Translational lung cancer research最新文献

Background: Immune checkpoint inhibitor (ICI) therapy has prolonged the survival of a proportion of patients with advanced non-small cell lung cancer (NSCLC). Histological quantification of programmed cell death-ligand 1 (PD-L1) in tumors is a widely adopted marker for predicting the efficacy of ICI treatment. However, its use in patients with malignant pleural effusion (MPE) is occasionally challenging because of the difficulty of tissue sampling. The aim of this study was to identify new predictive factors for ICI treatment in patients with MPE.

Methods: A total of 22 patients with MPE were included. Initially, we surveyed several parameters of pleural effusion in relation to overall survival (OS). Next, we attempted to reflect the response to ICI treatment in vitro, a simple co-culture bioassay was designed, in which tumor cells and immune cells were co-cultured with nivolumab. Binding of nivolumab to T cells was confirmed by flow cytometry, and the released interferon-gamma (IFN-γ) was evaluated by enzyme-linked immunosorbent assay.

Results: The parameter analysis demonstrated that the levels of albumin and the percentage of lymphocyte were significantly correlated with OS in all patients. Vascular endothelial growth factor (VEGF) and high mobility group box 1 (HMGB1) were negatively correlated with OS in only driver gene mutation-positive patients. In vitro bioassay showed that nivolumab-binding T cells predominantly produced IFN-γ compared with control antibody. Of the 22 patients, 12 showed an increase in IFN-γ release after treatment with nivolumab. Despite the lack of significant correlations between IFN-γ levels and OS, the duration of ICI treatment tended to be longer in patients with IFN-γ release versus those without IFN-γ release.

Conclusions: This immune assay of IFN-γ release after treatment with nivolumab in vitro may identify responders prior to ICI treatment.

Background: Differences in the immune microenvironment and responses to immunotherapy may exist between primary non-small cell lung cancer (NSCLC) and brain metastases (BMs). This study aimed to investigate discrepancies in programmed death-ligand 1 (PD-L1) expression, tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLS), and tumor mutational burden (TMB) between matched BMs and primary tumors (PTs) in NSCLC.

Methods: Twenty-six pairs of surgically resected BMs and corresponding PTs from NSCLC patients were collected. PD-L1 expression and TILs, including CD8, CD3, CD4, CD20, CD68, and CD21, were analyzed using immunohistochemistry (IHC) and quantitatively assessed through digital image analysis. Whole-exome sequencing (WES) was performed to investigate genomic discrepancies and variations in TMB.

Results: The density of PD-L1⁺ cells did not differ significantly between matched PTs and BMs (P>0.99). However, BMs exhibited a higher tumor proportion score (TPS) compared to PTs (mean TPS: 31.92% vs. 25.96%, P=0.049), with moderate agreement in categorized TPS (κ=0.653). Analysis of TILs revealed a significant reduction in CD3⁺ T cells (P<0.001), CD8⁺ cytotoxic T cells (P<0.001), CD20⁺ B cells (P<0.001), and CD68⁺ macrophages (P=0.02) in BMs compared to PTs. BMs also exhibited a loss of TLS, with no presence of mature TLS marked by CD21 expression. The number of non-synonymous mutations was generally higher in BMs than in PTs, with only 34.69% of mutations shared between paired PTs and BMs. TMB was slightly increased in BMs (mean TMB: 34.2 mutations/Mb in BMs vs. 26.8 mutations/Mb in PTs; P=0.30). Additionally, the log-rank test indicated that a higher density of CD20⁺ B cells in BMs was significantly associated with better overall survival (P=0.007).

Conclusions: Compared to primary NSCLC tumors, matched BMs show an increase in TPS of PD-L1 expression and TMB, but a significant reduction in TILs and loss of mature TLS, suggesting an immune-suppressive microenvironment in BMs. The infiltration of CD20⁺ B cells may serve as a potential prognostic biomarker in NSCLC with BMs.

Background: The role of pyroptosis in lung squamous cell carcinoma (LUSC) remains unclear. This study aimed to screen pyroptosis-related genes (PRGs) and construct a model to investigate the immune infiltration, gene mutations, and immune response of patients of LUSC.

Methods: We conducted a comprehensive evaluation of pyroptosis patterns in patients with LUSC with 51 PRGs. Pyroptosis-related clusters were identified using consistency clustering algorithm. Differences in the biologic and clinical characteristics between the clusters were analyzed. Cox regression analysis was performed to screen for differentially expressed genes (DEGs) related to prognosis, and a principal component analysis (PCA) algorithm was used to construct a model based on these genes. The pyroptosis score was calculated for each tumor sample, and the samples were classified into high- and low-score groups based on the score. The disparities in survival, single-nucleotide variation (SNV), copy number variation (CNV), and immunotherapy response between high-score and low-score groups were analyzed.

