GNAS1基因T393C多态性与EGFR突变状态未明复治晚期非小细胞肺癌TKI疗效的关联研究

Association between GNAS1 T393C Polymorphism and Therapeutic Efficacy of Tyrosine Kinase Inhibitor in Pretreated Advanced Non-small Cell Lung Cancer with Unknown EGFR Mutation Status

背景与目的晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)肿瘤组织表皮生长因子受体(epidermal growth factor recetor,EGFR)突变是酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)最重要的疗效预测指标,但患者常常因肿瘤组织量太少导致EGFR突变状态未明。TKI可以诱导肿瘤细胞凋亡,并与许多凋亡相关基因表达相关。通过检测GNAS1基因T393C多态性,探讨其与EGFR突变状态未明的复治晚期NSCLC小分子TKI治疗疗效的关系。方法入组2009年1月1日-2012年4月30日就诊于浙江省肿瘤医院的116例复治晚期NSCLC患者,所有患者既往均接受过化疗,进展后接受吉非替尼或厄洛替尼靶向治疗。采用多聚酶链反应方法检测患者外周血白细胞中GNAS1基因T393C多态性。采用SPSS 18.0统计软件分析。结果总有效率29.3%,GNAS1基因T393C各基因型患者间的有效率无明显差异。相比GNAS1基因其它基因型,CC型疾病控制率更低(46.2%vs 73.8%,P=0.039)。单因素分析中位PFS,CC型中位无进展时间短于其它基因型(2.3个月vs 6.0个月,P=0.005),而女性长于男性(10.2个月vs 4.6个月,P=0.04);不吸烟者长于有吸烟史者(11.9个月vs 2.5个月,P<0.001);病理类型为腺癌长于其他类型(11.9个月vs 4.1个月,P<0.001),均达到统计学差异。多因素分析结果显示,包括吸烟史、ECOG评分和病理类型、GNAS1基因多态性为PFS的独立预后因素(P=0.006)。结论对复治晚期EGFR突变状态未明的NSCLC,GNAS1基因T393C基因型为CC者是提示近期疗效较差的指标。

Background and objective Epidermal growth factor receptor （EGFR）-activating mutation predicts excellent response to EGFR tyrosine kinase inhibitors （TKIs）. However lung cancer patients are often with unknown EGFR mutation status because there are little tumor specimen to determine. TKIs induce tumor cell apoptosis which associates with several apoptosis-related genes. To explore the association between GNAS1 T393C polymorphism and therapeutic efficacy of TKI in pretreated advanced non-small cell lung cancer （NCSLC） with unknown EGFR mutation status. Methods A total of 116 patients were recruited for the study from Zhejiang Cancer Hospital, all of whom were treated with gefitinib or erlotinib after failure to prior chemotherapy. We detected the genotype of peripheral blood lymphocytes of patients with GNAS1 T393C polymorphism through polymerase chain reaction （PCR）. Statistical analysis was performed by SPSS version 18.0. ResultsThe overall response rate was 29.3%. No significant associations were found among GNAS1 T393C polymorphism and the objective response rate. The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype （Tr or CT） （46.2% vs 73.8%, P=0.039）. Univariate analysis identified gender, smoking history; histol- ogy and GNAS1 T393C polymorphism as predictive marker of PFS （P=0.04, P〈0.001, P〈0.001 and P=0.005）. Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrat- ed that GNASI T393C polymorphism was correlated independently with PFS （P=0.007）. Conclusion Our data suggest the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor.