吉非替尼获得性耐药的非小细胞肺癌患者临床特点

The treatment for acquired drug resistance of clinical characteristics of patients with non-small cell lung cancer

背景与目的：以吉非替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor，EGFR-TKI）在改善晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）疗效与生活质量中的作用已经得到国际多中心临床研究的充分肯定。但对EGFR-TKI有良好疗效的NSCLC患者不可避免地会发生获得性耐药，这将直接影响到EGFR-TKI的疗效。本研究旨在分析NSCLC患者经过吉非替尼治疗后引起获得性耐药的临床特点。方法：回顾性分析了从吉非替尼中获益的NSCLC患者。所有的资料来自2007年1月—2014年1月新疆肿瘤医院的住院患者。对吉非替尼治疗失败患者的获得性耐药的临床表现、疾病进展时间（time to progress，TTP）及进展后生存时间（post-progression survival，PPS）进行回顾性分析。结果：共收集417例NSCLC患者。中位TTP为10.2个月（95%CI：9.5~10.9）。其中女性、不吸烟、肺腺癌患者的TTP显著延长。发生获得性耐药时，63.3%的患者出现恶化症状。疾病进展情况如下：209例（58.4%）原发肺部病变出现进展，137例（38.3%）既往有转移的病变出现进展，194例（54.2%）出现新发转移。表皮生长因子受体（epidermal growth factor receptor，EGFR）野生型比突变型患者有更多的症状恶化、新发的中枢神经系统（central nervous system，CNS）转移的倾向。外显子19缺失和L858R突变的患者在新发转移上有很大不同（41.4%vs 6.3%，P=0.02）。PPS为8.9个月（95%CI：7.4~10.4）。吸烟史、体能状况（performance status，PS）评分、新CNS病变和随后的化疗是PPS的独立因素。结论：获得性耐药的临床表现根据EGFR突变状态和EGFR突变基因型可能会有所不同。此外，在吉非替尼治疗后获得性耐药的NSCLC患者，再进行后续的化疗也带来与PPS有关的临床受益。

Background and purpose：Non-small cell lung cancer （NSCLC） patients who have good curative effect on epidermal growth factor receptor tyrosine kinase inhibitor （EGFR-TKI） will inevitably acquired drug resistance. It will effect the survival directly. In contrast, few studies have found that EGFR-TKI effectively acquired drug resistance in patients with clinical characteristics. We investigated clinical characteristics of NSCLC patients who experienced acquired drug resistance during geiftinib therapy. Methods：To review the treatment from the beneift of patients with non-small cell lung cancer. All of the data were obtained from Jan. 2007 to Jan. 2014 in Xinjiang tumor hospital. The treatment for failure of acquired drug resistance of clinical manifestations, time to progress （TTP） and post-progression survival （PPS） were retrospectively analyzed. Results：The total collection of 417 patients. Median TTP was 10.2 months （95%CI：9.5-10.9）. The TTP of women adenocarcinoma patients who didn’t smoke signiifcantly extended. When acquired drug resistance happened, 63.3%of patients appeared worse symptoms. The progress of the disease is as follows：209 cases （58.4%） from the primary lesion, 137 cases （38.3%） before the transfer, 194 cases （54.2%） of new happened. Patients of epidermal growth factor receptor （EGFR） wild type had more tendencies of symptomatic deterioration and new central nervous system （CNS） transfer than patients of EGFR mutation type. Patients of exon 19 deletion and L858R mutations on the new transfer were different （41.4%vs 6.3%, P=0.02）. PPS was 8.9 months （95%CI：7.4-10.4）. Smoking history, performance status （PS） score, new CNS lesions and the subsequent chemotherapy is independent factors of PPS. Conclusion：This study suggests that the clinical manifestations of acquired drug resistance according to EGFR mutation status and EGFR mutation genotype may be different. In addition, after the treatment of acquired drug resistance in patients with non-small cell lung cancer, the subsequent clinical beneift from chemotherapy are also associated with PPS.