Subtype-associated clinicopathological and tumor immune microenvironment heterogeneity in primary EGFR T790M compound-mutant lung adenocarcinoma: a retrospective cohort study.
- 1Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract
Primary epidermal growth factor receptor (EGFR) T790M-mutant lung adenocarcinoma (LUAD) is rare, and the clinicopathological characteristics and tumor immune microenvironment (TIME) of different compound-mutant subtypes remain poorly characterized. This study aimed to characterize the clinicopathological and TIME features of primary EGFR T790M compound-mutant LUAD and explore subtype-specific associations with disease-free survival. We retrospectively analyzed 255 patients with surgically resected primary EGFR T790M compound-mutant LUAD. Tissue microarrays from 158 patients were evaluated using immunohistochemistry (IHC) and multiplex immunofluorescence (mIF). Disease-free survival (DFS) was analyzed using the Kaplan-Meier method, while prognostic factors were evaluated using Cox proportional hazards regression for clinicopathological variables and Firth's penalized Cox regression for immune markers. Primary EGFR T790M mutation predominantly occurred in compound-mutant form, with T790M+L858R being the most common subtype. Compared with T790M+L858R, T790M+19del had a larger maximum tumor diameter and higher frequencies of lymphovascular invasion, pleural invasion, and lymph node metastasis (all P<0.05). IHC and mIF analyses demonstrated subtype-associated TIME differences. The T790M+19del subtype showed an increased proportion of CD68+CD163+ macrophages and higher expression of immune-regulatory markers, whereas the T790M+L858R subtype showed relative enrichment of CD3+CD8+ T cells. In exploratory survival analyses, subtype-specific associations between TIME-related markers and DFS were observed: concurrent high expression of CD66b and CTLA4 was associated with shorter DFS in the T790M+19del subtype, whereas high TIGIT expression was associated with shorter DFS in the T790M+L858R subtype. Primary EGFR T790M compound-mutant LUAD exhibits subtype-associated clinicopathological and TIME heterogeneity. These findings highlight the importance of considering accompanying EGFR activating mutation subtypes when evaluating this rare molecular subgroup.
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BibTeX
@article{lin2026subtypeassociated,
title = {{Subtype-associated clinicopathological and tumor immune microenvironment heterogeneity in primary EGFR T790M compound-mutant lung adenocarcinoma: a retrospective cohort study.}},
author = {Yu Lin and Zhenbang Ye and Shuai Wu and Bingzhi Wang and Long Wang and Lina Gao and Dian Jiao and Weihua Li and Jianming Ying},
journal = {Translational lung cancer research},
year = {2026},
month = oct,
doi = {10.21037/tlcr-2026-0961},
url = {https://europepmc.org/article/MED/42999423},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Subtype-associated clinicopathological and tumor immune microenvironment heterogeneity in primary EGFR T790M compound-mutant lung adenocarcinoma: a retrospective cohort study.
AU - Yu Lin
AU - Zhenbang Ye
AU - Shuai Wu
AU - Bingzhi Wang
AU - Long Wang
AU - Lina Gao
AU - Dian Jiao
AU - Weihua Li
AU - Jianming Ying
PY - 2026
DA - 2026/10/20
JO - Translational lung cancer research
DO - 10.21037/tlcr-2026-0961
UR - https://europepmc.org/article/MED/42999423
AB - Primary epidermal growth factor receptor (EGFR) T790M-mutant lung adenocarcinoma (LUAD) is rare, and the clinicopathological characteristics and tumor immune microenvironment (TIME) of different compound-mutant subtypes remain poorly characterized. This study aimed to characterize the clinicopathological and TIME features of primary EGFR T790M compound-mutant LUAD and explore subtype-specific associations with disease-free survival. We retrospectively analyzed 255 patients with surgically resected primary EGFR T790M compound-mutant LUAD. Tissue microarrays from 158 patients were evaluated using immunohistochemistry (IHC) and multiplex immunofluorescence (mIF). Disease-free survival (DFS) was analyzed using the Kaplan-Meier method, while prognostic factors were evaluated using Cox proportional hazards regression for clinicopathological variables and Firth's penalized Cox regression for immune markers. Primary EGFR T790M mutation predominantly occurred in compound-mutant form, with T790M+L858R being the most common subtype. Compared with T790M+L858R, T790M+19del had a larger maximum tumor diameter and higher frequencies of lymphovascular invasion, pleural invasion, and lymph node metastasis (all P<0.05). IHC and mIF analyses demonstrated subtype-associated TIME differences. The T790M+19del subtype showed an increased proportion of CD68+CD163+ macrophages and higher expression of immune-regulatory markers, whereas the T790M+L858R subtype showed relative enrichment of CD3+CD8+ T cells. In exploratory survival analyses, subtype-specific associations between TIME-related markers and DFS were observed: concurrent high expression of CD66b and CTLA4 was associated with shorter DFS in the T790M+19del subtype, whereas high TIGIT expression was associated with shorter DFS in the T790M+L858R subtype. Primary EGFR T790M compound-mutant LUAD exhibits subtype-associated clinicopathological and TIME heterogeneity. These findings highlight the importance of considering accompanying EGFR activating mutation subtypes when evaluating this rare molecular subgroup.
SN - 2218-6751
SN - 2226-4477
ER -