DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany; Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: https://in.linkedin.com/linkedin.com/in/melanie-janning-a48a32153.
Department of Internal Medicine I, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
Ann Oncol. 2022 Jun;33(6):602-615. doi: 10.1016/j.annonc.2022.02.225. Epub 2022 Mar 6.
Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date.
In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).
Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1.
Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.
非小细胞肺癌（NSCLC）患者中存在 10%-30%的 EGFR 非典型突变，其对经典表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）的敏感性存在高度异质性。携带一组常见、反复出现的 EGFR 突变（G719X、S768I、L861Q）的患者对 EGFR-TKI 有反应。外显子 20 插入突变对 EGFR-TKI 大多不敏感，但对外显子 20 抑制剂敏感。目前，针对系统治疗后非常罕见的点突变和复合突变患者的临床结局数据仍然很少。
在德国国家网络基因组医学（nNGM）的这项回顾性、多中心研究中，报告了来自 12 个中心的 856 例包括共存突变在内的非典型 EGFR 突变 NSCLC 病例。260 例患者的不同 EGFR-TKI、化疗和免疫检查点抑制剂治疗后的临床随访数据可用。治疗反应在三个主要组中进行分析：（i）非典型突变（G719X、S7681、L861Q 和组合）、（ii）外显子 20 插入和（iii）非常罕见的 EGFR 突变（非常罕见的单点突变、复合突变、外显子 18 缺失、外显子 19 插入）。
我们的研究包含迄今为止报道的最大的真实世界队列，该队列接受了不同的系统治疗，治疗非常罕见的 EGFR 单点和复合突变。与化疗相比，我们验证了在组 1（非典型）中 EGFR-TKI 的更高疗效，而大多数外显子 20 插入（组 2）对 EGFR-TKI 无反应。此外，我们发现非常罕见的点突变（组 3）和包含外显子 19 缺失或 L858R 突变的复杂 EGFR 突变的 TKI 敏感性与组合伙伴无关。值得注意的是，组 3（非常罕见）的治疗反应高度异质性。在组 2 和组 3 中，共存的 TP53 突变对接受 EGFR-TKI 治疗的患者的预后有不利影响，但在组 1 中没有这种趋势。
基于我们的发现，我们提出了一种新的非典型 EGFR 突变 nNGM 分类。
