Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Cancer. 2012 Feb 1;118(3):729-39. doi: 10.1002/cncr.26311. Epub 2011 Jun 30.
The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype-specific subsets of never-smokers with nonsmall cell lung cancer (NSCLC).
The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never-smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing.
Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression-free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40-0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07-10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65-10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes.
To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never-smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype-specific subsets can lead to successful treatment with appropriate kinase inhibitors.
本研究旨在确定主要致癌改变的比例，并研究从不吸烟的非小细胞肺癌（NSCLC）患者中特定基因型亚组的生存情况。
作者同时分析了 229 例从不吸烟的 NSCLC 患者样本中表皮生长因子受体（EGFR）和 v-Ki-ras2 Kirsten 大鼠肉瘤病毒致癌基因同源物（KRAS）基因的突变情况，并研究了间变性淋巴瘤激酶（ALK）基因重排。ALK 重排通过荧光原位杂交鉴定，并通过免疫组化证实。EGFR（外显子 18 至 21）和 KRAS（密码子 12 和 13）的突变通过直接测序确定。
在 229 个肿瘤中，EGFR 突变、ALK 重排、KRAS 突变和 3 个基因均无突变（野生型[WT]）的频率分别为 48%、8.3%、3.5%和 40.2%。所有遗传改变均相互排斥。接受 EGFR 酪氨酸激酶抑制剂（TKI）治疗后，无 EGFR 突变、WT/WT/WT 基因型、KRAS 突变和 ALK 重排的患者中位无进展生存期分别为 12.8 个月、6.3 个月、2.1 个月和 1.6 个月。在 Cox 回归模型中，调整 EGFR TKI 治疗后疾病进展风险的校正危险比（HR）分别为 EGFR 突变患者 0.59（95%置信区间[CI]，0.40-0.87；P=0.008），ALK 重排患者 4.58（95%CI，2.07-10.15；P<0.001）和 KRAS 突变患者 4.23（95%CI，1.65-10.8；P=0.003）。总体生存也在基因型之间存在显著差异。
据作者所知，这是迄今为止对东亚从不吸烟的 NSCLC 患者队列中 3 种主要致癌改变进行的最大规模的综合和并发分析。由于不同基因型的生存结果存在差异，并且目前有针对特定改变的药物，因此通过基因谱识别特定基因型亚组可以导致使用合适的激酶抑制剂进行成功治疗。
