Yu Jiang-Yong, Yu Si-Fan, Wang Shu-Hang, Bai Hua, Zhao Jun, An Tong-Tong, Duan Jian-Chun, Wang Jie
The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100142, P. R. China.
Chin J Cancer. 2016 Mar 21;35:30. doi: 10.1186/s40880-016-0086-2.
Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment in lung adenocarcinoma. However, whether patients carrying EGFR 19 del and L858R mutations exhibit different responsiveness to EGFR-TKIs and what are the potential mechanism for this difference remain controversial. This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.
Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858R mutations, 532 received EGFR-TKI treatment and were included in this study. EGFR 19 del and L858R mutations were detected by using denaturing high-performance liquid chromatography (DHPLC). T790M mutation, which is a common resistant mutation on exon 20 of EGFR, was detected by amplification refractory mutation system (ARMS). Next-generation sequencing (NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858R mutations.
Of the 532 patients, 319 (60.0%) had EGFR 19 del, and 213 (40.0%) had L858R mutations. The patients with EGFR 19 del presented a significantly higher overall response rate (ORR) for EGFR-TKI treatment (55.2% vs. 43.7%, P = 0.017) and had a longer progression-free survival (PFS) after first-line EGFR-TKI treatment (14.4 vs. 11.4 months, P = 0.034) compared with those with L858R mutations. However, no statistically significant difference in overall survival (OS) was observed between the two groups of patients. T790M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment, and there was no significant difference in the co-existence of T790M mutation with EGFR 19 del and L858R mutations before EGFR-TKI treatment (5.6% vs. 8.8%, P = 0.554) or after treatment (24.4% vs. 35.4%, P = 0.176). In addition, 24 patients with EGFR 19 del and 19 with L858R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.
Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858R mutations. Whether the heterogeneity of tumors with EGFR 19 del and L858R mutations contribute to a therapeutic response difference needs further investigation.
表皮生长因子受体（EGFR）突变，包括已知的第19外显子缺失（19 del）和第21外显子L858R点突变（L858R突变），是肺腺癌对EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗反应的强预测指标。然而，携带EGFR 19 del和L858R突变的患者对EGFR-TKIs的反应是否不同以及这种差异的潜在机制是什么仍存在争议。本研究旨在调查EGFR-TKI治疗EGFR 19 del和L858R突变患者的临床结局，并探索具有这两种突变亚型肿瘤的基因异质性。
在1127例携带EGFR 19 del或L858R突变的晚期肺腺癌患者中，532例接受了EGFR-TKI治疗并纳入本研究。采用变性高效液相色谱（DHPLC）检测EGFR 19 del和L858R突变。采用扩增阻滞突变系统（ARMS）检测EGFR第20外显子上常见的耐药突变T790M突变。采用二代测序（NGS）探索EGFR 19 del和L858R突变肿瘤的基因异质性。
532例患者中，319例（60.0%）为EGFR 19 del，213例（40.0%）为L858R突变。与L858R突变患者相比，EGFR 19 del患者接受EGFR-TKI治疗的总缓解率（ORR）显著更高（55.2%对43.7%，P = 0.017），且一线EGFR-TKI治疗后的无进展生存期（PFS）更长（14.4个月对11.4个月，P = 用034）。然而，两组患者的总生存期（OS）无统计学显著差异。在88例EGFR-TKI治疗前和134例治疗后的患者中分析了T790M突变状态，EGFR-TKI治疗前T790M突变与EGFR 19 del和L858R突变共存情况无显著差异（5.6%对8.8%，P = 0.554），治疗后也无显著差异（24.4%对3比4%，P = 0.176）。此外，对24例EGFR 19 del患者和19例L858R突变患者进行了NGS分析，两种基因型在多个体细胞突变存在情况上无显著差异。
与L858R突变患者相比，EGFR 19 del患者的PFS更长且ORR更高。EGFR 19 del和L858R突变肿瘤的异质性是否导致治疗反应差异需要进一步研究。
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