Translational lung cancer research最新文献

Background and objective: The increasing use of neoadjuvant therapy in non-small cell lung cancer (NSCLC) has magnified the importance of pathologic response as a treatment endpoint. However, there are persistent challenges in its assessment and interpretation. This review aimed to synthesize current methods and challenges in evaluating pathologic response in patients with NSCLC, summarize available assessment techniques and biomarkers, and collate current data on pathologic response to neoadjuvant treatments and the association with survival outcomes.

Methods: We selected and reviewed articles proposing guidelines or approaches to the pathologic assessment of NSCLC, articles describing challenges in assessing pathologic response in NSCLC, and studies reporting pathologic response to neoadjuvant treatment and/or the association between pathologic response and survival outcomes. Data were extracted and summarized descriptively.

Key content and findings: In this review, we summarize methods for evaluating pathologic response in patients with resectable NSCLC and highlight current challenges, including variability in pathologic response assessment, the limited standardization of techniques and biomarkers, and the difficulty of interpreting pathologic response. We also review current clinical data on pathologic response to neoadjuvant chemotherapy, radiotherapy, immunotherapy, tyrosine kinase inhibitors (TKIs), and antiangiogenic therapies, and the association between pathologic response and survival outcomes. Finally, we review and discuss the selection of optimal treatment strategies for patients who achieve a pathologic response to neoadjuvant therapy.

Conclusions: Pathologic response is a valuable indicator of early response to treatment, but its current limitations necessitate a cautious and balanced approach in treatment decision-making for patients with early-stage resectable NSCLC, with consideration also given to other factors such as long-term survival and quality of life.

Background: The mesenchymal-epithelial transition factor (MET) gene is a key therapeutic target in non-small cell lung cancer (NSCLC), affecting the tumor expression of programmed cell death ligand 1 (PD-L1) and the immune microenvironment. This study examined the relationship between cellular MET (c-MET) expression, immune profiles, and survival in patients with NSCLC treated with radiochemotherapy and consolidative immunotherapy.

Methods: c-MET expression levels and immune profiles, including cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), lymphocyte-activation gene 3 (LAG3), forkhead box protein P3 (FOXP3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), were accessed in 60 locally advanced patients with NSCLC treated with radiochemotherapy and sequential immunotherapy at Shanghai Pulmonary Hospital. Correlations between c-MET gene expression and immune cell infiltration were additionally explored using publicly available transcriptomic datasets and bioinformatics analysis. Categorical data were analyzed with Chi-squared tests, survival functions were derived from Kaplan-Meier estimates, and Cox regression assessed the independent impact on overall survival (OS) and progression-free survival (PFS).

Results: PFS and OS for the cohort were 24.0 and 34.0 months, respectively. OS was significantly associated with reduced macrophage (CD68⁺) infiltration (P=0.03), while PFS was significantly associated with high c-MET expression (P=0.03). Correlation analysis indicated a significant correlation between c-MET expression and macrophage (CD68⁺) infiltration (P=0.01).

Conclusions: c-MET expression and macrophage (CD68⁺) infiltration were identified as potential predictors of survival and were found to be significantly correlated with one another. These findings suggest that antibody-drug conjugates targeting c-MET in combination with immune checkpoint inhibitors may represent a potentially effective consolidation therapy strategy following chemoradiotherapy in patients with locally advanced NSCLC.

Background: Liquid biopsy based on cell-free DNA (cfDNA) in oncology has emerged as a promising technique for tracking cancer dynamics, especially for detecting minimal residual disease. To date, most studies have used cfDNA for static evaluations of tumor burden. In this study, we propose a novel approach integrating serial cfDNA and computed tomography (CT) tumor volume to fully reflect the dynamic nature of tumor response after treatment.

Methods: This prospective study involved 25 patients treated with curative-intent radiotherapy for localized non-small cell lung cancer (NSCLC) between June 2019 and November 2020, with 17 subsequently included in final analysis. Longitudinal blood samples were divided into two phases relative to day 3 after treatment initiation, and kinetic parameters, such as velocity and acceleration of cfDNA levels, were calculated. To complement sparse samplings in later days, volume data from routine CT scans were incorporated. K-means clustering using two different variable sets (cfDNA only and cfDNA with volume parameters) and conventional assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were applied to stratify patients, and their performance was compared.

