晚期非小细胞肺癌一代EGFR-TKIs耐药后基因突变分析
An analysis of the genetic mutation of resistant advanced non-small cell lung cancer after treatment with the first generation of EGFR-TKIs
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摘要: 目的分析一代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）治疗后耐药晚期非小细胞肺癌（NSCLC）的基因突变情况,探讨其可能的耐药机制及与预后的关系及其后续治疗方案选择。方法收集31例对一代EGFR-TKIs获得性耐药的患者,做了肺癌123个肿瘤相关基因全外显子基因的二代测序；统计EGFR基因及其他肿瘤相关基因突变情况,并分析基因突变状态与临床特征的相关性。结果31例患者共发现121个基因突变,每例患者平均3.9个基因突变；有28例伴有EGFR敏感突变,其中19外显子突变15例（48.4％）,20 外显子中T790M突变14例（45.2％）,21外显子突变12例（38.7％）；同时存在 19 和 20 外显子突变7例（ 22.6％）,同时存在 20和 21外显子突变5 例（ 16.1％）。无肿瘤疾病家族史患者的T790M突变率为62.5％（10/16）,高于有肿瘤疾病家族史患者T790M突变率26.7%（4/15）,差异有统计学意义（P<0.05）。女性患者PIK3CA突变率〔21.4% (3/14)〕高于男性患者（0）,差异有统计学意义（P<0.05）。T790M阳性突变患者无进展生存期(PFS)为12.6个月,较阴性患者的7.8个月延长4.8个月,但差异无统计学意义（P＞0.05）。21外显子L858R阳性突变患者PFS为14.4个月,较阴性患者的7.4个月延长7个月,差异有统计学意义（P<0.05）；PIK3CA阳性突变患者PFS为3.0个月,较阴性患者的10.9个月缩短7.9个月,差异有统计学意义（P<0.05）。结论可依据一代EGFR-TKIs耐药后晚期NSCLC基因突变情况选择个体化治疗方案,L858R、PIK3CA与其预后有一定相关性。Abstract: ObjectiveTo analyze the genetic mutation of resistant advanced non-small cell lung cancer (NSCLC) after treatment with the first generation of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and to investigate possible mechanisms of drug resistance. MethodsA total of 31 patients resistant to the first-generation of EGFR-TKIs were enrolled. Their mutational profiling was determined in a cohort using targeted next generation sequencing (NGS) of 123 cancer-related genes. The mutation of EGFR genes and other tumor related genes were analyzed, and the correlations between genetic mutation and clinical characteristics were analyzed. ResultsA total of 121 genetic mutations were found in 31 patients, with an average of 3.9 mutations per patient. There were 28 patients with EGFR sensitive mutations, including exon 19 mutation in 15 patients (48.4%). There were 14 patients with T790M mutations, including exon 21 mutation in 12 patients (38.7%). Meanwhile, there were 7 patients with mutation in both exons 19 and 20 (22.6%), and 5 patients in both exons 20 and 21 (16.1%). The rate of T790M mutation was 62.5% (10/16) for patients without tumor family history, which was significantly higher than that of those with tumor family history 26.7% (4/15) (P<0.05). The PIK3CA mutation rate was 21.4% (3/14) for female patients, which was significantly higher than that of male patients (0) (P<0.05). The PFS of T790M positive mutation patients was 12.6 months, compared with 7.8 months of negative patients, without statistical difference (P>0.05). The PFS of exon 21 L858R mutation positive patients was 14.4 months, which was statistical different from 7.4 months of negative patients (P<0.05). The PFS PIK3CA mutation positive patients was 3.0 months, which was statistical different from 10.9 months of negative patients (P<0.05). ConclusionsAccording to the mutational profiles of NSCLC patients resistant to the first-generation of EGFR-TKIs, individualized therapy can be determined. L858R and PIK3CA are related with the prognosis.
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