Results: A total of 51 PRGs were used to classify LUSC samples into three pyroptosis clusters with significant differences in survival (P=0.005). Based on the 390 DEGs between the three clusters, two distinct pyroptosis gene clusters were identified by secondary clustering, with significant differences in prognosis (P=0.005). A pyroptosis scoring model was established to evaluate the regulatory patterns of PRGs, and patients were stratified into two groups with high and low scores, using the median pyroptosis score as the cutoff. The survival analyses indicated that patients with high scores had worse prognoses in The Cancer Genome Atlas (TCGA)-LUSC cohort (P=0.002), which was further supported by the analysis of the GSE37745 (P=0.006) and GSE135222 datasets (P=0.02).

Conclusions: The quantification of pyroptosis patterns was found to be important in predicting prognosis and devising personalized treatment strategies in patients with LUSC.

Background: Health-related quality of life (HRQoL) is critical for patients with lung cancer due to poor prognosis. We presented patient-reported outcomes in patients with non-small cell lung cancer (NSCLC) brain metastases (BM) who received whole-brain radiotherapy (WBRT) in combination with erlotinib or WBRT alone in the phase 3 ENTER study.

Methods: The patients' HRQoL was assessed by using the European Organization for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire (EORTC QLQ-C30). Mean changes in scores on different quality of life (QoL) scales relative to baseline were reported. The QoL response and time to deterioration of QoL were compared between different treatment arms.

Results: The absolute mean differences in global health status/QoL scores, all functional and symptom scale scores from baseline between the two arms were not significantly different at all follow-up time points. After month 5, there was an improvement in nausea/vomiting symptom scores in the WBRT arm relative to their pretreatment baseline (P=0.003), while the WBRT + erlotinib arm had improved scores in fatigue (P=0.01), nausea/vomiting (P=0.02), pain (P=0.04) and insomnia (P=0.01). Compared to the WBRT arm, a greater proportion of patients in the combination treatment arm had deteriorating diarrhea (P=0.009), along with significantly delayed time to deterioration in role function (4.4 vs. 7.0 months, P=0.03), insomnia (7.0 vs. 4.7 months, P=0.02), and constipation (12.7 vs. 9.3 months, P=0.02) symptoms.

Conclusions: The simultaneous addition of erlotinib during WBRT did not decrease the QoL in the overall or epidermal growth factor receptor (EGFR)-mutant patients with BM and resulted in improvements on more QoL scales and slower worsening of some self-reported symptoms compared to WBRT alone.

Trial registration: ClinicalTrials.gov identifier: NCT01887795.

Background: The Lung Cancer Staging Program of the International Association for the Study of Lung Cancer (IASLC) has proposed using solid component size, rather than overall tumor size, for T-staging. However, studies focusing on patients with ground-glass opacity (GGO) lesions with a diameter larger than 2 cm are limited. This study aims to validate the T stage classification strategy recommended by IASLC in this specific and less-studied patient group.

Methods: Patients diagnosed with primary non-small cell lung cancer (NSCLC) who underwent lobectomy between December 2009 and December 2018 were included in this study. Clinical, pathological, and prognostic data were prospectively collected and retrospectively reviewed. Patients were eligible if they were confirmed to have NSCLC, underwent lobectomy, had complete follow-up data, and were not diagnosed with any other malignancies. The propensity score matching (PSM) method was employed to ensure baseline characteristic balance. Two groups of patients matched with the GGO group at baseline were stratified based on overall tumor size (group matched by overall size) and solid component size (group matched by solid component size), respectively. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using the Cox proportional model and Kaplan-Meier method. Follow-up was conducted regularly to assess these outcomes. The T-staging applied was based on the solid component size according to the 8th edition IASLC staging guidelines.

