Liu Zhefeng, Wu Lin, Cao Jun, Yang Zhe, Zhou Chengzhi, Cao Liming, Wu Hao, Shen Haibo, Jin Meiling, Zhang Yong, Mao Xinru, Xiang Jianxing, Ma Ke, Li Bing, Zhang Tengfei, Hu Yi
Department of Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
Department of the Second Chest Medicine, Hunan Cancer Hospital, Changsha, Hunan, People's Republic of China.
Onco Targets Ther. 2018 Oct 23;11:7323-7331. doi: 10.2147/OTT.S173391. eCollection 2018.
exon 20 insertions (20ins) have been identified as oncogenic drivers in lung cancers. Lung cancer patients with 20ins benefit from afatinib. However, response heterogeneity was observed in patients harboring different 20ins subtypes. In this study, we interrogated clinical characteristics in -mutated Chinese lung cancer and investigated the clinical outcomes of specific 20ins in response to afatinib.
In this study, we retrospectively collected genomic profiling data of 7,520 lung cancer patients sequenced using next-generation sequencing in a Clinical Laboratory Improvement Amendments-certified laboratory. We analyzed the clinical and molecular features of patients harboring 20ins and evaluated clinical outcomes of 19 patients with clinical records after afatinib treatment.
20ins were identified in 2.27% (171/7,520) of this lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. 20ins was mutually exclusive with other well-established lung cancer oncogenic driver mutations. The most frequently appearing subtype was Y772_A775dup (69.6%) and several novel insertion subtypes were also identified. The correlations of specific 20ins subtypes and survival were investigated. The presence of a glycine at position 778 in was suggested to be a common feature of drug sensitivity mutations. Patients harboring G778_P780dup (G778) subtype achieved longer median progression-free survival and median overall survival than other 20ins (non-G778) subtypes (median progression-free survival, 10 vs 3.3 months, =0.32; median overall survival, 19.7 vs 7 months, =0.16). Moreover, we presented the first clinical case of a lung squamous cell carcinoma patient harboring 20ins who achieved partial response to afatinib.
This study interrogated the characteristics of 20ins in a large cohort from single ethnicity and demonstrated the response heterogeneity to afatinib among different 20ins subtypes. Further studies in a larger cohort are needed to investigate the underlying molecular mechanisms and clinical response of different 20ins subtypes.
外显子20插入（20ins）已被确定为肺癌中的致癌驱动因素。携带20ins的肺癌患者可从阿法替尼中获益。然而，在携带不同20ins亚型的患者中观察到反应异质性。在本研究中，我们探究了中国肺癌患者中20ins的临床特征，并研究了特定20ins对阿法替尼反应的临床结果。
在本研究中，我们回顾性收集了7520例肺癌患者的基因组分析数据，这些数据是在一家符合临床实验室改进修正案认证的实验室中使用下一代测序技术进行测序的。我们分析了携带20ins患者的临床和分子特征，并评估了19例接受阿法替尼治疗后有临床记录患者的临床结果。
在该肺癌队列中，20ins在2.27%（171/7520）的患者中被鉴定出来。它在腺癌组织学类型的女性患者中占比很高。20ins与其他已明确的肺癌致癌驱动基因突变相互排斥。最常见的亚型是Y772_A775dup（69.6%），同时还鉴定出了几种新的插入亚型。研究了特定20ins亚型与生存的相关性。778位存在甘氨酸被认为是药物敏感性突变的一个共同特征。携带G778_P780dup（G778）亚型的患者比其他20ins（非G778）亚型患者的中位无进展生存期和中位总生存期更长（中位无进展生存期，10个月对3.3个月，P=0.32；中位总生存期，19.7个月对7个月，P=0.16）。此外，我们展示了首例携带20ins的肺鳞状细胞癌患者对阿法替尼获得部分缓解的临床病例。
本研究探究了单一民族的一个大型队列中20ins的特征，并证明了不同2组ins亚型对阿法替尼的反应异质性。需要在更大的队列中进行进一步研究，以调查不同20ins亚型的潜在分子机制和临床反应。
