Li J M, Hu J, Bai C X, Zhang Y, Xu X B, Wang X D, Ding N
Department of Pulmonary Medicine, Zhongshan Hospital Fudan University, Shanghai 200032, China.
Zhonghua Jie He He Hu Xi Za Zhi. 2018 Oct 12;41(10):778-782. doi: 10.3760/cma.j.issn.1001-0939.2018.10.006.
To investigate if concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation. From November 2016 to December 2017, 51 patients (19 males and 32 females, age 37-85 years) with histology or cytology diagnosed,locally advanced or metastatic NSCLC from Zhongshan Hospital Fudan University were prospectively recruited in the study. All patients harboring EGFR sensitive mutation detected by a 123 lung cancer specific gene panel of next-generation sequencing(NGS) analysis were under treatment of EGFR-TKIs. Multi-factors analysis of the correlation between EGFR-TKIs efficacy and concomitant gene alterations were analyzed by multivariate Cox regression model. 82% of the NSCLC patients with EGFR mutation presented concomitant gene alterations with an average number of 2.1. Patients not harboring concomitant gene alterations had a longer median progression free survival (mPFS: not reached 8.8 m, 0.008). Those who had less than 2 concomitant genes had a higher objective response rate[ORR: 52% (17/33) 33% (6/18) , 0.251]and better mPFS (13.8 vs 8.0 m, 0.003). The top 3 concomitant gene alterations were TP53 gene mutation(55%, 28/51), EGFR gene amplification (26%, 13/51) and RB1 gene mutation (18%,9/51) respectively. The mPFS of EGFR-TKI treatment in patients with either one of these 3 concomitant genes was 8.0, 8.0, and 6.0 months respectively, significantly shorter than those without one of the 3 gene alterations (13.8, 13.1, and 10.8 months respectively). Multivariate Cox regression revealed that concomitant gene abnormalities (0.036) and accompanied by RB1 gene mutation (0.025) were independent risk factors for the survival benefit of EGFR-TKI in the treatment of advanced NSCLC with EGFR-sensitive mutation. The efficacy of EGFR-TKI decreased significantly in advanced NSCLC with EGFR-sensitive mutation who had concomitant gene abnormalities, especially accompanied by more than 2 of the 3 gene alterations (TP53 gene mutation, EGFR gene amplification or RB1 gene mutation). This study suggested that the concomitant gene alterations should be an important issue for consideration when applying a personalized combination therapy for advanced NSCLC harboring EGFR sensitive mutation.
探讨伴随基因改变是否会影响表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对具有表皮生长因子受体（EGFR）敏感突变的晚期非小细胞肺癌（NSCLC）患者的治疗效果。2016年11月至2017年12月，前瞻性纳入复旦大学附属中山医院51例经组织学或细胞学诊断为局部晚期或转移性NSCLC的患者（男性19例，女性32例，年龄37 - 85岁）。所有通过下一代测序（NGS）分析的123个肺癌特异性基因 panel检测到携带EGFR敏感突变的患者均接受EGFR-TKIs治疗。采用多因素Cox回归模型分析EGFR-TKIs疗效与伴随基因改变之间的相关性。82%的EGFR突变NSCLC患者存在伴随基因改变，平均数量为2.1个。未携带伴随基因改变的患者中位无进展生存期更长（mPFS：未达到对8.8个月，P = 0.008）。伴随基因少于2个的患者客观缓解率更高[ORR：52%（17/33）对33%（6/18），P = 0.251]，mPFS更好（13.8个月对8.0个月，P = 0.003）。前3种伴随基因改变分别为TP53基因突变（55%，28/51）、EGFR基因扩增（26%，13/51）和RB1基因突变（18%，9/51）。这3种伴随基因中任一基因改变的患者接受EGFR-TKI治疗的mPFS分别为8.0、8.0和6.0个月，显著短于无这3种基因改变之一的患者（分别为13.8、13.1和10.8个月）。多因素Cox回归显示，伴随基因异常（P = 0.036）和伴有RB1基因突变（P = 0.025）是EGFR-TKI治疗具有EGFR敏感突变的晚期NSCLC生存获益的独立危险因素。在具有EGFR敏感突变的晚期NSCLC患者中，若存在伴随基因异常，尤其是伴有3种基因改变（TP53基因突变、EGFR基因扩增或RB1基因突变）中的2种以上，EGFR-TKI的疗效显著降低。本研究提示，对于具有EGFR敏感突变的晚期NSCLC患者应用个体化联合治疗时，伴随基因改变应是一个重要的考虑因素。
