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EGFR T790M突变非小细胞肺癌患者的临床病理学、免疫微环境特征及对预后预测的意义
Clinical pathological characteristics and immune microenvironment significance of
EGFR T790M mutation in non-small cell lung cancer patients and its prognostic implications- 中国癌症杂志 2024年34卷第4期 页码：368-379
- 作者机构：
复旦大学附属肿瘤医院病理科，复旦大学上海医学院肿瘤学系，上海 200032
- 作者简介：
[ "林艺聪（ORCID: 0009-0009-1299-5889），硕士研究生。" ]
李 媛（ORCID: 0000-0001-5651-819X），主任医师，复旦大学附属肿瘤医院病理科副主任。
- 基金信息：国家自然科学基金(81972171)
DOI：10.19401/j.cnki.1007-3639.2024.04.004
中图分类号： R734.2收稿：2023-12-13，
修回：2024-02-25，
纸质出版：2024-04-30
- 稿件说明：
移动端阅览
林艺聪, 王悦, 薛倩倩, 等. EGFR T790M突变非小细胞肺癌患者的临床病理学、免疫微环境特征及对预后预测的意义[J]. 中国癌症杂志, 2024,34(4):368-379.
Yicong LIN, Yue WANG, Qianqian XUE, et al. Clinical pathological characteristics and immune microenvironment significance of
EGFR T790M mutation in non-small cell lung cancer patients and its prognostic implications[J]. China Oncology, 2024, 34(4): 368-379.林艺聪, 王悦, 薛倩倩, 等. EGFR T790M突变非小细胞肺癌患者的临床病理学、免疫微环境特征及对预后预测的意义[J]. 中国癌症杂志, 2024,34(4):368-379. DOI： 10.19401/j.cnki.1007-3639.2024.04.004.
Yicong LIN, Yue WANG, Qianqian XUE, et al. Clinical pathological characteristics and immune microenvironment significance of
EGFR T790M mutation in non-small cell lung cancer patients and its prognostic implications[J]. China Oncology, 2024, 34(4): 368-379. DOI： 10.19401/j.cnki.1007-3639.2024.04.004.
摘要
背景与目的：
表皮生长因子受体20号外显子T790M突变（epidermal growth factor receptor exon 20 threonine-to-methionine substitution mutation at position 790，EGFR T790M）是非小细胞肺癌（non-small cell lung cancer，NSCLC）对第一/二代EGFR酪氨酸激酶抑制剂（EGFR tyrosine kinase inhibitor，
EGFR
TKI）的获得性耐药机制之一，
EGFR
T790M突变也可见于未经EGFR TKI治疗的NSCLC，本研究旨在比较原发性和获得性
EGFR
T790M突变NSCLC中的临床病理学特征和预后差异，进一步探讨NSCLC中获得性T790M突变的免疫微环境特征。
方法：
本研究回顾性分析复旦大学附属肿瘤医院从2020年4月—2022年9月诊断的3762例NSCLC，其中2070例（55.02%）存在EGFR突变，556例（14.77%）接受EGFR TKI治疗。其中
EGFR
T790M突变的NSCLC 119例（3.16%），51例（1.35%）为原发性
EGFR
T790M突变，68例（1.81%）为获得性
EGFR
T790M突变。收集患者的临床资料，对原发性和获得性T790M突变NSCLC进行比较，采用多重免疫荧光组织化学（multiple immunofluorescence histochemistry，mIHC）探讨获得性T790M突变NSCLC免疫微环境特征。
结果：
原发性和获得性T790M突变在女性患者中的比例均高于男性；原发性T790M突变患者更为年轻；原发性和获得性T790M突变均更容易出现在差分化癌中；原发性T790M突变NSCLC患者中，程序性死亡受体配体1（programmed death-ligand 1，PD-L1）表达阳性率较高（60.00%）；获得性T790M突变NSCLC患者中，PD-L1表达阳性率较低（22.39%）。获得性T790M突变NSCLC往往伴随着
TP
53改变（39.7%）。单因素Cox回归分析结果显示，间质表皮转化因子（mesenchymal to epithelial transition factor，MET）改变是出现获得性T790M突变的危险因素（
P
= 0.000 5）。原发性和获得性T790M突变的平均总生存期（overall survival，OS）差异无统计学意义（分别为35.4和37.3个月）。然而，获得性T790M突变患者复发和转移的比例较高。获得性T790M突变中，间质区域存在更多的免疫细胞浸润，如CD20
+
B淋巴细胞、CD23
+
B淋巴细胞、CD8
+
T淋巴细胞、CD8
+
程序性死亡受体1（programmed death 1，PD-1）
-/+
细胞、CD20
+
PD-1
-/+
细胞及CD23
+
PD-1
-/+
细胞等。此外，研究发现
EGFR
伴有抑癌基因（tumor suppressor gene，TSG）改变时，肿瘤细胞与CD8
+
T淋巴细胞、CD20
+
B淋巴细胞、CD8
+
PD-1
+
细胞、CD20
+
PD-1
+
细胞和 CD23
+
PD-1
+
细胞的平均距离较仅有
EGFR
突变更近。
结论：
相较于原发性T790M突变，获得性T790M突变的病例中，PD-L1阳性率较低。获得性T790M突变常伴有
TP
53改变，而MET改变则是引发获得性T790M突变的一个危险因素。虽然获得性T790M突变患者的复发和转移风险较高，但其平均OS与原发性T790M突变患者并无显著差异。获得性T790M突变患者中，伴有TSG突变时可改变免疫细胞的空间分布，有望从免疫治疗中获益。
Abstract
Background and purpose:
Epidermal growth factor receptor exon 20 T790M (
EGFR
T790M) mutation is one of the acquired resistance mechanisms in non-small cell lung cancer (NSCLC) against first-/second-generation EGFR tyrosine kinase inhibitors (EGFR TKIs). Additionally
EGFR
