Sompallae Ramakrishna R, Dundar Bilge, Guseva Natalya V, Bossler Aaron D, Ma Deqin
Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, IA, United States.
Front Oncol. 2023 May 22;13:1163485. doi: 10.3389/fonc.2023.1163485. eCollection 2023.
Exon 20 (ex20) in-frame insertions or duplications (ins/dup) in epidermal growth factor receptor () and its analog erb-b2 receptor tyrosine kinase 2 () are each detected in 1.5% of non-small cell lung cancer (NSCLC). Unlike p.L858R or ex19 deletions, ex20 ins/dup is associated with resistance to classic EGFR inhibitors, lack of response to immune checkpoint inhibitors, and poor prognosis. US Food and Drug Administration has approved mobocertinib and amivantamab for targeting tumors with this aberration, but the number of comprehensive studies on ex20 ins/dup NSCLC is limited. We identified 18 cases of NSCLCs with ex20 ins/dup and correlated the findings with clinical and morphologic information including programed death-ligand 1 (PD-L1) expression.
A total of 536 NSCLC cases tested at our institution between 2014 and 2023 were reviewed. A custom-designed 214-gene next-generation sequencing panel was used for detecting DNA variants, and the FusionPlex CTL panel (ArcherDx) was used for the detection of fusion transcripts from formalin-fixed, paraffin-embedded tissue. Immunohistochemistry (IHC)for PD-L1 was performed using 22C3 or E1L3N clones.
Nine and nine ex20 ins/dup variants were identified from an equal number of men and women, 14 were non- or light smokers, and 15 had stage IV disease. All 18 cases were adenocarcinomas. Seven of the 11 cases with available primary tumors had acinar predominant pattern, two had lepidic predominant pattern, and the remainder had papillary (one case) and mucinous (one case) patterns. Ex20 ins/dup variants were heterogenous in-frame one to four amino acids spanning A767-V774 in and Y772-P780 in and were clustered in the loop following the C-helix and α C-helix. Twelve cases (67%) had co-existing variants. Copy number variation in amplification was identified in one case. No fusion or microsatellite instability was identified in any case. PD-L1 was positive in two cases, low positive in four cases, and negative in 11 cases.
NSCLCs harboring ex20 ins/dup are rare and tend to be acinar predominant, negative for PD-L1, more frequent in non- or light smokers, and mutually exclusive with other driver mutations in NSCLC. The correlation of different ex20 ins/dup variants and co-existing mutations with response to targeted therapy and the possibility of developing resistant mutations after mobocertinib treatment warrants further investigation.
表皮生长因子受体（EGFR）外显子20（ex20）框内插入或重复（ins/dup）以及其类似物erb-b2受体酪氨酸激酶2（HER2）的此类情况在1.5%的非小细胞肺癌（NSCLC）中均可检测到。与EGFR p.L858R或外显子19缺失不同，ex20 ins/dup与对经典EGFR抑制剂耐药、对免疫检查点抑制剂无反应以及预后不良相关。美国食品药品监督管理局已批准莫博替尼和阿美替尼用于靶向具有这种异常的肿瘤，但关于ex20 ins/dup NSCLC的全面研究数量有限。我们鉴定出18例具有EGFR ex20 ins/dup的NSCLC病例，并将这些发现与包括程序性死亡配体1（PD-L1）表达在内的临床和形态学信息相关联。
回顾了2014年至2023年在我们机构检测的总共536例NSCLC病例。使用定制设计的214基因下一代测序 panel检测DNA变异，使用FusionPlex CTL panel（ArcherDx）检测来自福尔马林固定、石蜡包埋组织的融合转录本。使用22C3或E1L3N克隆进行PD-L1的免疫组织化学（IHC）检测。
从数量相等的男性和女性中鉴定出9例EGFR和9例HER2 ex20 ins/dup变异，14例为不吸烟者或轻度吸烟者，15例为IV期疾病。所有18例均为腺癌。11例有可用原发肿瘤的病例中，7例以腺泡为主型模式，2例以鳞屑为主型模式，其余病例具有乳头型（1例）和黏液型（1例）模式。EGFR ex20 ins/dup变异为框内1至4个氨基酸的异质性，跨越EGFR中的A767 - V774和HER2中的Y772 - P780，且聚集在C螺旋和α C螺旋后的环中。12例（67%）存在共存的EGFR变异。在1例中鉴定出EGFR拷贝数变异扩增。在任何病例中均未鉴定出融合或微卫星不稳定性。2例PD-L1呈阳性，4例呈低阳性，11例呈阴性。
携带EGFR ex20 ins/dup的NSCLC罕见，倾向于以腺泡为主型，PD-L1阴性，在不吸烟者或轻度吸烟者中更常见，且与NSCLC中的其他驱动突变相互排斥。不同的EGFR ex20 ins/dup变异和共存突变与靶向治疗反应的相关性以及莫博替尼治疗后出现耐药突变的可能性值得进一步研究。
