0.76）。KRAS突变肿瘤的OBS患者更有可能发展为第二原发癌（HR = 2.76，95%CI，1.34 - 5.70; P = 0.005），而ACT患者则不然（HR = 0.66，95%CI，0.25 - 1.75; P = 0.40;交互作用，P = 0.02）。密码子-13突变患者的潜在相互作用需要验证。目前，不能推荐KRAS状态选择NSCLC患者进行ACT治疗。(C)2013年美国临床肿瘤学会
PurposeWe undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC).MethodsKRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model.ResultsAmong 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02).ConclusionKRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT. (C) 2013 by American Society of Clinical Oncology