Results: The model incorporating both cfDNA and volume parameters effectively separated responders (mean progression-free survival, 44.2 months) from non-responders [16.6 months, P=0.02; area under the receiver operating characteristic curve (AUC) =0.955], outperforming cfDNA only model (36.0 vs. 14.5 months, P=0.04; AUC =0.848). In contrast, RECIST v1.1-based conventional assessment showed no significant difference (P=0.62, AUC =0.70).

Conclusions: Therefore, our study demonstrates that integration of longitudinal cfDNA and tumor volume dynamics yielded improved assessment of treatment response and prognosis in NSCLC.

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC). However, their efficacy and safety in patients with idiopathic interstitial pneumonias (IIPs) or interstitial lung abnormalities (ILAs) remain poorly defined, as such patients have been largely excluded from pivotal clinical trials. This study aimed to assess real-world outcomes and adverse events associated with ICI-based therapies in patients with NSCLC and coexisting IIPs or ILAs.

Methods: We conducted a multicenter retrospective cohort study across 11 institutions affiliated with the North Japan Lung Cancer Study Group. Patients with advanced NSCLC and pre-existing IIPs or ILAs who received ICI monotherapy or ICI plus chemotherapy (chemo-ICI) between December 2015 and March 2020 were included. Data on progression-free survival (PFS), overall survival (OS), treatment response, and pneumonitis incidence were collected. High-resolution computed tomography (HRCT) images were centrally reviewed to classify the radiologic patterns of IIPs and ILAs.

Results: A total of 53 patients with IIPs and 18 with ILAs were analyzed. In the IIP cohort, the median PFS was 5.1 months with chemo-ICI, 7.3 months with first-line ICI monotherapy, and 5.7 months with second-line or later ICI monotherapy. The median OS ranged from 5.4 to 15.4 months, depending on the treatment type. Grade 3-4 pneumonitis occurred in 17.0% of patients with IIPs. In the ILA cohort, chemo-ICI resulted in a median OS of 27.0 months with no cases of pneumonitis, while ICI monotherapy was associated with a 22.2% pneumonitis incidence. Subpleural fibrotic ILAs were linked to a higher risk of pneumonitis. Long-term survivors were identified in both cohorts.

Conclusions: ICI therapy may provide durable survival benefits for patients with NSCLC and underlying IIPs or ILAs. However, the elevated incidence of high-grade pneumonitis-particularly in patients with IIPs or fibrotic ILAs-underscores the importance of careful patient selection. Prospective studies are needed to refine treatment strategies in this population.

Background: While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance.

Methods: We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors.

Results: A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window.

Conclusions: Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity.

Background: In non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression has moderate ability to predict immune checkpoint inhibitor (ICI) benefit. In clinical practice, PD-L1, a cell surface protein, cannot be characterized in currently available blood-based tests such as circulating tumor DNA assays. To understand the biologic effects of PD-L1 more fully and evaluate whether blood-based tests could provide insight into its expression, we determined the association between PD-L1 expression and systemic immune parameters.

Methods: We collected pre- and post-treatment (6-week) peripheral blood samples in patients with NSCLC treated with ICI. Using multiplex panels and cytometry by time of flight (CyTOF), we analyzed specimens for baseline and post-treatment changes in cytokines, autoantibodies, and immune cell populations. We determined the association between case characteristics, immune parameters, and tumor PD-L1 expression (categorized as <1%, 1-49%, and ≥50%) using Chi-square, one-way analysis of variance (ANOVA), and Kruskal-Wallis tests, accounting for multiple comparisons.

Results: A total of 119 patients were included in the analysis, of whom 41 (34%) had PD-L1 expression <1%; 44 (37%), 1-49%; and 34 (29%), ≥50%. PD-L1 expression was not associated with any demographic, tumor, or treatment characteristics. Among 39 cytokines evaluated, baseline levels of macrophage migration inhibitory factor (MIF) were significantly greater in high PD-L1 positive cases. Among 124 autoantibodies included in the analysis, three (anti-aggrecan, -proteoglycan, and -nucleosome) demonstrated significantly greater post-ICI treatment increases in cases with higher PD-L1 expression. In PD-L1 positive cases, baseline abundance of natural killer T (NKT) cells (P=0.001) and activated monocytes (P=0.04) were significantly lower, while post-treatment increases in mature natural killer (NK) cells were significantly greater (P=0.006).

