Background: The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment.
Materials and methods: Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed.
Results: Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1.
Conclusion: Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy.
Implications for practice: The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.
摘要
背景 辅助靶向治疗对可手术肺癌的疗效仍在争论中。在可切除的表皮生长因子受体 (EGFR) 突变肺腺癌 (ADC) 中检测共突变需要全面的遗传分析，这可能会影响辅助酪氨酸激酶抑制剂 (TKI) 治疗的疗效。
材料和方法 使用靶向的下一代测序技术，对 139 个具有 EGFR 突变的可切除的 I‐IIIa 期肺 ADC 进行416 个癌症相关基因突变分析。系统地分析了共突变谱。
结果 除了外显子 19 缺失和 L858R 外的罕见EGFR 改变，如 L861Q(~3%) 和 G719A(~2%)，较低频率被发现。大约 10% 的患者发生 EGFR 外显子 20 突变，这可能导致对第一代 TKI 耐药。除主要EGFR突变外，91% 的患者出现至少一种共突变。TP53是最常见的突变基因，在后期的突变频率较高。显然的是，NF1突变只在 II‐III 期 ADC 中发现。相反，RB1 突变在 I 期 ADC 中更为频发，而仅在该组中观察到 APC 突变。34% EGFR TKI 敏感突变患者的遗传变异涉及 EGFR 下游效应靶点或旁路途径，可能影响对 EGFR TKI 的反应，如PIK3CA、BRCA1，和NOTCH1。
结论 具有 EGFR TKI 敏感突变的可手术肺 ADC 与高比例的共突变相关。这些可切除肿瘤的突变谱有助于确定辅助 EGFR TKI 治疗策略的适用性和有效性。
实践意义:辅助表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗肺癌术后EGFR突变的疗效仍存在争议。在 139 例可切除的肺癌中，对 416 个癌症相关基因进行的下一代测序揭示了EGFR突变背景下的共突变图景。值得注意的是，该研究在 34.71% 的药物敏感性EGFR突变患者中发现了潜在的 EGFR TKI 耐药突变，而这些患者缺乏靶向治疗方面的经验。对这些可切除肿瘤进行全面的突变谱分析有助于确定辅助 EGFR TKI 治疗策略对这些患者的适用性和有效性。
Keywords: Adjuvant targeted therapy; EGFR; Lung adenocarcinoma; Next‐generation sequencing; TKI.
© AlphaMed Press 2019.