Results: A total of 4,472 NSCLC patients who underwent lobectomy were included in the study (including 4,083 cases of solid lesions and 389 cases of subsolid lesions). The median follow-up time was 75.4 months. Patients in the GGO group had significantly better OS and RFS than those in the solid group [OS: hazard ratio (HR) =0.55, 95% confidence interval (CI): 0.40-0.73, P<0.001; RFS: HR =0.53, 95% CI: 0.42-0.67, P<0.001]. Comparing patients' PSM by overall size, the GGO group still had better OS and RFS (OS: HR =0.60, 95% CI: 0.43-0.85, P=0.004; RFS: HR =0.59, 95% CI: 0.44-0.79, P<0.001). After PSM by solid component size, no significant difference was detected between the GGO group and the group matched by solid component size on OS and RFS (OS: HR =0.89, 95% CI: 0.61-1.28, P=0.52; RFS: HR =0.92, 95% CI: 0.67-1.26, P=0.61). In subgroup analysis, after PSM by solid component size, the results showed no difference in OS and RFS between the restaged patients (c-T1 and c-T2) and the corresponding patients in the solid group (for OS, HR =1.06, 95% CI: 0.61-1.83, P=0.83; HR =1.11, 95% CI: 0.60-2.07, P=0.73, respectively; and RFS, HR =1.17, 95% CI: 0.75-1.82, P=0.49; HR =0.80, 95% CI: 0.48-1.34, P=0.39, respectively).

Conclusions: The T stage classification strategy proposed by ISALC remains applicable in patients with GGOs larger than 2 cm.

Background: Dabrafenib plus trametinib (Dab + Tram) is an approved targeted therapy in patients with BRAF ^V600+ mutated metastatic non-small cell lung cancer (NSCLC). Here, we report the efficacy, safety, and quality of life (QoL) results of Dab + Tram treatment in Chinese patients with BRAF ^V600E mutation-positive metastatic NSCLC.

Methods: This is a single-arm, open-label, multicentre, phase II study (NCT04452877). Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. The primary endpoint was overall response rate (ORR) by central independent review per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. Secondary endpoints included ORR by investigator assessment, progression-free survival (PFS), duration of response (DOR), overall survival (OS), safety, tolerability, and QoL.

Results: At the data cut-off (March 11, 2021), 18 of 20 enrolled patients were still receiving treatment. The median age was 64 years; majority were female (55%), non-smokers (55%), and had ≥3 metastatic sites (70%). Nine patients received prior anticancer therapy in a therapeutic or metastatic setting. The median duration of follow-up was 5 months. The ORR by both central and investigator assessment was 75% [95% confidence interval (CI): 50.9-91.3%]. The median DOR, PFS, and OS were not reached/estimable at the cut-off date. The most common treatment-related adverse events (AEs) (all grades, in ≥30% of patients) were pyrexia, increased aspartate aminotransferase (AST), decreased neutrophil count, and decreased white blood cell (WBC) count. The self-reported QoL was improved or maintained during the treatment period.

Conclusions: Dab + Tram treatment is safe, effective, and can preserve or improve QoL in majority of Chinese patients with BRAF ^V600E mutation-positive metastatic NSCLC. The results are consistent with the global phase II study.

Background: Preoperative assessment of lymph node status is critical in managing lung cancer, as it directly impacts the surgical approach and treatment planning. However, in clinical stage I lung adenocarcinoma (LUAD), determining lymph node metastasis (LNM) is often challenging due to the limited sensitivity of conventional imaging modalities, such as computed tomography (CT) and positron emission tomography/CT (PET/CT). This study aimed to establish an effective radiomics prediction model using multicenter data for early assessment of LNM risk in patients with clinical stage I LUAD. The goal is to provide a basis for formulating lymph node dissection strategies before surgery in early-stage lung cancer patients.

Methods: A total of 578 patients with LUAD from three medical centers [Cancer Hospital, Chinese Academy of Medical Sciences (CCAM), the First Affiliated Hospital of Chongqing Medical University (1CMU), and Beijing Chao-Yang Hospital (BCYH)] who underwent preoperative chest CT were divided into three groups, the training group (n=336), the testing group (n=167), and the independent validation group (n=75). The records of 1,316 radiomics features of each primary tumor were extracted. The least absolute shrinkage and selection operator (LASSO) analysis and multivariable logistic regression were used to reduce the data dimensionality, select features, and construct the prediction models.

Results: In the training group, the area under the curve (AUC) for the clinical model, radiomics model, and composite model were 0.820, 0.871, and 0.883, respectively. In the testing group, the AUC for the clinical model, radiomics model, and composite model were 0.897, 0.915, and 0.934, respectively. In the validation set, the AUC of the radiomics model was the highest at 0.870, while the composite model and clinical model had AUCs of 0.841 and 0.710, respectively. The results of the Delong test showed that the AUCs of the radiomics model and composite model were significantly higher than those of the clinical model in both the training and validation groups. The decision curve analysis showed that the radiomics nomogram was clinically useful.

Conclusions: This study developed and validated a radiomics prediction model, which enables easy LNM prediction in stage I LUAD patients. This model provides a basis for formulating lymph node dissection strategies before surgery and helps to better determine the tumor node metastasis stage of the early-stage LUAD.