Conclusions: NSCLC PD-L1 expression is associated with few systemic immune parameters, suggesting that effects on anti-tumor immunity may occur predominantly in the tumor microenvironment and that blood-based assays are unlikely to provide meaningful surrogates of this biomarker.

Background: Lung cancer is a leading cause of cancer-related mortality worldwide, with heterogeneity and acquired resistance posing major challenges to treatment. Advances in next-generation sequencing (NGS) have enabled comprehensive genomic profiling, yet there remains a need for robust patient-derived models to study tumor biology and inform precision medicine. This study aims to establish and characterize patient-derived lung cancer organoids (LCOs) using whole-genome sequencing (WGS) to explore their genomic landscape and therapeutic potential.

Methods: We established a panel of LCOs from resected tumors and malignant pleural effusions (MPEs) of 14 non-small cell lung cancer (NSCLC) patients. Organoids were authenticated and subjected to WGS to profile somatic single nucleotide variants (SNVs), insertions/deletions (InDels), copy number variations (CNVs), structural variants (SVs), and microsatellite instability (MSI). Bioinformatic analyses were performed to annotate mutations, assess tumor mutation burden (TMB), and explore mutational signatures. Furthermore, deep learning-based drug response prediction and in vitro drug sensitivity assays were conducted to evaluate therapeutic potentials in the established LCOs.

Results: In the established LCOs, WGS revealed recurrent mutations in TP53, TTN, MUC16, and FLG, with approximately 80% of somatic variants located in non-coding regions, highlighting the potential role of regulatory elements in lung cancer pathogenesis. Early and locally advanced-stage tumor-derived LCOs exhibited higher TMB and MSI compared to those from advanced-stage disease, suggesting greater clonal diversity prior to therapeutic intervention. Drug screening demonstrated the feasibility of using genomic data for drug prediction, but requires more advanced models to fully utilize the WGS data.

Conclusions: Our comprehensive genomic characterization of patient-derived LCOs provides valuable insights into the mutational landscape and evolutionary dynamics of lung cancer. These well-annotated organoid models serve as a powerful resource for investigating tumor biology and developing genomically informed therapeutic strategies.

Background: Clinical trials have demonstrated the efficacy of both alectinib and crizotinib in anaplastic lymphoma kinase (ALK) fusion (ALK-positive) non-small cell lung cancer (NSCLC). However, a critical question persists regarding their real-world comparative effectiveness in Chinese patients, especially in light of divergent overall survival (OS) results from Western and Asian trials. To address this uncertainty, this real-world study aimed to directly compare the efficacy of alectinib and crizotinib as first-line therapies in a Chinese clinical setting.

Methods: Patients diagnosed with ALK-positive NSCLC from two centers in China were included in the study. Progression-free survival (PFS) was the primary endpoint, while OS, the disease control rate, the objective response rate, and safety were the secondary endpoints. Second-line therapy and prognostic factors were also investigated.

Results: In total, 261 treatment-naïve patients were evaluated, of whom, 128 received crizotinib, and 133 received alectinib. Compared with crizotinib, alectinib demonstrated significant superiority in terms of PFS [45.5 vs. 16.6 months, hazard ratio (HR) =0.36, P<0.001]. However, the PFS of the patients who received first-line alectinib therapy was comparable to that of the patients who received both first-line crizotinib therapy and second-line therapy (45.5 vs. 43.9 months, P=0.32). Similarly, the OS was comparable between the alectinib and crizotinib treatment groups (alectinib vs. crizotinib, not reached vs. 71.2 months, P=0.23). The alectinib treatment group also had a lower incidence of adverse events (AEs) than the crizotinib treatment group (34.6% vs. 50.0%, P=0.01). The occurrence rates of grade 3 or higher AEs were comparable between the two groups (alectinib vs. crizotinib, 4.5% vs. 5.5%). Further, receiving crizotinib instead of alectinib as the first-line therapy and the presence of bone and adrenal metastases at the baseline were independent risk factors for PFS. While the presence of bone, liver, and adrenal metastasis were independent risk factors for OS.

Conclusions: Alectinib is recommended over crizotinib in the treatment of patients with ALK-positive NSCLC.