复合表皮生长因子受体 (EGFR) 突变在非小细胞肺癌 (NSCLC) 中对酪氨酸激酶抑制剂 (TKI) 的反应性比单一 EGFR 突变低。然而，各种复合 EGFR 突变的详细临床特征和预后仍需阐明。我们回顾性研究了 1025 名 NSCLC 患者的治疗前瘤体次世代测序 (NGS) 数据，这些患者携带复合 EGFR 突变，可进一步细分为常见突变 (19-Del 和 EGFR 外显子 21 p.L858R)、罕见突变和不确定型变异 (VUSs) 的不同组合。分别在 174 名和 95 名患者中分析了预后和一线 TKI 的药物耐受性。 复合 EGFR 突变富含 EGFR 外显子 21 p.L858R 和罕见突变，但不富含 19-Del (P<0.001)。常见+罕见和罕见+罕见亚型在 PI3K 途径上具有较少的并发突变 (P=0.032)，而罕见+罕见和常见+ VUSs 亚型分别与与吸烟和替莫唑胺相关的突变签名呈增加关联 (P<0.001)。以罕见突变为主的亚型 (罕见+ VUSs 和罕见+罕见) 对一线 TKI 的预后为最差 (P<0.001)，并在外部队列表明 (P=0.0066) 。罕见+ VUSs 亚型中的 VUSs 选择性地存在于 EGFR 激酶结构域内 (P<0.001)，这暗示这些肿瘤可能选择额外突变来破坏激酶结构域的调控/功能。 不同亚型的复合 EGFR 突变显示出不同的临床特征和基因体系结构，罕见突变为主的复合 EGFR 突变与富含激酶结构域中的 VUSs 和不良预后相关。我们的研究结果有助于更好地了解复合 EGFR 突变的肿瘤发生过程，并预测个体化治疗的预后结果。 ©2023作者。

Compound epidermal growth factor receptor (EGFR) mutations are less responsive to tyrosine kinase inhibitors (TKIs) than single EGFR mutations in non-small cell lung cancer (NSCLC). However, the detailed clinical characteristics and prognosis of various compound EGFR mutations remain to be elucidated.We retrospectively studied the next-generation sequencing (NGS) data of treatment-naïve tumors from 1025 NSCLC patients with compound EGFR mutations, which were sub-categorized into different combinations of common mutations (19-Del and EGFR exon 21 p.L858R), rare mutations, and variants of uncertain significance (VUSs). Prognosis and drug resistance to first-line TKIs were analyzed in 174 and 95 patients, respectively.Compound EGFR mutations were enriched with EGFR exon 21 p.L858R and rare mutations, but not 19-Del (P < 0.001). The common + rare and rare + rare subtypes had fewer concurrent mutations in the PI3K pathway (P = 0.032), while the rare + rare and common + VUSs subtypes showed increased association with smoking- and temozolomide-related mutational signatures, respectively (P < 0.001). The rare mutation-dominant subtypes (rare + VUSs and rare + rare) had the worst clinical outcomes to first-line TKIs (P < 0.001), which was further confirmed using an external cohort (P = 0.0066). VUSs in the rare + VUSs subtype selectively reside in the EGFR kinase domain (P < 0.001), implying these tumors might select additional mutations to disrupt the regulation/function of the kinase domain.Different subtypes of compound EGFR mutations displayed distinct clinical features and genetic architectures, and rare mutation-dominant compound EGFR mutations were associated with enriched kinase domain-resided VUSs and poor clinical outcomes. Our findings help better understand the oncogenesis of compound EGFR mutations and forecast prognostic outcomes of personalized treatments.© 2023. The Author(s).