Background <?tk 4?>The aim of this study is to delineate clinicopathologic features, therapeutic outcomes, and tumor microenvironment (TME) remodeling in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) aberrations who experience histologic transformation (HT), with emphasis on post-transformation treatment efficacy. Methods <?tk 2?>This single-center retrospective cohort study included 6,230 patients with advanced NSCLC treated between December 2017 and January 2024. Patients who experienced histologic transformation after progression were identified through high-quality tumor biopsies or cytological samples. Treatment regimens for post-HT, including chemotherapy combined with tyrosine kinase inhibitors (CTK), chemotherapy combined with anti-angiogenic/immunotherapy (CAI), and palliative care (PC), were analyzed. Multiplex immunofluorescence was used to profile the tumor microenvironment in a subset of patients. Results <?tk 4?>Of the 6,230 patients, 84 (1.35%) experienced HT, with 73.81% transforming to small cell lung cancer (SCLC). The median time to HT was 22.27 months. Patients receiving CTK exhibited significantly longer median overall survival (OS1) after HT (OS1: 15.40 months) compared to CAI (11.23 months) and PC (4.37 months; P = 0.003). While CTK improved OS1, progression-free survival (PFS1) did not differ significantly across groups. In second-line treatment, incorporating tyrosine kinase inhibitors (TKIs) significantly prolonged PFS2 (PFS2; median: 6.70 months, compared with 2.87 months for regimens not incorporating TKIs; P = 0.016). Uncommon EGFR mutants exhibited paradoxical tumor microenvironment (TME) features, with elevated CD8+ infiltration (128.5 vs. 64.2 cells/mm²; p = 0.028) accompanied by Treg dominance (Foxp3+CD25+/CD8+ ratio: 0.41 vs. 0.19; p = 0.039). Immunotherapy-containing regimens improved PFS1 in uncommon mutants (3.10 vs. 1.83 months; P = 0.007); however, overall survival remained comparable. Conclusions: Histologic transformation poses a significant challenge in advanced NSCLC management. Chemotherapy combined with TKIs appears to offer the best survival benefit for post-HT, while second-line inclusion of TKIs improves PFS. Personalized strategies accounting for histologic subtype, molecular alterations, and immune contexture are essential for optimizing outcomes in this clinically distinct population. Further large-scale studies are warranted to refine therapeutic approaches.

Clinicopathologic features and therapeutic outcomes in EGFR/ALK-aberrations NSCLC with histologic transformation

期刊论文
出版模式：

开放获取
发表日期：

2025年12月23日

查看全文

Kaibo Ding,
Xinyue Li,
Hui Li,
Jing Qin,
Dujiang Liu,
Yanjun Xu

摘要

Background

The aim of this study is to delineate clinicopathologic features, therapeutic outcomes, and tumor microenvironment (TME) remodeling in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) aberrations who experience histologic transformation (HT), with emphasis on post-transformation treatment efficacy.

Methods

This single-center retrospective cohort study included 6,230 patients with advanced NSCLC treated between December 2017 and January 2024. Patients who experienced histologic transformation after progression were identified through high-quality tumor biopsies or cytological samples. Treatment regimens for post-HT, including chemotherapy combined with tyrosine kinase inhibitors (CTK), chemotherapy combined with anti-angiogenic/immunotherapy (CAI), and palliative care (PC), were analyzed. Multiplex immunofluorescence was used to profile the tumor microenvironment in a subset of patients.

Results

Of the 6,230 patients, 84 (1.35%) experienced HT, with 73.81% transforming to small cell lung cancer (SCLC). The median time to HT was 22.27 months. Patients receiving CTK exhibited significantly longer median overall survival (OS₁) after HT (OS₁: 15.40 months) compared to CAI (11.23 months) and PC (4.37 months; P = 0.003). While CTK improved OS₁, progression-free survival (PFS₁) did not differ significantly across groups. In second-line treatment, incorporating tyrosine kinase inhibitors (TKIs) significantly prolonged PFS₂ (PFS₂; median: 6.70 months, compared with 2.87 months for regimens not incorporating TKIs; P = 0.016). Uncommon EGFR mutants exhibited paradoxical tumor microenvironment (TME) features, with elevated CD8⁺ infiltration (128.5 vs. 64.2 cells/mm²; p = 0.028) accompanied by Treg dominance (Foxp3⁺CD25⁺/CD8⁺ ratio: 0.41 vs. 0.19; p = 0.039). Immunotherapy-containing regimens improved PFS₁ in uncommon mutants (3.10 vs. 1.83 months; P = 0.007); however, overall survival remained comparable. Conclusions: Histologic transformation poses a significant challenge in advanced NSCLC management. Chemotherapy combined with TKIs appears to offer the best survival benefit for post-HT, while second-line inclusion of TKIs improves PFS. Personalized strategies accounting for histologic subtype, molecular alterations, and immune contexture are essential for optimizing outcomes in this clinically distinct population. Further large-scale studies are warranted to refine therapeutic approaches.