JCO：不推荐以KRAS状态作为NSCLC患者接受辅助化疗的标准

在2013年4月29日在线出版的《临床肿瘤学杂志》(Journal of Clinical Oncology)上，发表了加拿大玛格丽特公主医院Frances A. Shepherd博士等人的一项研究结果，该研究通过4项对比考察辅助化疗(ACT)及观察治疗(OBS) 的临床试验，对KRAS突变进行了分析，以阐释KRAS突变在非小细胞肺癌(NSCLC)预后/预测方面的作用。

该研究以盲法形式对患者KRAS突变状态进行了确定。同时借助多变量Cox模型，通过探索性分析表征突变状态与亚型和患者生存结局间的关系。该研究发现，KRAS突变状态并不具有显著预后性。对于第13密码子突变患者存在的潜在相互作用则需要进一步验证。研究人员最终认为，目前不推荐通过KRAS状态进行接受ACT的NSCLC患者筛选。

研究人员发现，在1,543例患者(763例 OBS, 780例 ACT)中，有300例患者存在KRAS突变(第12密码子, n =275; 第13密码子, n=24; 第14密码子, n=1)。对于OBS患者，第12密码子(突变型 vs 野生型[WT] 风险比 [HR]=1.04; 95% CI, 0.77至1.40)或第13密码子(HR =1.01; 95% CI, 0.47至2.17)突变在总生存率预后方面并无差异。观察发现，对WT-KRAS (ACTv OBS HR=0.89; 95% CI, 0.76 至 1.04; P= .15)或第12密码子突变(HR = 0.95; 95%CI, 0.67至1.35; P = .77)患者并未从ACT中取得显著获益；而对第12密码子突变患者而言，ACT则存在毒害性(HR =5.78; 95% CI, 2.06 至16.2; P < .001; 相互作用P=.002)。第12密码子特定位置的氨基酸替换并无预后效应。对于第12密码子突变的患者而言，ACT的影响各异：G12A或G12R (HR =0.66; P = .48),G12C或 G12V (HR = 0.94; P = .77) 以及G12D或G12S (HR = 1.39; P= .48; 4项HR比较, 其中包括WT, 相互作用 P = .76)。此外，与ACT患者(HR = 0.66; 95% CI,0.25至1.75; P = .40; 相互作用, P = .02)相比，肿瘤存在KRAS突变的OBS患者中，出现第二原发癌的可能性更高(HR =2.76, 95% CI, 1.34 至5.70; P = .005)。

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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.
Purpose
We 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).
Methods
KRAS 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.
Results
Among 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).
Conclusion
KRAS 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.