T790M mutation can also be observed in NSCLC patients who have not undergone EGFR TKIs treatment. This study aimed to compare the clinical pathological characteristics and prognostic differences between NSCLC patients with
de novo
and acquired EGFR T790M mutation
and further explore the immune microenvironment features of acquired T790M mutation in NSCLC.
Methods:
This study retrospectively included 3 762 cases of NSCLC diagnosed at Fudan University Shanghai Cancer Center from April 2020 to September 2022. Among them
2 070 cases (55.02%) exhibited
EGFR
mutations
and 556 cases (14.77%) received EGFR TKIs treatment. Specifically
there were 119 cases (3.16%) of NSCLC with
EGFR
T790M mutation
including 51 cases (1.35%) of
de novo
T790M mutation and 68 cases (1.81%) of acquired
EGFR
T790M mutation. Clinical data of the patients were collected for comparative analysis between NSCLC patients with
de novo
and acquired T790M mutation. Multiple immunofluorescence histochemistry (mIHC) was employed to explore the immune microenvironment characteristics of NSCLC patients with acquired T790M mutation.
Results:
The proportion of
de novo
and acquired T790M mutations was higher in female patients compared to males. Patients with
de novo
T790M mutation tended to
be younger. Both
de novo
and acquired T790M mutations were more commonly found in poorly differentiated carcinomas. Among NSCLC patients with
de novo
T790M mutation
there was a higher rate of programmed death ligand-1 (PD-L1) expression (60.00%). In contrast
among NSCLC patients with acquired T790M mutation
the rate of PD-L1 expression was lower (22.39%). Acquired T790M mutation in NSCLC was often accompanied by
TP
53 alterations (39.7%). Cox regression analysis results indicated that mesenchymal to epithelial transition (MET) factor alteration was a risk factor for the occurrence of acquired T790M mutation (
P
=0.000 5). The average overall survival (OS) showed no significant difference between
de novo
and acquired T790M mutations (35.4 and 37.3 months respectively). However
patients with acquired T790M mutation exhibited a higher proportion of recurrence and metastasis. In acquired T790M mutation
there was a higher presence of immune cell infiltration within the stromal compartment
such as CD20
+
B cells
CD23
+
B cells
CD8
+
T cells
CD8
+
PD-1
-/+
cells
CD20
+
PD-1
-/+
cells and CD23
+
PD-1
-/+
cells. Additionally
the study found that when EGFR was accompanied by tumor suppressor gene (TSG) alterations
the average distance between tumor cells and CD8
+
T cells
CD20
+
B cells
CD8
+
PD-1
+
cells
CD20
+
PD-1
+
cells and CD23
+
PD-1
+
cells was closer compared to cases with only
EGFR
mutations.
Conclusion:
In comparison to patients with
de novo
T790M mutation
patients with acquired T790M mutation exhibit a lower rate of PD-L1 positivity. Acquired T790M mutation often accompanies
TP
53 alterations
and
MET
alteration is identified as a risk factor triggering acquired T790M mutatio
n. Although patients with acquired T790M mutation face higher risk of recurrence and metastasis
their average OS does not significantly differ from those with
de novo
T790M mutation. In cases of acquired T790M mutation
the presence of TSG mutations can alter the spatial distribution of immune cells
potentially leading to benefits from immunotherapy.
关键词
Keywords
references
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